Patent Application
20230045410
Dental enamel is a thin, hard layer of calcified material that covers the crown of teeth. Dental enamel is the first line of defense for tooth protection against acid challenge. The major mineral component of dental enamel is hydroxyapatite, a crystalline form of calcium phosphate. Dental enamel is formed by 7 hierarchical levels of hydroxyapatite crystals that enable the robust mechanical properties of enamel. Unlike other biomaterials such as bone, mature enamel does not contain cells and thus cannot regenerate itself after substantial mineral loss or structural damages, such as dental erosion and enamel microcracks.
Dental erosion occurs initially in the enamel and, if unchecked, may proceed to the underlying dentin. Dental erosion may be caused or exacerbated by acidic foods and drinks, and stomach acids arising from gastric reflux. Generally, saliva has a pH between 6.7 to 7.4. When the pH is lowered and concentration of hydrogen ions becomes relatively high, it chemically damages the enamel and creates a porous, sponge-like roughened surface. The erosion of dental enamel can lead to enhanced tooth sensitivity due to increased exposure of the dentin tubules and increased dentin visibility leading to the appearance of more yellow teeth. In addition, when enamel erodes, the tooth is more susceptible to cavities or tooth decay.
Early acid damage on enamel is reversible by remineralization, in which mineral ions from saliva are reintroduced into the demineralized enamel. It has been reported that hydroxyapatite possesses a remineralizing effect on teeth and can be used to reduce tooth sensitivity.
Enamel micro cracks (EMC) are described as incomplete fractures of the enamel without loss of tooth structure. They are also referred to as craze lines, enamel infractions, or hairline fractures with the order of microns in size. Although prevalence has not clearly been reported, enamel microcrack has been reported as “very common”, occurring more frequently with aging. The formation of enamel micro cracks could be caused by many external factors such as the temperature variations, traumas, and the physical insults from repeated loading (grinding) and some dental procedures. Another important intrinsic factor for the EMC formation is the chemical and physical changes of enamel with the ages. Studies have demonstrated that the enamel of primary teeth is more elastic and softer when compared to the enamel in adult teeth. In addition, the outer enamel of younger adult teeth shows lower fracture toughness and brittleness than the ones with senior adults. In other words, senior teeth are more brittle and susceptible to enamel damage and cracking along the surface of the enamel. In the field of endodontics there are five different types of longitudinal cracks that can be described, craze lines, fractured cusp, split tooth, cracked tooth, and vertical root fractures. Craze lines or enamel micro cracks only affect the enamel, while the other type of cracks can affect enamel, dentin and possibly the pulp.
Although enamel micro cracks or craze lines have been reported as “very common,” they are not the major concerns for dentists, especially in comparison to other potential cracks that can occur to the tooth. If it's asymptomatic, there is typically no treatment provided. However, our studies have suggested that the enamel microcracks could be associated with more problems, such as the visually unappealing and the potential to weaken enamel. For example, the microcracks in the enamel allow extrinsic stains to diffuse and accumulate resulting in more staining on the enamel surface. In addition, enamel is softer at the microcrack region. This can cause local areas of increased or deeper demineralization weakening the mechanical properties of enamel. Furthermore, when enamel is exposed to acid, the microcracks become wider and more damages are observed with microcracks.
Enamel microscratch is one form of early enamel damage that cannot be seen by naked eyes. Microscratch occurs where the teeth start to lose enamel irreversibly due to the external mechanical actions. Continuous scratching will lead to a tooth abrasion which has been widely observed clinically, especially at the cervical and occlusal surfaces. The prevalence studies have indicated that tooth wear including abrasion is an increasing problem, especially in the elderly, as it is more common in this age group. An investigation found that 42% of the 20-to-29-year age group associated with abrasions, while the 40-to-49-year age group exhibited 76% with abrasions. See Litonjua L A, Andreana S, Bush P J, Cohen R E. Tooth wear: attrition, erosion, and abrasion. Quintessence Int. 2003 June; 34(6):435-46. Another study has reported that the percentage of adults presenting with severe tooth wear increases from 3% at the age of 20 years to 17% at the age of 70 years. See Van′t Spijker A, Rodriguez J M, Kreulen C M, Bronkhorst E M, Bartlett D W, Creugers N H. Prevalence of tooth wear in adults. Int J Prosthodont. 2009 January-February; 22(1):35-42. Clearly increasing levels of tooth wear is significantly associated with age.
Therefore, there is a need for oral care compositions that provide improved enamel protection, remineralization and/or increase enamel microcrack and/or microscratch resistance.
In an aspect, the present disclosure provides an oral care composition comprising hydroxyapatite (HAP) and a basic amino acid (e.g., arginine). In some embodiments, the hydroxyapatite is present in an amount of from 1% to 10% by weight of the composition. In some embodiments, the hydroxyapatite is present in an amount of from 2% to 10%, from 3% to 10%, from 4% to 10%, from 5% to 10%, from 4% to 9%, 5% to 9%, from 4% to 9%, from 4% to 8%, from 5% to 9%, from 5% to 8%, about 5%, or about 8%, by weight of the composition. In some embodiments, the basic amino acid is present in an amount of from 1% to 15%, e.g., from 1% to 10%, from 1% to 5%, from 2% to 4%, from 3% to 4%, about 3% or about 4% by weight of the composition, being calculated as free base form.
