Patent Application
20190021957
The present embodiments are directed to dental compositions, more particularly water soluble dental varnish composition useful for effective fluoridation, in situ biomimetic remineralization and improved adhesion to enamel. The dental composition includes a hydrogel-forming polymer having cohesive properties to itself and adhesive properties to a dental enamel. The hydrogel forming polymer includes a water-soluble polymer and an adhesion promotor chemically and/or physically conjugated to the water-soluble polymer. The embodiments also provide methods of forming a hydrogel forming polymer and use of hydrogel forming polymer to prepare such dental composition.
Fluoride varnishes are applied to teeth to provide a prolonged source of fluoride ion to the tooth enamel so as to form a protective layer of calcium fluoride (CaF2) on the tooth enamel and convert a portion of the hydroxyapatite to fluorapatite directly. Under physiological pH, the CaF2 layer is insoluble and remains on the tooth, but the acid produced after carbohydrate intake and bacterial metabolism causes release of fluoride and calcium ions. The released fluoride ions may remain in the saliva or settle in free spaces on the tooth enamel and cavities. In particular, the fluoride ion is more electronegative than the hydroxide ion and reacts with the hydroxyapatite {[Ca3(PO4)2]3.Ca(OH)2} of the tooth enamel to convert it to fluorapatite {[Ca3(PO4)2]3.CaF2}. Thus, the formation of an acid-resistant layer of fluorapatite on the tooth surface can prevent tooth decay.
Conventional varnishes may include a natural resin as a tackifier, a synthetic polymer resin for film formation, a fluoride agent for fluoride release, an organic solvent to dissolve the resin, and additives to give the varnish a flavor or color. Natural resins may include, but are not limited to, rosin, rosin derivatives, mastic, or shellac. Synthetic polymer resins may include, but are not limited to, polyvinyl acetate (PVA), polyurethane methacrylate, or polyisocyanate. Such rosin/resin coatings tend to be hydrophobic and may not release sufficient fluoride in an effective manner. Fluoride agents may include, but are not limited to, sodium fluoride, stannous fluoride, acidulated phosphate fluoride, or fluorosilane. Additives may include, but are not limited to, titanium dioxide or sweeteners.
Solvents may include, but are not limited to, ethyl alcohol, isopropanol, ethyl acetate, butyl acetate, isoamyl propionate, hexane, or heptane. Solvents such as hexane or heptane, which may be effective for dissolving the resin/rosin, are not very biocompatible. Some conventional fluoride varnishes contain polymers dissolved in a solvent such as ethyl acetate or butyl acetate, which may be harsh on oral tissue and barely tolerable by the patient.
Sufficiently rapid adhesion between the varnish composition and the surface of the tooth ensures efficient delivery and maintenance of the varnish at the tooth surface.
Many conventional fluoride varnishes leave a long lasting hard coat on the teeth that must be broken and picked from the teeth. Moreover, many conventional fluoride varnishes may have a yellow color or other properties that make them not aesthetically pleasing to the patient.
There is continuing need for a varnish composition that overcomes the problems of existing varnish composition.
It is an object of the present disclosure to provide compositions that includes a hydrogel-forming polymer for efficient delivery and maintenance of the varnish at the tooth surface as well as that prevents discoloration of a hydrogel-forming polymer during conjugation and in the final varnish composition.
In a first aspect of the present disclosure disclosed herein is a method of forming a hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel that comprises conjugating an adhesion promoter to a water-soluble polymer in the presence of an antioxidant to form the hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel.
In one embodiment of the method of forming hydrogel-forming polymer, the antioxidant prevents discoloration of the hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel during the conjugating.
In a second aspect of the present disclosure disclosed herein is a hydrogel-forming polymer produced by a process comprising: conjugating an adhesion promoter to a water-soluble polymer in the presence of an antioxidant to form the hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel, wherein the antioxidant prevents discoloration of the hydrogel-forming polymer during the conjugating.
In a third aspect of the present disclosure disclosed herein is a composition that includes a hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel, and water. The hydrogel-forming polymer comprises a water-soluble polymer and an adhesion promoter chemically and/or physically conjugated to the water-soluble polymer.
In one embodiment of the composition, the hydrogel-forming polymer further includes at least one antioxidant.
In another embodiment of the composition, the composition further includes a metal ion source.
In one embodiment, a composition includes a hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel, a stimulus moiety, and water.
In a fourth aspect of the present disclosed herein, is a dental composition that includes a hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel, a fluoride agent, and water. The hydrogel-forming polymer includes a water-soluble polymer and dopamine chemically and/or physically conjugated to the water-soluble polymer. The conjugated dopamine on the water soluble polymer adheres to any calcium ion present on the enamel surface and also absorbs calcium ions from a surrounding medium to the hydrogel-forming polymer.
In one embodiment of the dental composition, the hydrogel-forming polymer further includes at least one antioxidant.
In another embodiment of the dental composition, the composition further includes a stimulus moiety.
In one embodiment of the dental composition, the stimulus moiety is a branched cationic polymer.
In a fifth aspect of the present disclosure disclosed herein is a method of preparing a water soluble dental composition; said method comprising:
In one embodiment of the method of preparing water soluble dental composition, the branched cationic polymer is selected to increase an adhesion kinetic between the composition and dental enamel.
Other features and advantages of the present disclosure will be apparent from the following more detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the disclosure.
The patent or application file contains at least one drawing executed in color. Copies of the patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Wherever possible, the same reference numbers will be used throughout the drawings to represent the same parts.
Provided herein are methods of forming a hydrogel forming polymer, use of the hydrogel forming polymer to prepare water-soluble, hydrogel-based dental compositions and methods of making and using the same.
