Bioactive fluoride & remineralization varnish compositions capable of forming mineral apatites in vivo & their methods of use

Abstract

Bioactive fluoride varnishes for caries prevention, remineralization of hard dental tissues, and desensitization of exposed tooth surfaces are disclosed. Methods of making and using the compositions are also disclosed.

Description

BIO ACTIVE FLUORIDE & REMINERALIZATION VARNISH COMPOSITIONS CAPABLE OF FORMING MINERAL APATITES IN VIVO & THEIR METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 516,699, filed July 31, 2023; the entire contents of this application is hereby incorporated by reference herein.BACKGROUND

[0002] Human teeth are living structures comprised of both hard and soft tissues. The hard tissue consists of enamel (the hard exterior surface tissue of teeth), dentin (immediately below and supporting the enamel), and cementum (a specialized hard tissue that covers the root of a tooth). All three of these tissues rely upon inorganic phosphate mineral crystals, known as mineral apatites, to maintain their structure and function. Specifically, apatite makes up 96% of enamel mass and 40-50% of dentin and cementum mass.

[0003] For the purposes of dental tissue, apatite is primarily categorized into hydroxyapatite and fluorapatite, which include a prevalence of unbound hydroxide and fluoride ions, respectively, in the environment surrounding the tissue surface. In some instances, fluorapatite is considered the superior variation due to its lower solubility and higher acid resistance, although it can make teeth more brittle and, at higher amounts, is less aesthetically pleasing as it exudes an unnatural tooth hue. Nevertheless, constant exposure of apatites to acid leads to demineralization of the structural matrix of the tooth, which is a key step toward bacterial penetration of enamel and dentin layers, leading to caries and subsequent dental infections. The body’s natural response to this acid-induced mineral loss is to reconstruct the hydroxyapatite or fluorapatite using unbound or loosely bound ions of calcium, phosphate, hydroxide, and fluoride present in biological fluids such as saliva, dentinal fluid, sulcular fluid, and periapical fluid.

[0004] Public health innovations such as fluoridated water and toothpaste have helped ensure easy access to a constant supply of fluoride ions for this remineralization process, but the high- concentration treatments of fluoride varnishes administered by dental professionals provide another avenue of exposure. Current varnish formulations contain approximately 22,600 ppm fluoride, much higher than the 0.7 ppm present in fluoridated water reservoirs. This massive release of fluoride ions into the saliva and tooth surfaces enables a greater rate of conversion ofhydroxyapatite to fluorapatite through the replacement of the hydroxide (OH-) group with fluoride (F-) due to the stoichiometric principle of large concentrations of reactants (hydroxyapatite and fluoride) relative to products (fluorapatite and hydroxide) in the oral cavity. The long-term intention of this treatment is increasing weight percentage (w / w %) of fluorapatite in the enamel and dentin, thereby increasing acid resistance and lowering the risk of caries development. The risk of overexposure to fluoride treatments can, however, include dental fluorosis, which can result in aesthetic issues as well as weakened tooth structure in more severe cases.

[0005] Varnish application generally follows one of two distinct methodologies: rosin-based formulas and resin-based formulas. As explained below, each method exhibits significantly different applications, bonding, and longevity characteristics.

[0006] Rosin-based formulations rely upon surface-layer deposition through evaporation of a volatile solvent, leaving the solutes (rosin, salts, etc.) bound to the tooth surface. This method is resistant to saliva presence due to the hydrophobic nature of rosins and is intended for multiple hours of contact (typically one to six or more hours). Routine daily activities such as tooth brushing and ingestion of food and beverages can erode rosin varnishes, so removal of the varnish is near complete within one to three days of application.

[0007] Resin-based formulations rely upon a polymerizable carrier consisting of various monomers that are applied to the tooth surface before curing. Typically, this curing is performed using specific wavelengths of light (i.e. photopolymerization), although certain formulations can self-polymerize via a chemical reaction when two separate components of the product are mixed. Along with being saliva resistant, the long polymer chains can provide long-term anti-plaque and acid neutralization benefits. A given application is intended to remain present and active for multiple weeks to several months, or more, with a high tolerance for mechanical and chemical wear. These formulations are generally reserved for geriatric or high-risk patients who need longer- than-average fluoride exposure to maintain dental health.

[0008] Newer varnish formulations have been developed to include calcium and phosphate release in addition to the standard fluoride regimen, which provides all reactants for hydroxyapatite and fluorapatite formation. In this manner, ions for remineralization are not needed from the saliva or other bodily fluids. Previous studies have shown, however, a negative association with the concentration of calcium and phosphate within these new varnish materials, and the subsequentfluoride uptake levels in the enamel layers. In other words, studies have demonstrated that the release of calcium and phosphate from fluoride varnishes negatively impacts fluoride uptake of dentin and formation of fluorapatite.