In another aspect, the present disclosure provides a method of reducing or inhibiting enamel erosion, repairing enamel erosion damage, and/or increasing enamel microcrack resistance, comprising applying an oral care composition comprising hydroxyapatite (HAP) and a basic amino acid (e.g., arginine) to the oral cavity. In some embodiments, the hydroxyapatite is present in an amount of from 1% to 10% by weight of the composition. In some embodiments, the hydroxyapatite is present in an amount of from 2% to 10%, from 3% to 10%, from 4% to 10%, from 5% to 10%, from 4% to 9%, 5% to 9%, from 4% to 9%, from 4% to 8%, from 5% to 9%, from 5% to 8%, about 5%, or about 8%, by weight of the composition. In some embodiments, the basic amino acid is present in an amount of from 1% to 15%, e.g., from 1% to 10%, from 1% to 5%, from 2% to 4%, from 3% to 4%, about 3% or about 4% by weight of the composition, being calculated as free base form. In some embodiments, the method increases enamel microcrack resistance, optionally wherein the enamel microcrack resistance efficacy of the composition is determined by one or more parameters selected from change in crack length, change in fracture toughness, change in brittleness and a combination thereof, i.e., wherein the method decreases crack length, increases fracture toughness, decreases brittleness, and a combination thereof.
In another aspect, the present disclosure provides the use of hydroxyapatite (HAP) and a basic amino acid (e.g., arginine) for the making of an oral care composition for reducing or inhibiting enamel erosion, repairing enamel erosion damage, and/or increasing enamel microcrack resistance.
Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the disclosure, are intended for purposes of illustration only and are not intended to limit the scope of the disclosure.
The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the disclosure, its application, or uses.
As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight. The amounts given are based on the active weight of the material.
The present disclosure provides, in an aspect, an oral care composition (Composition 1.0), e.g., toothpaste or gel, which comprises hydroxyapatite (HAP) and an amino acid (e.g., a basic amino acid). In one aspect, and without being bound theory, it is believed to be reasonable to consider the enamel microscratch is an early sign of tooth aging. In one aspect, the compositions and methods described herein can be used to increase the resistance to enamel microcrack and/or enamel microscratches.
For example, the disclosure includes:
The present disclosure provides, in another aspect, a method (Method 2.0) of reducing or inhibiting enamel erosion, repairing enamel erosion damage, increasing enamel microcrack resistance and/or increasing enamel microscratch resistance comprising applying an oral care composition comprising hydroxyapatite (HAP) and an amino acid (e.g., a basic amino acid) to the oral cavity of a subject in need thereof.
For example, the disclosure includes:
In the present disclosure, it has also been found that the oral care composition containing a basic amino acid and HAP increases enamel microcrack resistance. As used herein, enamel microcrack (EMC) refers to incomplete fractures of the enamel without loss of tooth structure. They are also referred to as craze lines, enamel infractions, or hairline fractures with the order of microns in size. Enamel microcrack is common, occurring more frequently as people age. Unlike enamel damage or microdamage resulting from chemical or biological derived acid such as enamel erosion or caries, enamel microcracks are mainly caused by physical insults from mechanical processes. These physical insults can initiate from an applied force to the enamel. Because the initiation of these conditions is different, the enamel structure changes correlated with microcracks are not the same as the changes observed in the early stage of erosion or caries. For example, as a result of the demineralization process, loss of enamel crystals with corresponding compositional changes can be observed under acid challenges (enamel erosion), while the repeated physical insults may cause the fracture of enamel prismatic structures (microcracks) without changing the chemical composition. Therefore, the technology of treatments for these two types of micro damages is not the same.
The enamel microcrack resistance efficacy of an oral care composition can be determined by an in vitro enamel microcrack resistance model as described in Example 4. In this model, microcrack may be generated, e.g., using a micro-hardness tester with an indenter, e.g., a Vickers diamond indenter. The enamel microcrack resistance efficacy of an oral care composition may be determined by measuring one or more parameters selected from change in crack length, change in fracture toughness, change in brittleness and a combination thereof. The fracture toughness (Kc) is calculated according to
where E, HV, F, L and c are the elastic modulus, Vickers hardness, indentation load, average indentation diagonal length and crack length, respectively.
The Vickers hardness (HV) for each indentation is calculated according to
where F is the indentation load and L the indentation diagonal.
The indentation brittleness (B) of enamel is calculated according to
where E and HV are the elastic modulus and Vickers hardness, respectively.
In the present disclosure, it has also been found that the oral care composition containing a basic amino acid and HAP increases enamel microscratch resistance.
Enamel microscratch is usually caused by the sliding or rubbing of abrasive external objects against the tooth surfaces. Several factors are reported to cause such enamel damage, including the use of an abrasive toothpaste, hard bristles, a vigorous brushing technique and ill-fitting dental appliances like retainers and dentures. It may also be caused by the use of toothpicks and miswaks, as well as the consumption of abrasive foods, such as tobacco and sunflower seeds. Beside these, people with habits such as nail biting and lip or tongue piercing, are subjected to higher risks of enamel microscratch. Another factor that can cause enamel microscratch is the combination of mechanical and chemical corrosion. Specifically an acid attack on the enamel could compromise its mechanical properties and make it more susceptible to scratches.
