WO2015157675A1 - Methods for protecting and repairing enamel - Google Patents
Methods for protecting and repairing enamel Download PDFInfo
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- WO2015157675A1 WO2015157675A1 PCT/US2015/025375 US2015025375W WO2015157675A1 WO 2015157675 A1 WO2015157675 A1 WO 2015157675A1 US 2015025375 W US2015025375 W US 2015025375W WO 2015157675 A1 WO2015157675 A1 WO 2015157675A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/20—Halogens; Compounds thereof
- A61K8/21—Fluorides; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/90—Block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Definitions
- the present invention is directed to advances in protecting and repairing enamel by administering to enamel, aqueous-free, stannous fluoride, brushing gels; whereby the protectant and repair ingredients are substantive to enamel surfaces, thereby extending the protecting and repairing processes with improved stannous fluoride effectiveness.
- Key protectant and repair combinations used in the methods of the present invention comprise brushing gels containing: stannous fluoride and calcium in aqueous-free, substantivity agents.
- Fluoride dentifrices have been shown in numerous clinical trials to be effective anticaries agents [Stookey, J. Dent. Res. 1990, 69(Special Issue): 805-812] and have been recognized as a major cause of the remarkable decline in caries prevalence in many developed countries. Dentifrices have been widely adopted around the world as the principle means of delivering topical fluoride and obtaining caries preventive benefits.
- the current market for fluoride brushing products includes: professional and consumer oral care fluoride treatments, both OTC and Rx brushing products; including: toothpastes, gels, pastes and varnishes.
- Rx fluoride toothpastes and Rx fluoride brushing gels are well outside fluoride Monograph levels containing up to 5000 ppm fluoride.
- Professional oral care, in-chair, fluoride varnishes contain up to about 22,000 ppm fluoride
- OTC fluoride toothpastes can contain up to 1 150 ppm total theoretical fluorine, the maximum level provided for by the Monograph.
- ADA American Dental Association
- FDA Food & Drug Administration
- oral care professionals including : general practitioners, periodontists, orthodontists, pediatric dentists, etc. as a group; are generally concerned over the trend of increasing fluoride levels.
- These organizations and oral care professionals generally favor using lower levels of fluoride in various in-chair treatments and various OTC and Rx, oral care, topical, home treatments for patients, provided.... enamel protection and repair, achieved with lower fluoride levels, are comparable to the results reported for brushing products with higher levels of fluoride.
- This preference for lower fluoride-brushing products is driven by the concern over toxicity, fluorosis in children, etc., associated with exposure to high fluoride levels, long term.
- fluoride varnishes containing 22,000 ppm fluoride applied to the enamel by an oral care professional, are designed to maintain substantive fluoride levels on the enamel after patient expectoration. Fluoride varnishes are generally applied professionally, at a frequency of about once every six months with the target audience comprising primarily children.
- caries continues to pose a challenge: in children, as well as adults including coronal caries in the elderly, caries in dry mouth patients, caries in immunocompromised patients, caries in patients undergoing medical or dental treatment, etc.
- EPF enamel protectant factor
- ERF enamel repair factor
- Aqueous-free is defined as: substantially free from water.
- Enamel Protectant Factor is defined as: the percent reduction in enamel solubility divided by the fluoride level in parts per million using FDA method #40.
- Enamel Repair Factor is defined as: the average increase in enamel fluoride concentration divided by the fluoride level of the fluoride brushing product tested using FDA method #33.
- “Mucoadhesive” is defined as: a substance that is retained for a period of time onto surfaces in the mouth that is not easily removed by the mechanical action of the tongue nor by flow of saliva.
- “Stable stannous fluoride” is defined as: compositions that, when chemically assayed, substantially retains the level of stannous and/or fluoride in an unreacted state.
- Biofilm is defined as: a surface adherent film comprised of bacteria, exuded polysaccharides, etc., that is not easily removed by mechanical means or saliva flow.
- Substantivity agent is defined as: a composition that improves the mucosal retention of the desired agents.