[0009] Additionally, a further limitation present in many current-market varnishes, particularly rosin-based formulations, is the tendency of the solute and solvent to gradually settle out of solution and revert to their original states during storage. This tendency forces the dental professional applying the varnish to vigorously recombine the components to restore the efficacy of the varnish, which may not only be cumbersome for the dental professional, but the recombination process may leave some sections of varnish, and by extension regions of the patient’s treated teeth, both over and under-concentrated given the intended ratio of active ingredients and carrier. Prolonging the emulsion time frame of varnishes continues to be a crucial focus of product design to improve product stability and homogenous application in vivo. There is a need in the art, therefore, for improved varnish compositions exhibiting improved and prolonged stability as well as improved efficacy through the introduction of calcium and phosphate releasing agents that do not negatively impact dentin fluoride uptake.BRIEF SUMMARY

[0010] The present disclosure provides a bioactive fluoride varnish for use on patients in vivo for caries prevention, remineralization of hard dental tissues, and desensitization of exposed tooth surfaces. The present disclosure provides active ions for remineralization (calcium, phosphate, hydroxide, and fluoride, among others) while also not negatively impacting fluoride release from the bioactive varnish and subsequent dentin fluoride uptake. In other words, the disclosure provides active ions for the formation of multiple mineral apatites in vivo, including inorganic mineral apatites such as hydroxyapatite and fluorapatite, although organic mineral apatites, such as carbonate-substituted hydroxyapatite may advantageously be formed in certain instances. Additionally, the present disclosure provides shelf-stable compositions that exhibit minimal separation over time compared to existing products on the market. In further embodiments, methods of use of the disclosed composition are described in detail. In yet another aspect, a product by process to create the bioactive fluoride varnish is disclosed where the application of heat is not needed. In an even further aspect, kits containing the composition are disclosed.

[0011] In one aspect, a bioactive rosin formulation for use as a fluoride varnish includes: at least one bioactive glass; at least one rosin; at least one organic solvent; at least one thickening fdler; at least one inorganic fluoride salt; and at least one sugar alcohol; where the at least one bioactive glass is a hygroscopic calcium sodium phosphosilicate comprising about 20-60% SiO2, 10-40% CaO, 10-40% Na2O, and 1-10% P2O5.

[0012] In some embodiments, the at least one bioactive glass comprises Bioglass 45S5 at a weight / weight concentration (w / w%) between 1% - 20%. In some embodiments, the at least one bioactive glass releases biologically active ions. In some embodiments, the at least rosin is a partially hydrogenated gum rosin with an acid number between 150-170 mg-KOH / g. In some embodiments, the at least one rosin is a partially hydrogenated gum rosin at a weight / weight concentration (w / w%) between 40-80%. In some embodiments, the at least one rosin is a partially hydrogenated gum rosin that provides a tacky surface when deposited on external surface of teeth. In some embodiments, the at least one organic solvent is substantially free of water. In some embodiments, the at least one organic solvent exhibits a vapor pressure between 4 kPa and 35 kPa. In some embodiments, the at least one rosin is soluble in the organic solvent at room temperature. In some embodiments, the at least one organic solvent is at a weight / weight concentration (w / w%) of about 10-55%. In some embodiments, the at least one inorganic fluoride salt has a weight / weight concentration (w / w%) between about 0.1-10%. In some embodiments, the at least one sugar alcohol displays anti-microbial functions. In some embodiments, the at least one sugar alcohol is at a weight / weight concentration (w / w%) between about 1-5%.

[0013] In another aspect, a bioactive rosin formulation for use as a remineralizing varnish includes: at least one bioactive glass; at least one rosin; at least one organic solvent; at least one thickening filler; and, at least one sugar alcohol; wherein the at least one bioactive glass is a hygroscopic calcium sodium phosphosilicate comprising about 20-60% SiO2, 10-40% CaO, 10- 40% Na2O, and 1-10% P2Os, and, wherein the varnish contains less than 100 parts per billion fluoride. In some embodiments, the at least one bioactive glass comprises Bioglass 45 S5 at a weight / weight concentration (w / w%) between 1% - 20%. In some embodiments, the at least rosin is a partially hydrogenated gum rosin with an acid number between 150-170 mg-KOH / g.

[0014] In another aspect, a method of remineralizing a tooth using a bioactive rosin composition includes: applying a bioactive rosin composition to at least one tooth surface, and, allowing the bioactive rosin composition to dwell on the at least one tooth surface for a duration of time,wherein, the bioactive rosin composition includes: at least one bioactive glass; at least one rosin; at least one organic solvent; at least one thickening filler; at least one inorganic fluoride salt; and at least one sugar alcohol; wherein the at least one bioactive glass is a hygroscopic calcium sodium phosphosilicate comprising about 20-60% SiCh, 10-40% CaO, 10-40% Na2O, and 1-10% P2O5. In some embodiments, the at least one inorganic fluoride salt readily dissociates upon contact with water and initiates fluoride ion release. In some embodiments, the at least one sugar alcohol acts as a palletizer for the product to increase patient receptibility. In some embodiments, the bioactive rosin composition further comprises at least one food grade flavoring acts as a palletizer for the product to increase patient receptibility.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 shows comparative test results of percentage surface microhardness recovery for various compositions.DETAILED DESCRIPTION