Since the enamel microscratch is a microscopic damage at the tooth surface, it is difficult to be detected by naked eyes or the common tools used in clinics. However, if left untreated, the continuous scratching can cause a massive wear through the enamel (i.e. abrasion) and lead to severe consequences. It has been reported that the enamel loss due to abrasion may lead to symptoms such as increased tooth sensitivity to hot and cold, increased plaque trapping which will result in caries and periodontal disease. It may also be aesthetically unpleasant to some people. Microscratches may result in a rough and dull enamel surface, and could also allow extrinsic stains to accumulate resulting in more staining on the enamel surface.
The oral care composition of the disclosure may be a toothpaste or gel. In some embodiments, the oral care composition is a toothpaste. In other embodiments, the oral care composition is a gel. The oral care composition may be a single-phase oral care composition. For example, all the components of the oral care composition may be maintained together with one another in a single phase and/or vessel. For example, all the components of the oral care composition may be maintained in a single phase, such as a single homogenous phase. In another embodiment, the oral care composition may be a multi-phase oral care composition.
As used herein, an “oral care composition” refers to a composition for which the intended use includes oral care, oral hygiene, and/or oral appearance, or for which the intended method of use comprises administration to the oral cavity, and refers to compositions that are palatable and safe for topical administration to the oral cavity, and for providing a benefit to the teeth and/or oral cavity. The term “oral care composition” thus specifically excludes compositions which are highly toxic, unpalatable, or otherwise unsuitable for administration to the oral cavity. In some embodiments, an oral care composition is not intentionally swallowed, but is rather retained in the oral cavity for a time sufficient to affect the intended utility. The oral care compositions as disclosed herein may be used in nonhuman mammals such as companion animals (e.g., dogs and cats), as well as by humans. In some embodiments, the oral care compositions as disclosed herein are used by humans. Oral care compositions include, for example, dentifrice and mouthwash.
The oral care composition of the disclosure may contain an orally acceptable carrier. As used herein, an “orally acceptable carrier” refers to a material or combination of materials that are safe for use in the compositions of the disclosure, commensurate with a reasonable benefit/risk ratio. Such materials include but are not limited to, for example, water, humectants, ionic active ingredients, buffering agents, anticalculus agents, abrasive polishing materials, peroxide sources, alkali metal bicarbonate salts, surfactants, titanium dioxide, coloring agents, flavor systems, sweetening agents, antimicrobial agents, herbal agents, desensitizing agents, stain reducing agents, and mixtures thereof. Such materials are well known in the art and are readily chosen by one skilled in the art based on the physical and aesthetic properties desired for the compositions being prepared. In some embodiments, the orally acceptable carrier may include an orally acceptable solvent. Illustrative solvents may include, but are not limited to, one or more of ethanol, phenoxyethanol, isopropanol, water, cyclohexane, methyl glycol acetate, benzyl alcohol, or the like, or any mixture or combination thereof. In a particular embodiment, the orally acceptable solvent includes benzyl alcohol.
Water may be present in the oral compositions of the disclosure. Water employed in the preparation of commercial oral compositions should be deionized and free of organic impurities. Water commonly makes up the balance of the compositions and includes about 10% to about 80%, about 20% to about 60%, about 20% to 40%, about 10% to about 30%, about 20% to 30%, or about 25% to 35% by weight of the oral compositions. This amount of water includes the free water which is added plus that amount which is introduced with other materials such as with sorbitol or any components of the disclosure.
The oral care composition of the disclosure comprises hydroxyapatite. Hydroxyapatite is a calcium phosphate having the chemical formula Ca5(PO4)3(OH), also usually written Ca10(PO4)6(OH)2 to denote that the crystal unit comprises two entities. Hydroxyapatite is the main component of tooth enamel and has a strong affinity to the tooth enamel surface. Hydroxyapatite can group together to form microscopic aggregates, called hydroxyapatite crystals. In some embodiments, the hydroxyapatite is micro-hydroxyapatite (m-HAP). In non-limiting examples, the micro-hydroxyapatites have a mean diameter of greater than 1 μm, e.g., 1 to 100 μm or 5 to 100 μm. In some embodiments, the hydroxyapatite is nano-hydroxyapatite (n-HAP). In non-limiting examples, such aggregates have a mean diameter of less than 1000 nm, e.g., 1 to 1000 nm, 50 to 1000 nm, 10 nm to 100 nm, 100 nm to about 1000 nm.