Embodiments of the present disclosure, for example, in comparison to concepts failing to include one or more of the features disclosed herein, include a biocompatible polymer, are soluble in water, are compatible with a non-toxic organic solvent, are water-based, do not result in resin crystallization, are non-flammable, require no mixing, rapidly adhere to the enamel surface of a tooth, form a film on the enamel surface of a tooth, allow better dissolution of fluorides, provide more rapid diffusion of the fluoride ions to the enamel, provide a higher uptake of fluoride ions to the enamel, have a lower viscosity, are white in color, are colorless, are transparent, have rapid adhesion kinetics to dental substrates, absorb calcium ions, may be applied without drying, or combinations thereof.
In some embodiments, the hydrogel-forming polymer comprises a water-soluble polymer and an adhesion promoter chemically and/or physically conjugated to the water-soluble polymer.
In a first aspect of the present disclosure disclosed herein is a method of forming a hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel that comprises conjugating an adhesion promoter to a water-soluble polymer in the presence of an antioxidant to form the hydrogel-forming polymer having cohesive properties to itself and adhesive properties to dental enamel.
The water-soluble polymer may be any hydrogel-forming polymer with adhesive and cohesive properties or any polymer that is hydrogel-forming and has adhesive and cohesive properties when conjugated to an adhesion promoter. In some embodiments, the water-soluble polymer is a natural polymer. In some embodiments, the water-soluble polymer is a synthetic polymer. In some embodiments, the water-soluble polymer is biocompatible.
In various embodiments, the phrase “adhesion promotor conjugated to the water soluble polymer” may be used interchangeably with “water soluble polymer conjugated to the adhesion promotor”.
In some embodiments of the method of forming hydrogel-forming polymer, the water-soluble polymer contains at least one functional group selected from the group consisting of carboxylic acid, amine, hydrazide, thiol, acrylic, methacrylic, and acrylamide.
In one embodiment of the method of forming hydrogel-forming polymer, the water-soluble polymer contains carboxylic acid.
In some embodiments of the method of forming hydrogel-forming polymer, the water soluble polymer has a weight average molecular weight in a range of 1 kDa to about 4000 kDa; such as from about 100 kDa to about 1500 kDa.
Suitable water-soluble polymers may include, but are not limited to, hyaluronic acid (HA), polyacrylic acid (PAA), chitosan, hydroxypropyl methylcellulose (HPMC), a water-soluble polyethylene glycol (PEG)-modified polymer, a water-soluble PEG-crosslinked polymer (such as, for example, a bis-thiol PEG), a water-soluble or partially water-soluble modified rosin, or combinations thereof.
HA is a naturally-occurring, water-soluble polymer found in connective tissue, epithelial tissue, and neural tissue. More specifically, HA is a non-sulfated, anionic glycosaminoglycan (GAG). HA was used as a starting polymer for the conjugation of an adhesion promoter, because HA is highly biocompatible, biodegradable, and non-immunogenic and has shown anti-inflammatory, antioedematous, antioxidant, and antibacterial effects after the treatment of periodontal disease and during wound healing. Unlike rosins and synthetic resins, which are difficult to remove and are irritating to the gingiva, HA may be easily removed by brushing and/or self-degradation and is non-irritating and beneficial to the gingiva.
In some embodiments, the water soluble polymer is the polyacrylic acid (PAA).
In some embodiments of the method of forming hydrogel-forming polymer, the adhesion promotor may be any compound that promotes adhesion and cohesion of the hydrogel-forming polymer. In one embodiment, the adhesion promoter is a natural compound. In some embodiments, the adhesion promoter is a synthetic compound. In some embodiments, the adhesion promoter is biocompatible.
In some embodiments of the method of forming hydrogel-forming polymer, the adhesion promotor contains at least one functional group selected from the group consisting of amine, carboxylic acid, thiol, acrylic, methacrylic, and acrylamide group.
In some embodiments of the method of forming hydrogel-forming polymer, the adhesion promotor contains an amine group.
Suitable adhesion promotors may include, but are not limited to, dopamine, dopamine with a conjugated electron-withdrawing group conjugated at the 6-position on the dopamine aromatic ring, dopamine complexed to an electron-withdrawing group at the hydroxyl groups of the dopamine, gallic acid, caffeic acid, ferulic acid, protocatechuic acid, coumaric acid, ellagic acid, resveratrol, rosmarinic acid, quercetin, or combinations thereof. In some embodiments, the conjugated electron-withdrawing group is a nitro group (—NO2), a chloro group (—Cl), or a fluoro group (—F). In some embodiments, the complexed electron-withdrawing group is a borate or a borate derivative.
Biomaterials in nature have precisely-controlled adhesiveness and cohesiveness properties. For example, mussel adhesive foot protein (Mafp), secreted by certain marine mussels, has dual adhesive and cohesive features that are controlled by a dopamine amino acid found in the protein. An adhesion promoter grafted water-soluble polymer with both adhesive and cohesive film formation properties provides effectiveness in a water-soluble dental varnish system in accordance with exemplary embodiments. The molecular basis for adhesion is the reversible coordination of metal oxides, π-π interactions with various synthetic polymers and irreversible covalent bonding to any surface. For cohesive function, catechol undergoes pH-dependent oxidative reactions by the dopamine-to-quinone transition. Thus, dopamine may promote both adhesion and cohesion.
In some embodiments, the adhesion promoter is a modified version of a naturally-occurring compound. The modification preferably improves the adhesive and cohesive properties and/or the stability of the adhesion promoter in the water-soluble hydrogel-based dental varnish.
In some embodiments of the method of forming hydrogel-forming polymer, conjugating the adhesion promoter to the water-soluble polymer occurs through an amidation reaction in an aqueous solution using carbodiimide catalysis system in the presence of a co-catalyst to form a reaction solution.