[0016] The following paragraphs define in more detail the embodiments of the present disclosure. The following embodiments are not meant to limit the disclosure or narrow the scope thereof, as it will be readily apparent to one of ordinary skill in the art that suitable modifications and adaptations may be made without departing from the scope of the disclosure, embodiments, or specific aspects described herein.Rosin-based varnish specifics

[0017] In some embodiments, the bioactive fluoride rosin varnish composition may be a nonaqueous solution comprised of water-soluble salts, or ions, critical to the structural integrity of mineralized dental tissues. The composition may be generally comprised of at least one organically soluble base molecule exhibiting high bonding abilities to enamel and dentin upon deposit, one bioactive glass that releases biologically active ions in the present of water, at least one sugar alcohol for palletizing and anti-microbial properties, at least one dissociable fluoride salt, optionally at least one viscosity modifier, optionally at least one flavorant, and an organic solvent with strong evaporation characteristics.

[0018] The bioactive fluoride rosin varnish may be comprised of an organically soluble base molecule, such as a rosin or a partially hydrogenated gum rosin with an acid number between 150-170 mg-KOH / g. Characteristics of partially hydrogenated gum rosin exhibits exceptional pale color, resistance to oxidation and discoloration, low odor, and wide solubility range. In certain aspects, the rosin provides a tacky feel to the tooth surface following application of the bioactive rosin, which is advantageous for the varnish to remain sticky on the tooth surface (as opposed to easily coming off). The rosin may have a weight / weight concentration (w / w%) between 40% and 80%, and in certain embodiments, between 55% and 65%.

[0019] A substantially water-free organic solvent may serve as the carrier for the organically soluble base molecule and all other varnish ingredients. This solvent may not adversely affect or inhibit any varnish ingredients and must possess sufficient volatility at standard atmospheric pressure to facilitate rapid and even evaporation. In certain embodiments, at room temperature (20 °C) the organic solvent has a preferred vapor pressure between 4 kPa and 35 kPa, and in some embodiments, a vapor pressure between 4 kPa and 10 kPa. Additionally, the solvent may be capable of dissolving the rosin material without the aid of heat or secondary chemical processes. In certain embodiments, the organic solvent is palatable. The organic solvent may have a weight / weight concentration (w / w%) between 10% and 55%, and in some embodiments, between 15% and 35%. In certain embodiments, the organic solvent is ethanol. In other embodiments, the organic solvent is not ethyl acetate, which is considered non-palatable. The ratio between solute (rosin) and solvent may be between 1 : 1 and 4:1, and in some embodiments, approximately 3: 1. Resin-based varnish specifics

[0020] In some embodiments, the bioactive fluoride resin varnish composition is a non-aqueous solution comprised of water-soluble salts, or ions, critical to the structural integrity of mineralized dental tissues. The composition may be generally comprised of at least one monomeric molecule that polymerizes upon curing, one bioactive glass that releases biologically active ions in the present of water, at least one sugar alcohol for palletizing and anti-microbial properties, at least one dissociable fluoride salt, optionally at least one viscosity modifier, optionally at least one flavorant, and an organic solvent with strong evaporation characteristics. Depending on clinical use, various other ingredients for polymerization can be optionally included. For example, at least one photoinitiator shall be included in the composition if the bioactive fluoride resin varnish is desired to be photopolymerized.

[0021] The bioactive fluoride resin varnish may contain at least one monomeric molecule that polymerizes upon curing at a weight / weight concentration (w / w%) between 40 and 80%, and insome embodiments, between 55% and 70%. Monomers for polymerization upon curing are exemplified by, but not limited to, bisphenol a-glycidyl methacrylate (Bis-GMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA), bisphenol a-polyetheylene glycol diether dimethacrylate (Bis-EMA(6)), 2-hydroxy ethyl methacrylate (HEMA), 2- hydroxy ethylmethacrylate acid phosphate (HEMA phosphate), 1,3 -glycerol dimethacrylate / succinate adduct, 1,3 -glycerol dimethacrylate / maleate adduct, phthalic acid monoethyl methacrylate (HEMA phthalate), bis (glyceryl dimethacrylate) pyromellitate (PMGDM), a,P-unsaturated acidic compounds such as glycerol phosphate mono(meth)acrylates, glycerol phosphate di(meth)acrylates, hydroxyethyl (meth)acrylate (e.g., HEMA) phosphates, bis((meth)acryloxyethyl)phosphate, ((meth)acryloxypropyl)phosphate, bis((meth)acryloxypropyl)phosphate, bis((meth)acryloxy)propyloxy phosphate, (meth)acryloxyhexyl phosphate, bis((meth)acryloxyhexyl)phosphate, (meth)acryloxyoctyl phosphate, bis((meth)acryloxyoctyl)phosphate, (meth)acryloxydecyl phosphate, bis((meth)acryloxydecyl)phosphate, caprolactone methacrylate phosphate, citric acid di- or trimethacrylates, poly(meth)acrylated oligomaleic acid, poly(meth)acrylated polymaleic acid, poly(meth)acrylated poly(meth)acrylic acid, poly(meth)acrylated polycarboxyl-polyphosphonic acid, poly(meth)acrylated polychlorophosphoric acid, poly(meth)acrylated polysulfonate, 2- sulfoethyl methacrylate, 3 -sulfopropyl methacrylate, 2-acrylamido 2-methylpropane sulfonate, poly(meth)acrylated polyboric acid, and the like. Monomers, oligomers, and polymers of unsaturated carbonic acids such as (meth)acrylic acids, aromatic (meth)acrylated acids (e.g., methacrylated trimellitic acids), and anhydrides are also contemplated. For certain embodiments, ethylenically unsaturated compounds with acid functionality may include hydroxyethyl methacrylate phosphate, methacryloyloxyhexyl phosphate, methacryloyloxydecyl phosphate, glycerol dimethacrylate phosphate, citric dimethacrylate, and propionic dimethacrylate, amongst others.Shared rosin-based varnish and resin-based varnish specifications