The oral care compositions of the disclosure can comprise a basic amino acid in free or salt form. The basic amino acids which can be used in the compositions include not only naturally occurring basic amino acids, such as arginine, lysine, and histidine, but also any basic amino acids having a carboxyl group and an amino group in the molecule, which are water-soluble and provide an aqueous solution with a pH of about 7 or greater. Accordingly, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutyric acid, diaminopropionic acid, salts thereof or combinations thereof. In a particular embodiment, the basic amino acids are selected from arginine, lysine, citrulline, and ornithine. The basic amino acids of the oral care composition may generally be present in the L-form or L-configuration. The basic amino acids may be provided as a salt of a di- or tri-peptide including the amino acid. In some embodiments, at least a portion of the basic amino acid present in the oral care composition is in the salt form. In some embodiments, the basic amino acid is arginine, for example, L-arginine, or a salt thereof. Arginine may be provided as free arginine or a salt thereof. For example, Arginine may be provided as arginine phosphate, arginine hydrochloride, arginine sulfate, arginine bicarbonate, or the like, and mixtures or combinations thereof. The basic amino acid may be provided as a solution or a solid. For example, the basic amino acid may be provided as an aqueous solution. In some embodiments, the amino acid includes or is provided by an arginine bicarbonate solution. For example, the amino acid may be provided by an about 40% solution of the basic amino acid, such as arginine bicarbonate or alternatively called as arginine carbamate. In some embodiments, the basic amino acid is present in an amount of from 1% to 15%, e.g., from 1% to 10%, from 1% to 5%, from 1% to 3%, from 1% to 2%, or about 1.5% by weight of the composition, being calculated as free base form.
In another aspect, in addition to the basic amino acid included in the formulation, the compositions of the disclosure (e.g., any of Compositions 1.0 et seq or Method 2.0 et seq) can further include a neutral amino acid, which can include, but are not limited to, one or more neutral amino acids selected from the group consisting of alanine, aminobutyrate, asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine, and combinations thereof.
In still another aspect, the compositions and methods of the disclosure (e.g., any of Compositions 1.0 et seq or Method 2.0 et seq) can include a neutral amino acid (e.g., either alone or in combination with a basic amino acid), which can include, but are not limited to, one or more neutral amino acids, in free or salt form, selected from the group consisting of alanine, aminobutyrate, asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine, and combinations thereof.
In other embodiments, the oral care composition may contain a thickening agent. Suitable thickening agents may be any orally acceptable thickener or thickening agent configured to control the viscosity of the oral care composition. Illustrative thickeners may be or include, but are not limited to, cellulose derivatives (e.g., hydroxyethyl cellulose, carboxymethyl cellulose) colloidal silica, fumed silica, a cross-linked polyvinylpyrrolidone (PVP) polymer, cross-linked polyvinylpyrrolidone (PVP), or the like, or mixtures or combinations thereof. In some embodiments, the thickening system includes a cross-linked polyvinylpyrrolidone (PVP) polymer. The thickening system may also include POLYPLASDONE® XL 10F, which is commercially available from Ashland Inc. of Covington, Ky. Illustrative thickeners may also be or include, but are not limited to, carbomers (e.g., carboxyvinyl polymers), carrageenans (e.g., Irish moss, carrageenan, iota-carrageenan, etc.), high molecular weight polyethylene glycols (e.g., CARBOWAX®, which is commercially available from The Dow Chemical Company of Midland, Mich.), cellulosic polymers, carboxymethylcellulose, and salts thereof (e.g., CMC sodium), natural gums (e.g., karaya, xanthan, gum arabic, and tragacanth), colloidal magnesium aluminum silicate, or the like, or mixtures or combinations thereof.
The oral care composition of the disclosure may include fluoride, such as one or more fluoride ion sources (e.g., soluble fluoride salts). A wide variety of fluoride ion-yielding materials may be employed as sources of soluble fluoride. Illustrative fluoride ion sources include, but are not limited to, sodium fluoride, stannous fluoride, potassium fluoride, sodium monofluorophosphate, fluorosilicate salts, such as sodium fluorosilicate and ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof. In some embodiments, the fluoride ion source includes sodium fluoride. The amount of the fluoride ion source present in the oral care composition may be greater than 0 weight % and less than 0.8 wt. %, less than 0.7 wt. %, less than 0.6 wt. %, less than 0.5 wt. %, or less than 0.4 wt. %. The fluoride ion sources may be present in an amount sufficient to supply 25 ppm to 5,000 ppm of fluoride ions, generally at least 500 ppm, e.g., 500 to 2000 ppm, e.g., 1000 ppm to 1600 ppm, e.g., 1450 ppm.
The oral care composition of the disclosure may comprise a zinc ion source. The zinc ion source may be or include a zinc ion and/or one or more zinc salts. For example, the zinc salts may at least partially dissociate in an aqueous solution to produce zinc ions. Illustrative zinc salts may include, but are not limited to, zinc lactate, zinc oxide, zinc chloride, zinc phosphate, zinc citrate, zinc acetate, zinc borate, zinc butyrate, zinc carbonate, zinc formate, zinc gluconate, zinc glycerate, zinc glycolate, zinc picolinate, zinc propionate, zinc salicylate, zinc silicate, zinc stearate, zinc tartrate, zinc undecylenate, and mixtures thereof. In some embodiments, the zinc ion source is present in an amount of from 0.01% to 5%, e.g., 0.1% to 4%, or 1% to 3%, by weight of the composition.