In some embodiments, the carbodiimide in carbodiimide catalysis system is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).
In some embodiments, the co-catalyst is selected from the group consisting of hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (NHS) and sulfo-N-hydroxysuccinimide (Sulfo-NHS).
In some embodiments of the method of forming hydrogel-forming polymer, the carbodiimide catalysis system is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/N-hydroxysuccinimide (NHS), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/sulfo-N-hydroxysuccinimide (Sulfo-NHS).
In some embodiments of the method of forming hydrogel-forming polymer, the water soluble polymer is present at a concentration of from about 0.01 weight percent to about 50 weight percent based on total volume of the reaction solution, such as in the range of from about 0.1 weight percent to 20 weight percent or in the range of from about 1 weight percent to about 10 weight percent.
In some embodiments of the method of forming hydrogel-forming polymer, the adhesion promoter may be added in a 1:100 to 50:100 molar ratio with respect to the number of available functional groups on a repeating unit of the water-soluble polymer; such as 30:100 molar ratio with respect to the number of available functional groups on the repeating unit of the water-soluble polymer.
In some embodiments of the method of forming hydrogel-forming polymer, the adhesion promotor is present in concentration of from about 1 mole percent to about 80 mole percent based on repeating unit of functional groups on the water-soluble polymer.
In some embodiments, the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) is added in the range of from 1 to 10 mmol per mol of available functional groups on a repeating unit of water-soluble polymer; alternatively in the range of 2 to 5 mmol, alternatively about 3 mmol, or any value, range, or sub-range there between, per mol of available functional groups on the repeating unit of water-soluble polymer.
In some embodiments, the co-catalyst is added in the range of from 1 to 10 mmol based on per mol of available functional groups on a repeating unit of water-soluble polymer; alternatively in the range of 2 to 5 mmol, alternatively about 3 mmol, or any value, range, or sub-range there between, per mol of available functional groups on the repeating unit of water-soluble polymer.
In some embodiments, the hydrogel forming polymer is HA-g-dopamine or PAA-g-dopamine.
In some embodiments, HA-g-dopamine or PAA-g-dopamine were synthesized by the process described above. The synthesis scheme to produce HA-g-dopamine is shown in
In some embodiments, HA-g-dopamine or PAA-g-dopamine were characterized by percentage of conjugation, molecular weight, and distribution.
In some embodiments, the percent conjugation of the adhesion promoter, for example, dopamine in the HA-g-dopamine or PAA-g-dopamine may be in a range of 5 to 80%. In one embodiment the percent conjugation of the dopamine in the HA-g-dopamine or PAA-g-dopamine is in the range of 20 to 30%.
Under certain conditions, including high pH or in the presence of an oxidant, the catechol group in dopamine oxidizes to a quinone group, which causes a black coloration during the synthesis of dopamine-grafted polymers. Formation of the quinone causing the black coloration may be prevented by adding an antioxidant during the synthesis.
In one embodiment, the antioxidant prevents discoloration of the hydrogel-forming polymer having cohesive properties and adhesive properties to dental enamel during the conjugating.
In some embodiments of the method of forming hydrogel-forming polymer, the antioxidant is selected from the group consisting of ascorbic acid, sodium metabisulfite, boric acid, sodium tetraborate, 4,4′-Biphenyldiboronic acid, benzene-1,4-diboronic acid, 2,5-thiophenediyl bisboronic acid, sulfur dioxide, uric acid, tocopherol and mixtures thereof.
Dopamine-grafted polyacrylic acid was synthesized in the presence of ascorbic acid, and no discoloration or black color formation was observed during or after the synthesis.
In some embodiments of the method of forming hydrogel-forming polymer, the antioxidant is present in the hydrogel-forming polymer in amounts of from 0.1 to 14 mmol based on per mol of available functional groups on a repeating unit of the water-soluble polymer; alternatively in the range of 0.5 to 10 mmol, alternatively in the range of 0.5 to 5 mmol, alternatively in the range of 1 to 5 mmol, or any value, range, or sub-range there between, per mmol of available functional groups on the repeating unit of the polymer.
In certain aspect of the present disclosure provided herein is a hydrogel-forming polymer produced by a process comprising: conjugating an adhesion promoter to a water-soluble polymer in the presence of an antioxidant to form the hydrogel-forming polymer having cohesive properties and adhesive properties to dental enamel, wherein the antioxidant prevents discoloration of the hydrogel-forming polymer during the conjugating.
In certain aspect of the present disclosure, a composition includes a hydrogel-forming polymer with cohesive properties to itself and adhesive properties to dental enamel in water.
In some embodiments, the composition does not include any ethanol, iso propanol, ethyl acetate, butyl acetate, isoamyl propionate or hexane.
As discussed above, the hydrogel-forming polymer comprises a water-soluble polymer and an adhesion promoter chemically and/or physically conjugated to the water-soluble polymer.
In some embodiments of the composition, the adhesion promoter provides the hydrogel-forming polymer with cohesive properties to itself and adhesive properties to dental enamel.
In some embodiments of the composition, the hydrogel-forming polymer further includes at least one antioxidant.
In some embodiments of the composition, the composition includes a metal ion source. It will be understood that there is no particular limitation to the source of the metal ions.
In some embodiments of the composition, the metal ion source is selected from the group consisting of a divalent metal ion source, a trivalent metal ion source, and mixtures thereof.
Examples of suitable divalent metal ion sources include, but are not limited to, a salt of calcium, salt of zinc, salt of magnesium, salt of tin, salt of strontium, salt of chromium, salt of manganese, salt of beryllium, salt of barium, salt of cobalt, salt of nickel, salt of lead and salt of copper.