[0022] In certain embodiments, the bioactive glass is a hygroscopic calcium sodium phosphosilicate. In some embodiments, the bioactive glass includes about 20-60% SiCh, about 10- 40% CaO, about 10-40% Na?O, and about 1-10% P2O5. In some embodiments, the bioactive glass includes about 30-50% SiCh, about 20-30% CaO, about 20-30% Na2O, and about 3-9% P2O5. In certain embodiments, the bioactive glass is Bioglass 45S5 (a calcium sodium phophosilicate),which consists of a weight / weight concentration (w / w%) of about 45% SiCh, about 24.5% CaO, about 24.5% Na20, and about 6.0% P2O5. Once in contact with water, the bioactive glass releases biologically active ions such as calcium, phosphate, fluoride, hydroxide, magnesium, carbonate, and others as deemed clinically advantageous that help facilitate remineralization of tooth structures, such as dentin. The release of these biologically active ions occurs immediately when in contact with water but can last for days, weeks, or months depending on the bioactive glass composition and particle size. While the bioactive glass is releasing the biologically active ions, the bioactive glass also serves as a structural filler for increasing the strength of the varnish formulation. In certain embodiments, the bioactive glass may release antimicrobial chemicals, compounds or agents upon contact with water. In further embodiments, the ions released from the bioactive glass may modify the pH of the surrounding environment to inhibit bacteria, promote tissue healing, or reduce inflammation. Within the disclosed composition, the bioactive glass may have a 325 mesh size (44 um) or smaller. Within the disclosed composition, the bioactive glass may have a weight / weight concentration (w / w%) between 1% and 20%, between 5% and 10%, or about 5%.

[0023] Sugar alcohol and flavorings may be used as a palletizer with the bioactive varnish at a weight / weight concentration (w / w%) between 1% and 5%, and in some embodiments, between 1% and 2%. Anti -microbial properties may be a reason to include at least one sugar alcohol due to the minimal caloric value it supplies to bacteria, thereby preventing multiplication of colonies that otherwise may use sucrose or other sweeteners as a food source. Suitable sugar alcohols may include, but are not limited to, sorbitol, mannitol, erythritol, xylitol, and the like.

[0024] An inorganic fluoride salt may be used to supply ionic fluoride upon dissociation with aqueous contact. In certain embodiments, fluoride encompasses at least 30% of the salt’s molecular weight, and in some embodiments, at least 50%. The fluoride salt may readily dissociate to liberate fluoride upon contact with water (e.g. sodium fluoride), although certain salts may be used which provide prolonged fluoride release (e.g. sodium monofluorophosphate). Suitable non-limiting examples of appropriate salts include sodium fluoride (NaF), calcium fluoride (CaF2), and sodium monofluorophosphate (Na2PO3F). Overall fluoride contribution from this salt may be at a weight / weight concentration (w / w%) between 0.1% and 10%, and in some embodiments between 0.5% and 6%. In some embodiments, the varnish is appreciably fluoride-free (preferably less thanIppm fluoride, more preferably less than lOOppb fluoride, and most preferably less than lOppb) and only promotes remineralization through the included bioglass material.