In some embodiments, the zinc ion source is selected from zinc oxide, zinc citrate, and a combination thereof. Zinc oxide may be present in an amount of 0.5% to 2%, e.g., 0.5% to 1.5%, or about 1% by weight of the composition. Zinc citrate may be present in an amount of 0.1% to 1%, 0.25% to 0.75%, about 0.5% by weight of the composition by weight of the composition. In some embodiments, the composition comprises zinc oxide and zinc citrate. The composition may comprise zinc oxide in an amount of 0.5% to 2%, e.g., 0.5% to 1.5%, about 1% or about 1.2% by weight of the composition and zinc citrate in an amount of 0.1% to 1%, 0.25% to 0.75%, about 0.5% by weight of the composition. In certain embodiments, the composition comprises zinc oxide in an amount of about 1% by weight of the composition and zinc citrate in an amount of about 0.5% by weight of the composition.
The oral care composition of the disclosure may include a stannous ion source. The stannous ion source can be a soluble or an insoluble compound of stannous with inorganic or organic counter ions. Examples include the fluoride, chloride, chlorofluoride, acetate, hexafluorozirconate, sulfate, tartrate, gluconate, citrate, malate, glycinate, pyrophosphate, metaphosphate, oxalate, phosphate, carbonate salts and oxides of stannous. In some embodiments, the stannous ion source is selected from the group consisting of stannous chloride, stannous fluoride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and mixtures thereof.
In some embodiments, the oral care compositions may include one or more abrasives or an abrasive system including one or more abrasives. As used herein, the term “abrasive” may also refer to materials commonly referred to as “polishing agents”. Any orally acceptable abrasive may be used, but preferably, type, fineness (particle size), and amount of the abrasive may be selected such that the tooth enamel is not excessively abraded in normal use of the oral care composition. The one or more abrasives may have a particle size or D50 of less than or equal to about 10 μm, less than or equal to about 8 μm, less than or equal to about 5 μm, or less than or equal to about 3 μm. The one or more abrasives may have a particle size or D50 of greater than or equal to about 0.01 μm, greater than or equal to about 0.05 μm, greater than or equal to about 0.1 μm, greater than or equal to about 0.5 μm, or greater than or equal to about 1 μm. Illustrative abrasives may include, but are not limited to, metaphosphate compounds, phosphate salts (e.g., insoluble phosphate salts), such as sodium metaphosphate, potassium metaphosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium orthophosphate, tricalcium phosphate, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate, calcium carbonate (e.g., precipitated calcium carbonate and/or natural calcium carbonate), magnesium carbonate, hydrated alumina, silica, zirconium silicate, aluminum silicate including calcined aluminum silicate, polymethyl methacrylate, or the like, or mixtures and combinations thereof. The amount or concentration of the abrasives present in the oral care composition may vary widely. In some embodiments, the amount of the abrasives present in the oral care composition may be from about 15 weight % to about 70 weight %, e.g., from about 20 weight % to about 50 weight %, from about 25 weight % to about 45 weight %, from about 30 weight % to about 40 weight %, or from about 10% to about 20 weight %, or about 15 weight %, based on a total weight of the oral care composition.
In some embodiments, the oral care composition comprises a silica abrasive. In some embodiments, the silica abrasive is present in an amount of from 10% to 30%, e.g., 10% to 20%, 15% to 25%, or about 15%, by weight of the composition. In some embodiments, the oral care composition comprises a calcium-free silica abrasive.
In some embodiments, the oral care composition of the disclosure comprises a calcium-containing abrasive (e.g., calcium carbonate). In some embodiments, the calcium-containing abrasive is selected from calcium carbonate, calcium phosphate (e.g., dicalcium phosphate dihydrate), calcium sulfate, and combinations thereof. In some embodiments, the oral care composition comprises calcium carbonate as an abrasive. In one embodiment, the oral care composition comprises precipitated calcium carbonate or natural calcium carbonate. Precipitated calcium carbonate may be preferred over natural calcium carbonate.