Examples of suitable trivalent metal ion sources include, but are not limited to, a salt of aluminum, salt of iron, salt of chromium, salt of bismuth, salt of manganese, salt of cobalt and salt of indium.
In some embodiments of the composition, the composition further comprises at least one stimulus moiety.
A stimulus moiety, as used herein, refers to any molecule or part of a molecule that increases the adhesion kinetics of the hydrogel-forming polymer having cohesive properties and adhesive properties to dental enamel in a dental composition upon inclusion in the dental composition. The stimulus moiety may be cationic, linear (unbranched) or branched, and non-polymeric or polymeric.
In some embodiments, the at least one stimulus moiety is a branched cationic polymer.
In some embodiments, the branched cationic polymer are included in the composition to improve the adhesion kinetics of the hydrogel-forming polymer having cohesive properties and adhesive properties to dental enamel.
Stimulus moieties may include, but are not limited to, lysine, arginine, polylysine, polyarginine, linear polyethyleneimine, branched polyethyleneimine, or poly(diallyldimethylammonium chloride) (polyDADMAC), or combinations thereof.
In some embodiments, the ratio of stimulus moiety cationic groups to hydrogen-forming polymer repeating unit functional groups is in a range of 1:2 to about 2:1, alternatively in the range of 1:2 to 1:1, alternatively in the range of 1:1 to 2:1, alternatively about 1:1, or any value, range, or sub-range there between.
Certain mussel foot proteins, such as, for example, mfp-3 and mfp-5, are rich in dopamine as well as the amino acid lysine, which is frequently in adjacent positions along the protein backbone. These proteins have impressive wet adhesion to mineral, oxide, and organic surfaces. The dopamine units in mfp-3 and mfp-5 form bidentate coordination and hydrogen bonds to mineral and oxide surfaces and hydrophobic interactions on polymeric surfaces, but only if protected from oxidation in a low pH environment and in the presence of antioxidant during deposition. Further, the lysine being present in positions adjacent to the dopamine serves as a stimulus moiety to further enhance the adhesion by disrupting the hydration layer formed by water on the polar surfaces.
The presence of alkyl ammonium functionalities, such as, for example, in the amino acids lysine and 2,4-diaminobutyric acid (Dab), in catecholic polymers or compounds limits the oxidation, and the amine and catechol moieties may interact synergistically to mediate surface priming by the catechol alkylamine compounds to mineral surfaces and promote higher adhesion to surfaces. Increasing the ratio of cationic amines to catechols in a molecule reduces adhesion, and the catechol-cation synergy is greatest when both functionalities are present within the same molecule.
In some embodiments, polyethylene imine, a branched cationic polymer, was selected to provide stimulus moieties and was mixed with a dopamine-grafted polymer to have amine and catechol functionalities together on same polymer network. The relative adhesion was tested for formulations prepared with and without the cationic polymer, which clearly demonstrated higher and rapid adhesion of the polymer network containing branched cationic polymer.
In certain aspect of the present disclosure, a water-soluble dental varnish is provided that includes a hydrogel-forming polymer with cohesive properties to itself and adhesive properties to dental enamel. In some embodiments, the cohesive and adhesive properties are provided by an adhesion promoter that is conjugated chemically and/or physically to a water-soluble polymer to provide the hydrogel-forming polymer. The hydrogel-forming polymer is dissolved in water with a fluoride agent to form the water-soluble hydrogel-based dental varnish.
In some embodiments, the primary solvent in the water-soluble hydrogel-based dental varnish is water.
In some embodiments, the only solvent in the water-soluble hydrogel-based dental varnish is water.
In some embodiments, the water-soluble hydrogel-based dental varnish does not include any ethanol, iso propanol, ethyl acetate, butyl acetate, isoamyl propionate or hexane.
In some embodiments, the water-soluble hydrogel-based dental varnish is free of rosins or substantially free of rosins.
In some embodiments, the water-soluble dental varnish further includes a metal ion source as described above.
In some embodiments, the water-soluble dental varnish further includes a stimulus moiety as described above.
In certain embodiments of the water-soluble dental varnish composition disclosed herein, the fluoride agent is selected from the group consisting of sodium fluoride, stannous fluoride, acidulated phosphate fluoride, amine fluoride, fluorosilane and mixture thereof.
In some embodiments, the amine fluoride is selected from the group consisting of N′,N′-tri-(polyoxyethylene)-N-hexadecylpropylene diamine dihydrofluoride; 9-octadecylamine hydrofluoride, hexadecylamine hydrofluoride and bis-(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine dihydrofluoride.
In certain embodiments of the water-soluble dental varnish composition disclosed herein, the fluoride source is present in a concentration of from about 0.01 weight percent to about 10 weight percent based on a total weight of the composition; such as in the range of from about 1 weight percent to about 8 weight percent or in the range of from about 2 weight percent to about 7 weight percent.
In certain embodiments of the dental varnish composition disclosed herein, the dental varnish releases fluoride ions in a concentration ranging from 1000 ppm to 22600 ppm.
The fluoride ion source may be in an amount such that it is capable of providing a high level of fluoride ion in the composition, that is at least about 1,000 ppm, and in some instances up to as much as 30,000 ppm, e.g., from about 7,000 ppm to about 27,000 ppm, from about 15,000 ppm to about 25,000 ppm, or about 22,000 or 23,000 ppm. In order to provide such a concentration in the optimal ppm range, the exact weight percentage of the fluoride ion source in the composition may vary, depending upon the stoichiometric properties of different fluoride ion sources.
In certain embodiments of the water-soluble dental varnish composition disclosed herein, the hydrogel-forming polymer is present in a concentration of from about 0.01 weight percent to about 50 weight percent based on a total volume of the composition; such as in the range of from about 0.1 weight percent to 20 weight percent or in the range of from about 1 weight percent to about 10 weight percent.