[0025] A thickening agent may be used to increase the viscosity of the bioactive varnish formulation, thereby enabling an easier application experience for the patient and healthcare provider. Additionally, the thickening agent may help keep undissolved particulate suspended within the material to minimize crash out and setting. Silicon dioxide accomplishes these goals without enabling side reactions or unwanted taste / handling issues. In some embodiments, silicon dioxide is at a weight / weight concentration (w / w%) between 1% and 10%, and in certain embodiments, between 3% and 7%. In some instances, the thickening agent may introduce thixotropic properties to the bioactive varnish formulations, which may make them easier to spread on the surface of teeth and permeate into pits, fissures, and other dental anatomies during application. Additional thickeners may be added depending on the consistency of the bioactive varnish formulation desired for clinical use. The disclosed varnish formulation may have a viscosity of 1 - 100,000 cP, of 10 - 1,000 cP, or of 20 - 100 cP. The bioactive varnish formulation has a viscosity allowing it to be easily placed or brushed on the tooth surface. In certain aspects, the bioactive varnish may be non-Newtonian or pseudoplastic. Suitable thickeners can include silicates and polymers, such as polystyrene, polypropylene, polyethylene, polyacrylates, polyacrylamides, polyvinyl alcohol, poloxamers, and copolymers and surfactant combinations.

[0026] In some embodiments, the bioactive varnish may additionally comprise surfactants that decrease the varnish’s surface tension, thereby facilitating easier and more even application to the tooth surface and ensuring penetration into any pits, fissures, or other difficult to reach tooth anatomies or structures. In some embodiments, the surfactants are non-ionic such that they do not interact with the biologically active ions released from the Bioglass. Examples of suitable surfactants include, but are not limited to, nonionic surfactants, such as alcohol ethoxylates, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, polyoxyethylene glycol sorbitan alkyl esters, sorbitan alkyl esters, copolymers of polyethylene glycol and / or propylene glycol, Poloxamers, sodium sterates, fluorosurfactants, among others.

[0027] Optionally, the bioactive varnish includes at least one humectant. In some embodiments, the bioactive varnish includes at least one lubricant. Optionally, the bioactive varnish includes at least one hydrotrope. In some embodiments, at least one hygroscopic additive is included in thebioactive varnish to expedite the reaction of water with certain components of the bioactive varnish. In some embodiments, antimicrobial compounds may be added to the formulation.

[0028] Generally, all ingredients should exhibit long-term biocompatibility for safety and toxicity considerations. Furthermore, the selection of ingredients within the bioactive varnish may also exhibit more favorable biocompatibility than other varnishes commercially available. The pH of water in contact with the disclosed bioactive varnish is preferably alkaline (i.e. pH is preferably greater than 7, greater than 9, or greater than 10) such that a source of hydroxide anions is present for remineralization. In certain embodiments, weak bases or salts yielding weak bases may be added to the composition in an effort to increase the pH of water once in contact with the bioactive varnish.

[0029] In further aspects of the disclosure, the bioactive varnish composition provides a suitable shelf life of preferably 6-48 months when stored at room temperature without displaying significant characteristics of chemical instability (e.g. crash out or separation) or significant decreased clinical efficacy. The bioactive varnish may optionally be stored in a hermetically sealed pouch to help minimize moisture absorption and solvent evaporation, thereby extending the product’s shelf life. An example of chemical instability would be the formation of a precipitate, or significant phase separation, during storage that renders the composition less effective or useless.

[0030] In certain aspects, the bioactive varnish may be packaged in various containers sized between 0.1 mL and 100 mL, or in unit dose containers sized between 0.25 mL and 1 mL. In some embodiments, it may be beneficial to have the bioactive varnish composition stored in separate containers (e.g. two separate containers, dual barrel syringe, etc.) and mixed by the user immediately prior to use.

[0031] The packaging of the components must be compatible for long-term storage (months to years). Satisfactory plastic resins for the packaging material may include, but are not limited to, polypropylene, polycarbonate, polyethylene, styrene acrylonitrile, methyl methacrylate- acrylonitrile-butadiene-styrene, poly-cyclohexylenedimethylene terephthalate glycol, among others.

[0032] In certain aspects, the bioactive varnish is provided as an item within a kit. In some embodiments, the kit may include any one or more of the following components: application tips, application brushes, mixing tips, mixing vessels, empty syringes, an instruction for use, mixing wells or other single use vessels, a dental etchant or etchants, a dental adhesive or adhesives, adental primer or primers, a dental composite or composites, a dental cement or cements, among other common dental and endodontic products.

[0027] The method in which the bioactive rosin varnish and resin varnish are manufactured is advantageous since the formulation is manufacturable without the need for heating the material above ambient room temperature. Heat is avoided for two main reasons: maintaining product efficiency and reducing manufacturing-related risks. On the processing side, heat exposure has been shown to modify the solubility and compatibility characteristics of many rosins, as well as catalyze a wide range of possible side-interactions of the photopolymerizable resin composite ingredients, all of which may encourage premature degradation of material. Further, heating of organic rosin materials, resin materials, and solvents may present a fire and safety hazard due to the inherent volatility and flammability properties of raw ingredients.