The oral care composition of the present disclosure may include at least one surfactant or solubilizer. Suitable surfactants include neutral surfactants (such as polyoxyethylene hydrogenated castor oil or fatty acids of sugars), anionic surfactants (such as sodium lauryl sulfate), cationic surfactants (such as the ammonium cation surfactants) or zwitterionic surfactants. These surfactants or solubilizers may be present in amounts typically from 0.01% to 5%, from 0.01% to 2%; or from 1% to 2%; or about 1.5%, by weight of the composition. In some embodiments, the composition may comprise an anionic surfactant. Suitable anionic surfactants include without limitation water-soluble salts of C8-20 alkyl sulfates, sulfonated monoglycerides of C8-20 fatty acids, sarcosinates, taurates and the like. Illustrative examples of these and other classes include sodium lauryl sulfate, sodium lauryl ether sulfate, ammonium lauryl sulfate, ammonium lauryl ether sulfate, sodium cocoyl monoglyceride sulfonate, sodium lauryl sarcosinate, sodium lauryl isethionate, sodium laureth carboxylase, and sodium dodecyl benzenesulfonate. In some embodiments, the anionic surfactant, e.g., sodium lauryl sulfate (SLS), is present in an amount of from about 0.3% to about 4.5% by weight, e.g., 1-2% by weight of the composition. In some embodiments, the composition may comprise a zwitterionic surfactant, e.g., a betaine zwitterionic surfactant. The betaine zwitterionic surfactant may be a C8-C16 aminopropyl betaine, e.g., cocamidopropyl betaine. In some embodiments, the betaine zwitterionic surfactant, e.g., cocamidopropyl betaine, is present in an amount of from 1% to 1.5%, from 1.1% to 1.4%, from 1.2% to 1.3%, or about 1.25% by weight of the composition. In some embodiments, the composition may comprise a non-ionic surfactant, e.g., a non-ionic block copolymer. The non-ionic block copolymer may be a poly(propylene oxide)/poly(ethylene oxide) copolymer. In some embodiments, the copolymer has a polyoxypropylene molecular mass of from 3000 to 5000 g/mol and a polyoxyethylene content of from 60 to 80 mol %. In some embodiments, the non-ionic block copolymer is a poloxamer. In some embodiments, the non-ionic block copolymer is selected from: Poloxamer 338, Poloxamer 407, Poloxamer, 237, Poloxamer, 217, Poloxamer 124, Poloxamer 184, Poloxamer 185, and a combination of two or more thereof.
In some embodiments, the oral care composition of the disclosure may include one or more humectants. Humectants can reduce evaporation and also contribute towards preservation by lowering water activity and can also impart desirable sweetness or flavor to compositions. Illustrative humectants may be or include, but are not limited to, glycerin, propylene glycol, polyethylene glycol, sorbitol, xylitol, or the like, or any mixture or combination thereof. In a preferred embodiment, the orally acceptable vehicle may be or include, but is not limited to, glycerin or sorbitol. In some embodiments, the humectant is selected from glycerin, sorbitol and a combination thereof. In some embodiments, the humectant may be present in an amount of from 20% to 60%, for example from 15% to 40%, from 15% to 35%, from 20% to 40%, from 30% to 50%, from 30% to 40%, or from 40% to 45%, by weight of the composition. In some embodiments, the composition comprises glycerin, optionally wherein glycerin is present in an amount of from 15% to 40%, from 20% to 40%, from 30% to 40%, or about 35% by weight of the composition. In some embodiments, the composition comprises sorbitol, optionally wherein sorbitol is present in an amount of from 15% to 40%, from 20% to 40%, from 30% to 40%, or about 35% by weight of the composition.
The oral care composition of the present disclosure may include a preservative. Suitable preservatives include, but are not limited to, sodium benzoate, potassium sorbate, methylisothiazolinone, paraben preservatives, for example methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and mixtures thereof.
The oral care composition of the present disclosure may include a sweetener such as, for example, saccharin, for example sodium saccharin, acesulfam, neotame, cyclamate or sucralose; natural high-intensity sweeteners such as thaumatin, stevioside or glycyrrhizin; or such as sorbitol, xylitol, maltitol or mannitol. One or more of such sweeteners may be present in an amount of from 0.005% to 5% by weight, for example 0.01% to 1%, for example 0.01% to 0.5%, by weight of the composition.
The oral care composition of the present disclosure may include a flavoring agent. Suitable flavoring agents include, but are not limited to, essential oils and various flavoring aldehydes, esters, alcohols, and similar materials, as well as sweeteners such as sodium saccharin. Examples of the essential oils include oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, and orange. Also useful are such chemicals as menthol, carvone, and anethole. The flavoring agent is typically incorporated in the oral composition at a concentration of 0.01 to 3% by weight.
The oral care composition of the disclosure may include one or more pH modifying agents. For example, the oral care composition may include one or more acidifying agents and/or one or more basifying agents configured to reduce and/or increase the pH thereof, respectively. Illustrative acidifying agents and/or one or more basifying agents may be or include, but are not limited to, an alkali metal hydroxide, such as sodium hydroxide and/or potassium hydroxide, citric acid, hydrochloric acid, or the like, or combinations thereof.
The oral care composition of the disclosure may also include one or more buffering agents configured to control or modulate the pH within a predetermined or desired range. Illustrative buffering agents may include, but are not limited to, sodium bicarbonate, sodium phosphate, sodium carbonate, sodium acid pyrophosphate, sodium citrate, and mixtures thereof. Sodium phosphate may include monosodium phosphate (NaH2PO4), disodium phosphate (Na2HPO4), trisodium phosphate (Na3PO4), and mixtures thereof. In a typical embodiment, the buffering agent may be anhydrous sodium phosphate dibasic or disodium phosphate and/or sodium phosphate monobasic. In another embodiment, the buffering agent includes anhydrous sodium phosphate dibasic or disodium phosphate, and phosphoric acid (e.g., syrupy phosphoric acid; 85%-Food Grade).
The oral care composition of the disclosure may include anticalculus agents. Illustrative anticalculus agents may include, but are not limited to, phosphates and polyphosphates (e.g., pyrophosphates), polyaminopropanesulfonic acid (AMPS), hexametaphosphate salts, zinc citrate trihydrate, polypeptides, polyolefin sulfonates, polyolefin phosphates, diphosphonates. In some embodiments, the anticalculus agent includes tetrasodium pyrophosphate (TSPP), sodium tripolyphosphate (STPP), or a combination thereof.