In some embodiments, the water-soluble dental varnish also includes one or more of a thickener, a tackifier, a flavoring agent, a sweetener, and a colorant.
Examples of thickener include, but are not limited to fumed silica, carboxyvinyl polymers, carrageenans, karaya, gum arabic and tragacanth, magnesium aluminum silicate. The amount of thickener present in the dental varnish in amounts of from about 0.1 weight percent to about 1.0 weight percent, such as from about 0.5 weight percent to about 5.0 weight percent or from about 1 weight percent to about 10 weight percent.
Examples of a tackifier suitable for use herein may include, but are not limited to rosin, mastic, shellac, cellulose and cellulose derivatives, pullulan, xanthan gum, gellan gum. Such tackifiers as described herein may be present in the dental varnish in amounts of from about 0.01 weight percent to about 0.1 weight percent, such as from about 0.05 weight percent to about 1 weight percent or from about 1 weight percent to about 10 weight percent.
Examples of a suitable flavoring agent include but are not limited to peppermint, watermelon, wintergreen, spearmint, cherry, citric acid, orange, strawberry, vanilla, coconut, bubble gum flavors and mixtures thereof. Such flavoring agents if present, may be in the dental varnish in amounts of from about 0.001 weight percent to about 0.05 weight percent, such as from about 0.005 weight percent to about 0.5 weight percent or from about 0.01 weight percent to about 5 weight percent.
Examples of a suitable sweetener include but not limited to xylitol, sorbitol, sucralose, aspartame, sodium saccharin, and mixtures thereof. Such sweeteners may be in the dental varnish in amounts of from about 0.001 weight percent to about 0.02 weight percent, such as from about 0.005 weight percent to about 0.2 weight percent or from about 0.01 weight percent to about 2.0 weight percent.
Examples of a suitable colorant may be caramel, beta-carotene, annatto or titanium dioxide. Such colorant may be in the dental varnish in amounts of from about 0 weight percent to about 2 weight percent, such as from about 0.01 weight percent to about 1.0 weight percent or from about 0.08 weight percent to about 1.0 weight percent.
In some embodiments, the dental varnish formulation is optimized for stability, cohesive and adhesive properties, fluoride loading and release kinetics, biocompatibility, and uptake of fluoride to enamel and remineralization. To further improve the gelation kinetic and mechanical properties, one or more stimuli-sensitive polymers, which may include, but are not limited to, chitosan and hydroxypropyl methylcellulose (HPMC), may be included in the final varnish formulation. In some embodiments, the stimuli-sensitive polymers are present in the range of 0.1 weight percent to 50 weight percent with respect to the volume of the hydrogel-forming polymer in the formulation.
Also, disclosed herein are methods of preparing a water soluble dental composition. The water soluble dental composition of the present disclosure may be prepared in general by
In one embodiment water soluble dental composition may be prepared by
In certain embodiments of methods of preparing a water soluble composition, the branched cationic polymer is selected to increase an adhesion kinetic between the composition and dental enamel.
In certain embodiments of methods of preparing a water soluble composition as described herein, the hydrogel-forming polymer may be present in amounts of from about 0.01 weight percent to about 50 weight percent based on the total volume of composition such as from about 0.1 weight percent to about 20 weight percent or from about 1.0 weight percent to about 10 weight percent.
In certain embodiments of methods of preparing a water soluble composition, the antioxidant may be present in the dental composition in amounts of from about 0.005 mmole/ml to about 20 mmole/ml based on the total volume of hydrogel-forming polymer, such as from about 0.025 mmole/ml to about 10 mmole/ml or from about 0.05 mmole/ml to about 5 mmole/ml.
In certain embodiments of methods of preparing a water soluble composition, the metal ion source may be present in the dental composition in amounts of from about 0.001 mmole/ml to about 5 mmole/ml based on the total volume of hydrogel-forming polymer, such as from about 0.002 mmole/ml to about 1 mole/ml or from about 0.01 mmole/ml to about 2 mmole/ml.
In certain embodiments of methods of preparing a water soluble composition, the branched polyethylene imine having an average molecular weight of about 600 Da, 1200 Da, and 1800 Da was added to the solution of an antioxidant and metal ion source to form a form a branched cationic polymer solution.
In certain embodiments of methods of preparing a water soluble composition, the branched cationic polymer may be present in the dental composition in amounts of from about 0.1 weight percent to about 50 weight percent based on the total volume of composition, such as from about 0.5 weight percent to about 20 weight percent or from about 1 weight percent to about 10 weight percent.
In some embodiments, a method includes applying a composition to a dental surface. The composition includes a hydrogel-forming polymer having cohesive properties and adhesive properties to dental enamel, a fluoride agent, and water.
In certain embodiments of the dental varnish composition disclosed herein, the hydrogel-forming polymer promoted increased adhesion of the varnish composition to a tooth surface.
The catechol moiety of dopamine-grafted polymers (e.g. polyacrylic acid-g-dopamine) has the capacity to bind strongly to certain metal ions, including calcium. Such a feature may accelerate remineralization of teeth by hydroxyapatite formation via co-precipitation of calcium and phosphate ions from saliva in situ. Thus, a dopamine-grafted polymer-based varnish system is not only capable of rapid fluoride release and uptake but may also promote in situ biomimetic remineralization by absorbing calcium from surrounding saliva. Conventional varnish systems do not have such an in situ biomimetic remineralization feature.