[0028] Specifically related to manufacturing of the rosin-based bioactive varnish, the solvent is first added to a mixing vessel. Next, a rosin of the present disclosure is added to the mixing vessel and solubilized at about room temperature. The disclosed rosin is fully soluble at room temperature up to a solute to solvent ratio of approximately 3:1 given adequate agitation and prevention of solvent evaporation. The agitation should be less than 400 revolutions per minute (rpm) for a stand or stir-bar mixer and is preferably between 200 and 300 rpm, although various mixing speeds may be employed depending on the mixing vessel and equipment used. In some embodiments, dissolving the rosin solute in the solvent is completed within 120 minutes, and in certain embodiments, between 10 and 50 minutes.

[0029] Once the rosin is fully dissolved in the solvent, the addition of mineral-release components, palletizers, surfactants, and thickeners may be initiated in no specific order. No special environmental precautions, such as non -white light sources are necessary in this stage. As with the prior stage, no significant sources of direct or indirect heat are utilized to aid in the formulation. In some embodiments, the above components are emulsified within the rosin base through a dual asymmetric centrifugal process, using shear forces to encourage a homogenous mixing of the varnish. Formulations may be mixed in approximate one-minute cycles at 1500 to 3000 rpm, with a minimum of two cycles to ensure consistency and full emulsion of additives and homogeneity within the rosin solvent mixture.

[0030] Specifically related to manufacturing of the resin varnish formulation, the formulation must be manufactured under non-white or restricted spectrum lighting sources to preventphotopolymerization of the initiator chemical, or chemicals, with ultraviolet or blue light. All necessary components are combined into a vessel sufficient for long-term bladed mixing at high speeds between 300-500 rpm, although dual asymmetric centrifugal mixing can be employed. Emulsion of the components is stable for the majority of stated shelf life, requiring only minor mixing by the healthcare professional in a minority of cases.Definitions

[0031] For purposes of interpreting this specification, the following abbreviations, terms and definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth below shall control.

[0032] The term “room temperature” or ambient temperature as used herein refers to common ambient temperatures ranging from about 18 °C to about 27 °C.

[0033] As used herein, “a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably.

[0034] The terms “comprises” and variations thereof do not have a limiting meaning where these terms appear in the description and claims.

[0035] The term “patient” or “subject” refers to mammals and humans. Thus, in one aspect, the subject is a mammal, or a mammal in need thereof. In one aspect, the subject is a human, or human in need thereof. In one aspect, the human or human in need thereof is a medical patient. The subject can be from ~0 years of age to 99 years of age or older.

[0036] The term “composition” generally refers to the chemical makeup of certain embodiments of the disclosed invention and is synonymous with “formula”.

[0037] The term “bioactive” is a contraction of “biologically active” which generally refers to a material exhibiting properties that actively interact with surrounding biological tissue and environment. This term contrasts with “biologically inert” which describes a material that does not interact with the surrounding biological tissue and environment.

[0038] The term “partially hydrogenated rosin” generally refers to the chemical structure comprised of a mixture of double carbon bonds and single carbon-hydrogen bonds in the rosin acid chain. Progressive hydrogenation has been linked to higher resistance against oxidation, reduced UV absorption, as well as a lighter final color of the dried product.

[0039] The term “photopolymerization” generally refers to the process through which a photo initiator is excited by the presence of UV, blue or other spectrum light sources. The result of photo initiator excitement, whether through the release of ions or free-radicals, begins the reaction. This is characterized by polymerization or joining of many monomers into evergrowing polymer chains, transforming the material into a cured substance with many divergent properties when compared to the original monomer state.

[0040] The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the description, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.EXAMPLES:

[0041] : Table 1 summarizes the chemical constituents that comprise the disclosed bioactive rosin varnish. Additionally, Table 2 provides example formulas or compositions of the disclosure.Table 1: Chemical constituents that comprise the disclosed bioactive rosin varnish.Table 2: Example formulas or compositions that comprise the disclosed bioactive rosin varnish.

[0042] : Table 3 summarizes the chemical constituents that comprise the disclosed bioactive resin photopolymerizable varnish. Additionally, Table 4 provides example formulas or compositions of the disclosure.Table 3: Chemical constituents that comprise the disclosed bioactive resin photopolymerizable varnish.Table 4: Example formulas or compositions that comprise the disclosed bioactive resin photopolymerizable varnish.

[0043] Test #1. Many common calcium and phosphate releasing agents have been known to inhibit the uptake process of fluoride ions into enamel and dentin. Testing on human teeth show that there is no difference in elemental fluoride uptake (EFU) or fluoride release (F- release) between a non-bioactive rosin varnish formulation (FluoroDose, Centrix, Shelton, CT) and the same material with 10% Bioglass 45 S5 added. See Table 5 below for normalized test results. This result implies that the Bioglass 45 S5 does not inhibit the uptake of fluoride to the dentin or enamel even though it is a provider of calcium and phosphate ions for remineralization. This preliminary experiment is significant due to the possible impact on in vivo remineralization processes leading to an enhanced recovery of enamel and dentin. Existing research has not shown equivalent results and the ability of a varnish to effectively provide calcium, phosphate and fluoride simultaneously to dentin or enamel.Table 5: EFU and F-release testing between a bioactive rosin varnish formulation (labeled Bioglass) and non-bioactive formulation of Centrix FluoroDose Varnish (labeled Centrix).