- Cation bridging is defined as: electrical attraction between two films or membranes initiated by cation moieties.
- Liquid nonionic surfactant is defined as: a liquid composition that indicates surface active properties with the absence of charged species.
- Solid nonionic surfactant is defined as: a solid composition that indicates surface active properties with the absence of charged species.
- CaF + moiety is defined as: a monodentate calcium fluoride ion.
- Linear, polymeric, polycarboxylates, substantivity enhancer is defined as: a linear polymer with carboxylate substituents that increases retention of compositions onto charged surfaces.
- Embodision discontinuous phase is defined as: the minor component in an emulsion that is surrounded by a continuous phase.
- Emmulsion continuous phase is defined as: an emulsion component that surrounds discontinuous phase component.
- the present invention is directed to methods of treating enamel with aqueous-free, brushing gel compositions, wherein the brushing gels contain stannous fluoride and calcium in an aqueous-free, substantivity agent.
- the methods of the present invention protect and repair enamel more effectively than prior methods relying on brushing gels and toothpaste compositions containing comparable or substantially higher levels of fluoride, as indicated by comparative EPF and ERF values reported herein.
- the methods of administering enamel protectant and enamel repair, brushing gel compositions onto enamel form substantive, mucoadhesive gels in the presence of saliva; which mucoadhesive gels gradually release stable stannous fluoride and calcium onto enamel. This slow release continues until the mucoadhesive gel is eventually totally solubilized by saliva. This gradual release minimizes the "wash-out" effect traditionally experienced with fluoride brushing products.
- the resultant enamel protectant and enamel repair increases in EPF and ERF values, resulting from the extended enamel residence time of stannous fluoride, calcium and cation bridging associated with microbial fluoride binding to biofilm. This improved stannous fluoride efficiency reduces the need to resort to elevated fluoride levels.
- FIG. 1 of the drawings summarizes comparative, in vitro, enamel protectant factor (EPF) values for methods of treatment of the present invention with a brushing gel with stannous fluoride at 970 ppm fluoride, as described in Example 1 ; compared with: (a) an Rx 5000 ppm, sodium fluoride toothpaste, and (b) an OTC, 1 100 ppm, stannous fluoride toothpaste.
- EPF enamel protectant factor
- FIGS 2 and 3 of the Drawings illustrate enamel repair factor (ERF) values for methods of treatment of the present invention using brushing gels with compositions, as described in Examples 1 and 2; with stannous fluoride at 970 ppm compared with toothpastes having stannous fluoride at 1 100 ppm and sodium fluoride at 900 ppm or sodium fluoride at 5000 ppm, respectively.
- EPF enamel repair factor
- Figures 4 through 6 present ERF values for methods of treatment of the present invention using brushing gels comprising compositions, as described in Examples 3 through 5.
- These brushing gels of the present invention contain stannous fluoride at a level of 970 ppm, compared with: (a) a 900ppm sodium fluoride toothpaste, and (b) an 1 100 ppm stannous fluoride toothpaste or (c) a 5000 ppm sodium fluoride toothpaste.
- Methods of the invention for protecting and repairing enamel with aqueous-free, stannous fluoride, calcium, brushing gels that comprise substantivity agents that contain various enamel protectant and enamel repair ingredients. These substantivity agents function as carriers for various enamel protectant and repair ingredients. These substantivity agents are characterized by their ability, in the presence of saliva, to form mucoadhesive gels which are substantive to enamel with biofilm. These substantive, mucoadhesive gels are further characterized by their ability to: (a) gradually dissolve when exposed to saliva flow, and (b) gradually release various enamel protectant and enamel repair ingredients, in an unreacted state, onto enamel surfaces with biofilm as they dissolve.
- the substantivity agents extend the duration of enamel protectant and enamel repair treatments of the present invention, and support cation bridging associated with microbial fluoride binding; thereby enhancing the EPF and ERF values of various methods of treatment of the present invention, while simultaneously reducing the level of fluoride required to achieve the unexpected increases in EPF and ERF values.