Although hydrogel-forming polymers having cohesive properties and adhesive properties to dental enamel have been described herein in water-soluble hydrogel-based dental varnishes, hydrogel-forming polymers having cohesive properties and adhesive properties to dental enamel may also be included in compositions for osseo-integration of dental implants, in compositions for repair of cracked teeth, in dental adhesive compositions, in medicament delivery systems, in remineralization compositions, or in paint-on strips with whitening agents.
The disclosure discussed herein is further illustrated by the compositions described in the following Examples, but these Examples should not be construed as limiting the scope of the present disclosure.
300 mg of HA, having a weight average molecular weight of about 100 kDa, was dissolved in 100 mL of deionized (DI) water at room temperature over a period of 5 to 10 hours. The pH of the solution was adjusted to 5.5 with 0.1 N hydrochloric acid (HCl) and 0.1N sodium hydroxide (NaOH) aqueous solutions. Ascorbic acid was then added to the solution to achieve a concentration of 1 mg/mL, and dopamine was added in a 30:100 molar ratio with respect to the number of available carboxylic groups on the repeating unit of HA. The pH of this resulting solution mixture was then adjusted to about 6.8. Then, 3 mmol of EDC per mol of available carboxylic groups on the repeating unit of hyaluronic acid (HA) was added and the pH was readjusted to about 6.8. Next, 3 mmol of HOBt per mol of available carboxylic groups on the repeating unit of HA was added and the reaction solution was maintained at a pH of about 6.8 for about 9 hours. Subsequently, sodium chloride (NaCl) was dissolved at a concentration of 5 mg/mL in final reaction mixture. Precipitation in ethanol removed the unreacted reagents. A final precipitate was redissolved in DI water and dialyzed using a dialysis membrane with a 3-5 kDa molecular-weight cut-off (MWCO) against an aqueous solution containing 0.5 g/mL NaCl. Water was removed by freeze-drying to obtain the HA-g-dopamine final product.
Similar HA-g-dopamine conjugates were synthesized from HA having a weight average molecular weight of about 350 kDa, about 700 kDa, and about 1500 kDa.
In one example, the obtained HA-g-dopamine was characterized by proton (1H) nuclear magnetic resonance (NMR) spectroscopy.
Because dopamine absorbs UV light at around 280 nm, as shown in
In one example, the viscosity of a 5 wt % solution of HA-g-dopamine in DI water was measured in a rheometer using cone-plate geometry at 37° C. at 10 Pa shear stress, where the HA had a weight average molecular weight of about 700 kDa. The viscosity of the solution was about 150 centipoise (cP), as shown in
Performance Test: Adhesion of HA-g-dopamine to Wet Bovine Teeth
In one example, the adhesion of HA-g-dopamine to wet bovine teeth was performed using a conventional protocol. Namely, a 1 wt % solution of HA-g-dopamine in DI water containing aluminum chloride (AlCl3) was prepared. Bovine teeth were incubated in water at 37° C. overnight. The bovine teeth were removed from the water 30 seconds prior to applying the HA-g-dopamine solution to the bovine teeth, and the teeth were then dried for 2-3 minutes. The teeth were then incubated in water at 37° C. for 2 hours. An Alcian blue solution (1 wt % Alcian blue dye in acidic acid at a pH in the range of 3-5), which specifically stains certain polysaccharides including HA, was used to stain the bovine teeth to check the level of adhesion of the HA to the teeth. The teeth were dipped in the Alcian blue solution for 30 min at 37° C., extensively washed with water, and then photographed in color.
Referring to
Although the HA-g-dopamine system showed good adhesion, the temperature sensitivity and levels of degradation of that system were greater than ideal for use in a dental varnish. Dopamine was conjugated to PAA, as an alternative to the HA-g-dopamine system, by using a similar protocol to the protocol used for the synthesis of HA-g-dopamine. Dopamine was conjugated to PAA by way of an amine bond formed between the amine group of the dopamine and a carboxylic acid group on the PAA using EDC/HOBt catalysis chemistry. In one embodiment, the percent conjugation of dopamine in the PAA-g-dopamine may be in the range of 5 to 80%. In some embodiments, the percent conjugation of dopamine in the PAA-g-dopamine is in the range of 20 to 30%.
500 mg of polyacrylic acid (PAA) having a weight average molecular weight of about 450 kDa was dissolved in 150 mL of DI water at room temperature for 5 to 10 hours. The pH of the solution was then adjusted to about 6.8 with 0.1N HCl and 0.1N NaOH aqueous solutions. Ascorbic acid was then added to the solution as the antioxidant to achieve a concentration of 1 mg/mL. About 3 mmol of EDC per mol of available carboxylic groups on the repeating unit of polyacrylic acid was added, and the pH was readjusted to about 6.8. Next, 3 mmol of HOBt per mol of available carboxylic groups on the repeating unit of polyacrylic acid was added to the reaction mixture and a pH of about 6.8 was re-established. Subsequently, dopamine was added to the solution in a 30:100 molar ratio with respect to the number of available carboxylic groups on the repeating unit of PAA, and the solution was then maintained at a pH of about 6.8 for about 9 hours. Finally, the reaction mixture was dialyzed using a dialysis membrane with a 3-5 kDa MWCO against an aqueous solution containing 0.5 g/mL NaCl for two days and then against DI water for one day. Water was removed by freeze-drying to obtain the PAA-g-dopamine final product.
Synthesis of a control PAA-g-dopamine was repeated using above-described protocol without adding ascorbic acid during the synthesis.
Referring to
In one example, the obtained PAA-g-dopamine was characterized by proton (1H) nuclear magnetic resonance (NMR) spectroscopy.