[0044] Test 2. Another test was performed to analyze the protective effect of varnishes on human enamel using surface Knoop microhardness testing following protocols from the literature (Pediatr Dent. 2014 Jun 15;36(3):85-89). Briefly, a hardness measurement of enamel sample was obtained initially (measurement A), following demineralization for 1 hour at 37C(measurement B), and following varnish application for 1 hour at 37C (measurement C). From these hardness values, a percentage surface microhardness recovery (%SMHR) metric was calculated as follows: %SMHR = (measurement C - measurement B) / (measurement A minus measurement B) * 100. Results are summarized in Figure 1 and illustrate the significant increase in %SMHR results for the disclosed Formula A compared to two existing varnish products on the market (3M ESPE Varnish and Colgate Prevident Varnish). Interestingly, and unexpectedly, the disclosed Formula B that is fluoride-free performed equivalently to Colgate Prevident Varnish and significantly better than 3M ESPE Varnish, which illustrates how a substantially fluoride-free bioactive varnish can remineralize enamel and increase the enamel hardness rapidly and effectively without the use of fluoride.Statements (Rosin-based bioactive varnish):1. A bioactive rosin formulation for use as a fluoride varnish comprising: a. At least one bioactive glass; b. At least one rosin c. At least one organic solvent d. At least one thickening filler e. At least one inorganic fluoride salt f. At least one sugar alcohol2. The composition of statement 1, wherein the at least one bioactive glass comprises a hygroscopic calcium sodium phosphosilicate.3. The composition of statement 1, wherein the at least one bioactive glass comprises Bioglass 45 S5 at a weight / weight concentration (w / w%) between 1% - 20%.4. The composition of statement 1, wherein the at least one bioactive glass comprises a calcium sodium phosphosilicate that releases biologically active ions.5. The composition of statement 1, wherein the at least rosin is a partially hydrogenated gum rosin with an acid number between 150-170 mg-KOH / g.6. The composition of statement 1, wherein the at least one rosin is a partially hydrogenated gum rosin at a concentration between 40-80%The composition of statement 1, wherein the at least one rosin is a partially hydrogenated gum rosin that provides a tacky surface when deposited on external surface of teeth. The composition of statement 1, wherein the at least one organic solvent is substantially free of water. The composition of statement 1, wherein the at least one organic solvent exhibits a vapor pressure between 4 kPa and 35 kPa and the ability to solubilize the at least one rosin at about room temperature. The composition of statement 1, wherein the at least one organic solvent is at a weight / weight concentration (w / w%) of 10-55% The composition of statement 1, wherein the at least one inorganic fluoride salt readily dissociates upon contact with water and initiates fluoride ion release. The composition of statement 1, wherein the at least one inorganic fluoride salt has a weight / weight concentration (w / w%) between 0.1-10% The composition of statement 1, wherein the at least one sugar alcohol acts as a palletizer for the product to increase patient receptibility. The composition of statement 1, wherein the at least one sugar alcohol displays antimicrobial functions. The composition of statement 1, wherein the at least one sugar alcohol is at a weight / weight concentration (w / w%) between 1-5% The composition of statement 1, wherein the at least one food grade flavoring acts as a palletizer for the product to increase patient receptibility. The composition of statement 1, wherein the at least one food grade flavoring is at a weight / weight concentration (w / w%) between 1-5% The composition of statement 1, wherein the strengthening filler is also a rheology modifier. The composition of statement 1, wherein the strengthening filler is at a weight / weight concentration (w / w%) between 0.5 - 5%. The composition of statement 1, whose manufacturing process is completed at room temperature to achieve homogeneity and functional formulation. The composition of statement 1, wherein the solvent evaporates shortly after application depositing all other materials onto tooth surface.22. The composition of statement 1, wherein the varnish displays a viscosity between 1 - 100,000 cPStatements (Resin-based bioactive varnish)1. A bioactive resin formulation for use as a fluoride varnish comprising: a. At least one bioactive glass b. At least one polymerizable monomer c. At least one photo-initiator d. At least one co-initiator e. At least one thickening filler f. At least one inorganic fluoride salt2. The composition of statement 1, wherein the at least one bioactive glass comprises a hygroscopic calcium sodium phosphosilicate.3. The composition of statement 1, wherein the at least one bioactive glass comprises Bioglass 45S5 at a weight / weight concentration (w / w%) between 1% - 20%.4. The composition of statement 1, wherein the at least one bioactive glass comprises a calcium sodium phosphosilicate that releases biologically active ions.5. The composition of statement 1, wherein the at least one polymerizable monomer is capable of polymerizing when in reaction with an activated photo-initiator.6. The composition of statement 1, wherein the at least one polymerizable monomer is at a weight / weight concentration (w / w%) between 5-20%7. The composition of statement 1, wherein the at least one photo-initiator is excitable in the UV or blue range of the electromagnetic spectrum, releasing free radicals to start the polymerization reaction of the at least one polymerizable monomer.8. The composition of statement 1, wherein the at least one photo-initiator is in a weight / weight concentration (w / w%) between 0.1 -0.5%.9. The composition of statement 1, wherein the at least one co-initiator is present to catalyze and facilitate curing to completion under various non-ideal circumstances.10. The composition of statement 1, wherein the at least one co-initiator is in a weight / weight concentration (w / w%) of between 40-80%The composition of statement 1, wherein the at least one inorganic fluoride salt readily dissociates upon contact with water and initiates fluoride ion release. The composition of statement 1, wherein the at least one inorganic fluoride salt has a weight / weight concentration (w / w%) between 0.1-10% The composition of statement 1, wherein the strengthening filler is also a rheology modifier. The composition of statement 1, wherein the strengthening filler is at a weight / weight concentration (w / w%) between 0.1 - 5%. The composition of statement 1, whose manufacturing process is completed at room temperature to achieve homogeneity and functional formulation. The composition of statement 1, wherein the varnish displays a viscosity between 1 - 100,000 cP