The oral care composition of the disclosure may include an antioxidant. Any orally acceptable antioxidant may be used, including, but not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin A, carotenoids, vitamin E, flavonoids, polyphenols, ascorbic acid and derivatives thereof, herbal antioxidants, chlorophyll, melatonin, or the like, or combinations and mixtures thereof.
The oral care composition of the disclosure may include one or more pigments, such as whitening pigments. In some embodiments, the whitening pigments include particles ranging in size from about 0.1 μm to about 10 μm with a refractive index greater than about 1.2. Suitable whitening agents include, without limitation, titanium dioxide particles, zinc oxide particles, aluminum oxide particles, tin oxide particles, calcium oxide particles, magnesium oxide particles, barium oxide particles, silica particles, zirconium silicate particles, mica particles, talc particles, tetracalcium phosphate particles, amorphous calcium phosphate particles, alpha-tricalcium phosphate particles, beta-tricalcium phosphate particles, hydroxyapatite particles, calcium carbonate particles, zinc phosphate particles, silicon dioxide particles, zirconium silicate particles, or the like, or mixtures and combinations thereof. The whitening pigment, such as titanium dioxide particles, may be present in an amount that is sufficient to whiten the teeth.
All ingredients for use in the compositions described herein should be orally acceptable. As used herein, “orally acceptable” may refer to any ingredient that is present in a composition as described in an amount and form which does not render the composition unsafe for use in the oral cavity.
In another aspect, the disclosure provides the use of hydroxyapatite (HAP) and the basic amino acid (e.g., arginine) for the making of an oral care composition, e.g., any of oral care compositions disclosed herein, e.g., any of Compositions 1 et seq. for inhibiting enamel erosion, repairing enamel erosion damage, increasing enamel microscratch resistance and/or increasing enamel microcrack resistance.
It is believed that the hierarchical organization of HAP crystals can enable the robust mechanical properties of enamel. Calcium carbonate-based formulations with arginine and HAP are subject to testing to understand the enamel protection and repair efficacy of these formulations in established in vitro protocols.
Here we explore the incorporation of HAP in a fluoride-free calcium carbonate-based composition with arginine. In one aspect, arginine is believed to function as an effective anti-caries ingredient by balancing the pH and microbial activity of the oral environment. In addition to arginine, xylitol is believed to disrupt energy production of cariogenic bacteria, which ultimately reduces acid production, and to aid in remineralization. The combination of xylitol with arginine is believed to have improved anti-caries effects. The addition of HAP to this dentifrice backbone is believed to have potential to enhance anti-erosion benefits.
Formulations of arginine with and without 5% xylitol are developed as controls. 5% and 8% HAP are in the backbone without xylitol. 8% HAP is in the backbone with xylitol.
1-2
1-2
1-2
1-2
1-2
1-2
The formulations are subject to 3 months of accelerated aging. As summarized in Table 2, the incorporation of HAP is not believed to impact arginine stability in the formulas with xylitol.
Viscosity data of formulas with the combination of HAP, arginine and xylitol, represented in Tables 3 and 4, indicate that the incorporation of HAP does not increase the viscosity significantly and is comparable with commercial chalk bundles. In addition, viscosity is shown to be stable at room temperature and 40° C. (75% Relative Humidity) throughout the aging process.
The ability of the test formulations specified in Example 1 to protect tooth enamel are tested and compared against a commercial dentifrice containing fluoride at a concentration of 1450 ppm. The enamel protection efficacy is determined as follows.
Above method focuses on chemical erosion challenge only, the biological effect of arginine and xylitol is not investigated. Enamel protection results are shown in Table 5 below. After the 16× acid challenge cycles, severe enamel softening is observed for the water control (66.43% demineralization). The arginine calcium carbonate backbone does not show any enamel protection effect resulting in parity demineralization (66.12%) compared to water. The formula with the addition of 5% HAP is able to reduce demineralization by 7.95% which is statistically better than the control (58.48% vs 66.12%). Increasing HAP concentration to 8% further reduces demineralization to 52.39%. In terms of the backbone, the incorporation of 5% xylitol shows directionally lower demineralization compared to the backbone without xylitol. Statistically significant reduction is observed when adding 8% HAP to the backbone with xylitol (49.20% vs 63.29%). Both of the formulas with 8% HAP show parity with a regular fluoride toothpaste formula (1450 ppm NaF), which is summarized in Table 6. This is an important milestone for a non-fluoride toothpaste to achieve parity efficacy to a fluoride toothpaste on acid protection.
The ability of the test formulations specified in Example 1 to protect tooth enamel are tested. The enamel protection efficacy is determined as follows.
In terms of repairing acid damaged enamel, all the toothpaste treatments show significant remineralization effects compared to water (Table 7). The arginine calcium carbonate backbone formula without fluoride demonstrates good remineralization efficacy. Each of the formulas contain more than 25% calcium carbonate which may boost free calcium ion concentration. Without being bound by theory, it is hypothesized that higher availability of calcium ions drives remineralization. The addition of 5% and 8% HAP shows only directional remineralization improvement in the backbone without xylitol. However, 8% HAP addition to the backbone with xylitol does not achieve statistically significant better remineralization than the control without HAP (44.42% vs 30.89%).