Adhesion of PAA-g-dopamine to Wet Bovine Teeth
In one example, the adhesion of PAA-g-dopamine to wet bovine teeth was performed using a conventional protocol similar to that used for HA-g-dopamine. A 10 wt % solution of PAA-g-dopamine dissolved in DI water was painted on wet teeth. After 2 to 3 minutes, a varnish was applied to the painted teeth and similar teeth that were unpainted. The teeth were incubated in artificial saliva at 37° C. for about 2 hours. After the incubation, the teeth were each dipped in a 0.01 wt % aqueous neutral red solution, which stains PAA since neutral red is positively charged and PAA is negatively charged for 5 minutes at room temperature. The teeth were then washed with DI water and left overnight in DI water. Finally, the teeth were removed from the DI water and photographed. A comparison of the photograph of the painted tooth, as shown in
Remineralization: Calcium Absorption by Hydrogel-Forming Polymer Formulation
In one example, a dental varnish composition promoted in situ biomimetic remineralization by being capable of absorbing calcium from surrounding saliva. About 200 mg of PAA-g-dopamine was dissolved in about 4.4 mL of DI water. Separately, a solution was formed by combining about 60 mg of ascorbic acid, about 20 mg of aluminum chloride in 0.5 mL DI water, and about 0.55 mL of 5 M NaOH and then combined with the PAA-g-dopamine solution. Next, about 100 mg of boric acid was dissolved in about 1 mL of DI water and added to solution. Finally, about 0.27 mL of 48-50 wt % hydrofluoric acid was added to the solution and the pH was adjusted to 8.0 using 5 M NaOH.
The prepared varnish formulation was applied to a glass slide, and the glass slide was incubated in a 25-mM calcium chloride solution for about 30 minutes. As a control, another glass slide with the prepared varnish formulation was incubated in DI water for about 30 minutes.
Referring to
Preparation of Water Soluble Dental Composition
In one example, improved adhesion of a dental varnish to enamel was achieved by including stimulus moieties in the varnish formulation. First, about 175 mg of PAA-g-dopamine was dissolved in about 4.4 mL of DI water. Separately, about 60 mg of ascorbic acid and 20 mg of aluminum chloride were dissolved in about 0.5 mL of DI water, and then about 0.55 mg of a branched polyethylene imine having an average molecular weight of about 600 Da was added. After mixing thoroughly, the branched polyethylene imine solution was added to the PAA-g-dopamine solution. Then, about 100 mg boric acid was dissolved in about 1 mL DI water and added to the PAA-g-dopamine/branched polyethylene imine mixture. Next, another 0.55 mg of the branched polyethylene imine was added followed by 0.27 mL of hydrofluoric acid, to provide a fluoride source in the final stimulus-moiety-containing varnish formulation. The branched polyethylene imine provided the stimulus moieties for the varnish formulation.
A control varnish formulation was prepared for comparison by the same method as the stimulus-moiety-containing varnish formulation, except for replacing the branched polyethylene imine with 5 M NaOH.
Adhesion of Varnish Formulation to Enamel-Like Hydroxyapatite Discs
An adhesion test was then performed on enamel-like hydroxyapatite discs. Before the stimulus-moiety-containing varnish formulation or the control varnish formulation was applied, however, the hydroxyapatite discs were incubated in DI water for 1 to 2 hours. The prepared varnishes were then applied to the wet hydroxyapatite discs and were given about 2 to 3 minutes to bind to the discs. As a second control, a wet hydroxyapatite disc received no varnish formulation to confirm that the Alcian blue dye is absorbed by the varnish and not by the hydroxyapatite discs.
The three hydroxyapatite discs were then separately dipped in an artificial saliva solution. After 2 hours of incubation at about 37° C., the hydroxyapatite discs were washed with DI water and then air-dried. Finally, the hydroxyapatite discs were stained with Alcian blue dye (pH 1.5-2.0). Referring to
Synthesis of Varnish Formulation for Biocompatibility, F Release and F Uptake Testing
Polyacrylic acid (1000 mg) was dissolved in PBS buffer (100 mL) at room temperature for 1 hr and pH was adjusted to 12.00 with 0.1N hydrochloric acid (HCl) and 0.1N sodium hydroxide (NaOH) aqueous solution. Then, EDC (1200 mg) was added and pH was adjusted to 9 and NHS (1200 mg) was added and pH was adjusted ˜6.2. Next, dopamine (984 mg) was added to reaction mixture, then maintained the pH of reaction mixture ˜6.1 for ˜2 hr. Then, ascorbic acid (200 mg) was added to reaction mixture and pH was adjusted around 6.1 and reaction was continued for 24 hr. After overnight, pH of solution was reduced to 4.00 using 0.1M NaOH and 0.1M HCl, and white precipitate of PAA-g-dopamine was settled and supernatant was discarded. The white precipitate was redissolved in DI water containing sodium tetraborate decahydrate solution (1 gm/17.5 mL) at pH 6.00. Precipitation step was repeated two times. Then, collected precipitate was mixed with 5 ml of aluminum fluoride solution 32 mg/1 ml) and 14 ml of sodium tetraborate decahydrate solution and add DI water to make total volume 50 mL, then mixed thoroughly until ingredient dissolved uniformly. In 20 ml of this solution, 2 ml polyethylene imine (PEI) 600 Da and 0.5 ml HF (48-51%) were mixed thoroughly, then 1.0 ml PEI 1200 Da and another 0.5 ml of HF (48-51%) were mixed. Finally, 1 ml aluminum chloride solution (20 mg/ml) was mixed and pH was adjusted 7.5-8.00 from prepared pH 10 using concentrated hydrochloric acid.
Biocompatibility
Quantitative MTT Cytotoxicity Assay was used for determining the cytotoxic response of extraction of varnish formulations using L-929 mammalian fibroblast cells. The assay measures viability of cells through metabolic activity, as the mitochondrial dehydrogenases of living cells convert the yellow MTT solution into blue-violet insoluble formazan. Formazan crystals are dissolved in isopropanol to make a homogeneous solution for photometric measurements. The number of viable cells correlates to the color intensity.