Claims

CLAIMSWhat is claimed is:

1. A bioactive rosin formulation for use as a fluoride varnish comprising: at least one bioactive glass; at least one rosin; at least one organic solvent; at least one thickening filler; at least one inorganic fluoride salt; and at least one sugar alcohol; wherein the at least one bioactive glass is a hygroscopic calcium sodium phosphosilicate comprising about 20-60% SiCh, 10-40% CaO, 10-40% Na2O, and 1-10% P2O5.

2. The composition of claim 1, wherein the at least one bioactive glass comprises Bioglass 45 S5 at a weight / weight concentration (w / w%) between 1% - 20%.

3. The composition of claim 1, wherein the at least one bioactive glass releases biologically active ions.

4. The composition of claim 1, wherein the at least rosin is a partially hydrogenated gum rosin with an acid number between 150-170 mg-KOH / g.

5. The composition of claim 1, wherein the at least one rosin is a partially hydrogenated gum rosin at a weight / weight concentration (w / w%) between 40-80%6. The composition of claim 1, wherein the at least one rosin is a partially hydrogenated gum rosin that provides a tacky surface when deposited on external surface of teeth.

7. The composition of claim 1, wherein the at least one organic solvent is substantially free of water.

8. The composition of claim 1, wherein the at least one organic solvent exhibits a vapor pressure between 4 kPa and 35 kPa.

9. The composition of claim 9, wherein the at least one rosin is soluble in the organic solvent at room temperature.

10. The composition of claim 1, wherein the at least one organic solvent is at a weight / weight concentration (w / w%) of about 10-55%.

11. The composition of claim 1 , wherein the at least one inorganic fluoride salt has a weight / weight concentration (w / w%) between about 0.1-10%.

12. The composition of claim 1, wherein the at least one sugar alcohol displays antimicrobial functions.

13. The composition of claim 1, wherein the at least one sugar alcohol is at a weight / weight concentration (w / w%) between about 1-5%.

14. A bioactive rosin formulation for use as a remineralizing varnish comprising: at least one bioactive glass; at least one rosin; at least one organic solvent; at least one thickening filler; and, at least one sugar alcohol; wherein the at least one bioactive glass is a hygroscopic calcium sodium phosphosilicate comprising about 20-60% SiC , 10-40% CaO, 10-40% Na O, and 1-10% P2O5, and, wherein the varnish contains less than 100 parts per billion fluoride.

15. The composition of claim 14, wherein the at least one bioactive glass comprises Bioglass 45 S5 at a weight / weight concentration (w / w%) between 1% - 20%.

16. The composition of claim 14, wherein the at least rosin is a partially hydrogenated gum rosin with an acid number between 150-170 mg-KOH / g.

17. A method of remineralizing a tooth using a bioactive rosin composition comprising: applying a bioactive rosin composition to at least one tooth surface, and, allowing the bioactive rosin composition to dwell on the at least one tooth surface for a duration of time, wherein, the bioactive rosin composition comprises: at least one bioactive glass; at least one rosin; at least one organic solvent; at least one thickening filler; at least one inorganic fluoride salt; andat least one sugar alcohol; wherein the at least one bioactive glass is a hygroscopic calcium sodium phosphosilicate comprising about 20-60% SiCh, 10-40% CaO, 10-40% Na2O, and 1-10% P2O5.

18. The method of claim 17, wherein the at least one inorganic fluoride salt readily dissociates upon contact with water and initiates fluoride ion release.

19. The method of claim 17, wherein the at least one sugar alcohol acts as a palletizer for the product to increase patient receptibility.

20. The method of claim 17, wherein the bioactive rosin composition further comprises at least one food grade flavoring acts as a palletizer for the product to increase patient receptibility.

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