Formulations containing arginine and calcium carbonate significantly boost remineralization but are not believed to prevent the acid demineralization of enamel. The addition of 5% xylitol to this backbone directionally reduces acid damage. The incorporation of HAP to a non-fluoride arginine calcium carbonate backbone significantly enhances the acid protection properties of the formulation. The prototypes with 8% HAP reach parity performance as regular toothpaste with 1450 ppm NaF in protecting the native enamel during acid challenge. These prototypes also provide a significant remineralization effect to acid damaged enamel. The incorporation of HAP directionally boosts the remineralization effect of the backbone.
The present formulations are tested in a microscratch model to evaluate their efficacy in resisting microscratch, according to the following procedure.
Enamel Sample Preparation
Nanoindentation with a Berkovich diamond tip indenter is used to generate a baseline (“scratch-1”) microscratch on the enamel surfaces. In order to generate microscratch with sizes close to natural scratch, the normal force is maintained at 10 mN during the scratching. At least 5 indents are made at each specimen.
The following toothpastes and gels are tested:
Measurements and Calculations
The images of microscratch are recorded before and after treatment procedure and analyzed according to the procedure above. The scratch sizes (width, depth and volume) are measured using a Keyence laser scanning microscope. The changes in size are calculated according to the following equations:
ΔVolume=Volumepost-treatment−Volumebaseline
ΔWidth=Widthpost-treatment−Widthbaseline
ΔDepth=Depthpost-treatment−Depthbaseline
Smaller values in ΔVolume, ΔWidth and ΔDepth indicate a better performance in resisting microscratch.
Results for Toothpastes
Two commercially available products (Commercial Toothpaste I and Commercial Toothpaste II) and three test toothpaste formulations are tested in the micro scratch resistant model as shown in Table 10. Commercial Toothpaste I and Commercial Toothpaste II are claimed to resist enamel microdamage.
The post-treatment microscratch with the Commercial Toothpaste I-treated sample is much deeper than the other microscratches with the samples treated with other toothpastes. For the samples treated with Commercial Toothpaste II and Arginine toothpastes, the post treatment scratches are less deep than the one observed in the Commercial Toothpaste I group. In contrast, it is clearly observed that the microscratches are significantly shallower when the samples are treated with HAP-containing toothpastes. Similar trends could be found when comparing the changes in microscratch sizes. The changes in scratch volumes after different toothpaste treatments are shown in Table 10, where a larger change in volume indicates a larger enamel loss:
The changes in microscratch widths after different toothpaste treatments are shown in Table 11, where a larger change in width indicates a larger enamel loss:
The changes in microscratch depths after different toothpaste treatments are shown in Table 12, where a larger change in depth indicates a larger enamel loss:
For the samples treated with HAP toothpaste, the size changes (volume, width and depth) are significantly smaller than the samples treated with other toothpaste. The results indicate that the HAP toothpaste has shown a better performance in improving the microscratch resistance than other toothpastes.
Results for Gels
The leave-on gels with 5% and 8% HAP are also tested with the microscratch resistance model. The changes in scratch volumes after different treatments are shown in Table 13, where a larger change in volume indicates a larger enamel loss:
The changes in microscratch widths after different gel treatments are shown in Table 14, where a larger change in width indicates a larger enamel loss:
The changes in microscratch depths after different gel treatments are shown in Table 15, where a larger change in width indicates a larger enamel loss:
Compared to the control group (HEC gel), only shallow microscratches are observable for the samples treated with HAP gels, and their scratch-size changes (volume, width and depth) are significantly smaller than the samples treated with gel without HAP. Furthermore, a smaller microscratch is observed when the HAP concentration is increased from 5% to 8%. The results indicate that the HAP with the gel form is effective in resisting the microscratch on the enamel surface.
In order to compare the performance in microscratch resistance among the tested toothpaste and gels, the changes in microscratch sizes (width and depth) from different tests are mapped out. The results clearly demonstrated that the HAP technology has a great potential in resisting the microscratch on the enamel surface.
The data from the microscratch resistance model demonstrates that the HAP formulations described herein have a great potential in resisting microscratches on the enamel surface.
The following are representative base formulas to which hydroxyapatite (e.g., at 5% or 8%) can be optionally added (amounts given in % by wt. relative to the total weight of the composition):
1.5
4.0
8.0
1.5
20-45
20-45
20-45
20-45
10-30
10-20
10-20
10-20
1.5
8.0
8.0
While the disclosure has been described with respect to specific examples including presently preferred modes of carrying out the disclosure, those skilled in the art will appreciate that there are numerous variations and permutations of the systems and techniques described above. It is to be understood that other embodiments may be utilized and structural and functional modifications may be made without departing from the scope of the present disclosure. Thus, the scope of the disclosure should be construed broadly as set forth in the appended claims.
This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 63/223,713, filed Jul. 20, 2021 the contents of which are incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63223713 | Jul 2021 | US |