To collect extraction, 20 hydroxyapatite discs were used for preparation per article. 200 mg of each test article was applied to the 20 discs (10 mg per disc) and the discs were allowed to sit at room temperature for 5 minutes. The hydroxyapatite discs were then rinsed with 10 mL of media for ˜10 seconds to remove the excess varnish. The rinsed discs were then incubated in extraction media. The comparison article consisted of 1 unrinsed hydroxyapatite disc with no varnish applied. The controls were prepared aseptically according to ISO rations and were tested in parallel with the test article. The MTT Media+10% FBS was added to the articles and controls based on the extraction ratio. The test and control articles were extracted with continuous agitation on an orbital shaker. The test and control article extraction media were visually inspected immediately prior to and post extraction. The extracts were used for testing within 24 hours of incubation completion. After extraction, extracts were centrifuged at 3000 RPM for 5 minutes then used for creating dilutions for assessing cell viability using the following dilutions: 100%, 50%, 25% and 12.5%. Then, cytotoxicity of collected extracts was tested in compliance to the International Organization for Standardization (ISO) 10993-5: 2009 and British Standard European Noun ISO (BS EN ISO) 10993-5: 2009 (Tests for in vitro Cytotoxicity).
Fluoride Uptake by Enamel
Three formulations of varnish (DHGV 30, DHGV 32 and DHGV 36) were synthesized by varying the ingredient of varnish and tested for F uptake. For fluoride uptake experiment, sound bovine incisor enamel was embedded in the end of a plexiglass rod (¼″ diameter×2″ long) using methylmethacrylate. Subsequently, an artificial incipient lesion was formed in them by immersion into an about 0.1M lactic acid/0.2% Carbopol 907 50% saturated with calcium phosphate solution at about pH 5.0 for about 24 hours at about room temperature. The specimens were kept hydrated and stored at 40C until time of use.
The 8 specimens per group were numbered and placed into a neoprene stopper with the enamel surface of the specimens being flush with the stopper. The stoppers have been specifically designed to evenly distribute the 8 enamel specimens around the outer edge of the stopper. A single layer of test varnish (approx. 0.0050±0.001 g) was applied to the surface of each individual specimen. The stopper was place in a specimen cup, enamel surfaces facing up. Tubing from the solution container (Artificial Saliva, see Appendix) passed through a multi-channel peristaltic pump and was affixed to a hole in the lid of the specimen cup. The multi-channel pump was set to provide a slow drip of solution (approximately 1.0 ml/min) centrally over the stopper (drip of solution did not fall directly onto any of the 8 specimens). The solution collecting on the surface (evenly covering all 8 specimens) eventually broke the tension holding it on the stopper and ran off into the bottom of the specimen cup. The specimen cup was equipped with a drain to ensure the solution level never reached the surface of the stopper. Therefore, the solution in contact with the varnish treated enamel specimens was slowly replaced by fresh solution, mimicking intra-oral salivary flow.
Following a 2-hour treatment time, the specimens were removed from the stopper and excess varnish was carefully removed (physical removal using a spatula and subsequent removal using a cotton swab saturated with reagent grade ethyl alcohol). The specimens were then rinsed well under running DI water for 30 seconds. One layer of enamel was removed from each specimen by immersion in 0.5 ml of 1.0 N perchloric acid (HClO4) for 15 seconds. A sample of each solution was buffered with TISABII to a pH of 5.2 (0.25 ml sample, 0.5 ml TISABII and 0.25 ml 1N NaOH) and the fluoride content determined using a fluoride specific electrode by comparison to a similarly prepared fluoride standard curve. A second sample was analyzed via atomic absorption for calcium content for use in depth determination (0.05 ml sample diluted to 5.0 ml).
Result: DHGV 30 supported the highest F uptake (4910±154) compare to DHGV 32 (2776±223) and DHGV 36 (2626±140).
F Release Experiment
For each test sample, a minimum of two (2) replicates were prepared. Known amount of varnish formulations were applied to glass slides and varnish painted glass slides were transferred to container containing 10 ml artificial saliva. F release from the varnishes was allowed for 2 hours at room temperature. After two (2) hours, 10 ml of artificial saliva was transferred into a small plastic beaker containing 10 ml of TISAB II and both solutions were mixed to determine the release F ions in the solution.
Table 3 shows a comparison of certain components and properties of certain commercial varnishes to a water-soluble hydrogel-based dental varnish.
In some embodiments, a method includes applying a water-soluble hydrogel-based dental composition to a surface of a tooth, as shown in
In some embodiments, the adhesive and cohesive properties of the conjugate are pH-sensitive. In some embodiments, a method of applying the water-soluble hydrogel-based dental varnish to a tooth at physiological pH includes adjusting the pH at which the water-soluble hydrogel-based dental varnish is prepared, to an application pH, at which the level of cohesion of the water-soluble hydrogel-based dental varnish to itself and level of adhesion of the water-soluble hydrogel-based dental varnish to the tooth surface is higher.
In one embodiment, the pH at which the water-soluble hydrogel-based dental varnish is prepared may be about 10.
In another embodiment, the application pH may be from about 7.5 to about 8.5.
While the present disclosure has been described with reference to one or more embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from the essential scope thereof. Therefore, it is intended that the disclosure not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this disclosure, but that the disclosure will include all embodiments falling within the scope of the appended claims. In addition, all numerical values identified in the detailed description shall be interpreted as though the precise and approximate values are both expressly identified.
| Number | Date | Country | |
|---|---|---|---|
| 62534288 | Jul 2017 | US | |
| 62583093 | Nov 2017 | US |