- phosphate components are also included in the brushing gels. These are described by Ming Tung in U.S. Patents: 5,037,639; 5,268,167; 5,427,768; 5,437,857; 5,460,803; 5,562,895; by Tung in the American Dental Association Foundation publication, "ACP Technology,"; by Schemehorn, et. al., in The Journal of Clinical Dentistry Vol. XXII : No 2. 51 -54, 201 1 ; by the 19 references cited by Schemehorn, et. al. ; and by the description of various Gantrez® resins containing calcium, including Gantrez® MS-955 available from International Specialty Products, Wayne, NJ, USA.
- the aqueous-free, substantivity agents used in the methods of treatment of the present invention hold the various enamel protectant and enamel repair ingredients, including stannous fluoride, calcium and phosphate components, in a condition where these ingredients remain stable and unreacted.
- this aqueous-free, substantivity agent When this aqueous-free, substantivity agent is exposed to saliva, it forms a mucoadhesive gel that is substantive to enamel with biofilm. This mucoadhesive gel continues to hold the enamel protectant and enamel repair ingredients onto enamel surfaces with biofilm without the ingredients reacting. These ingredients eventually react upon being released onto saliva- and biofilm-coated, enamel surfaces.
- Aqueous-free, brushing gels used in the treatment methods of the present invention contain enamel protectant and enamel repair ingredients, suitable for protecting and repairing dental enamel ; wherein :
- substantivity agents are gradually released onto the enamel in an unreacted state as the saliva soluble, substantivity agent undergoes saliva dissolution at rates, which are controlled by saliva flow and the composition of the substantivity agent;
- saliva soluble, aqueous-free emulsions used as substantivity agents include those emulsions that are comprised of polydimethylsiloxane polymers in solid nonionic surfactants, as described in U.S. Patents: 5,032,387; 5,098,71 1 ; 5,538,667; 5,651 ,959; having the structural formula:
- liquid, nonionic surfactants comprise the continuous phase of the aqueous-free emulsions.
- liquid, nonionic surfactants are selected from the group consisting of: poloxamer, having the structural formula set out above, as well as mixtures of such liquid, nonionic surfactants with solid, nonionic surfactants; wherein the mixture is liquid, including: solid, nonionic surfactants having the structural formula set out above.
- aqueous-free emulsions include a liquid, nonionic, surfactant, continuous phase and a discontinuous phase PDMS at viscosities between about 10,000 cs and 2.5 million cs.
- Solid surfactants useful as adjuncts to liquid, nonionic, surfactant, continuous phase are described in detail in U.S. 5,651 ,959. These liquid and liquid/solid, nonionic, surfactant emulsion mixtures are liquid and form mucoadhesive gels in the presence of saliva.
- Preferred polydimethylsiloxanes are selected from the group consisting of polydimethylsiloxane: at 1500 cs, at 10,000 cs, at 100,000 cs, at 250,000 cs, at 500,000 cs, at 750,000 cs, at 1 .5 million cs, at 2.2 million cs, at 2.5 million cs and combinations thereof.
- Foam modulators are useful in the methods of treatment of the present invention. These include, without limitation: materials operable to control amount, thickness or stability of foam generated by the brushing gel composition upon agitation. Any orally acceptable foam modulator can be used, including polyethylene glycols (PEGs), also known as polyoxyethylenes. High molecular weight PEGs are suitable, including those having an average molecular weight of about 200,000 to about 7,000,000, for example about 500,000 to about 5,000,000 or about 1 ,000,000 to about 2,500,000. One or more PEGs are optionally present in a total amount of about 0.1 % to about 10%, for example about 0.2% to about 5% or about 0.25% to about 2%.
- PEGs polyethylene glycols
- High molecular weight PEGs are suitable, including those having an average molecular weight of about 200,000 to about 7,000,000, for example about 500,000 to about 5,000,000 or about 1 ,000,000 to about 2,500,000.
- One or more PEGs are optionally present in a total amount of about 0.1 % to about 10%
- Humectants useful for the brushing gels used in the methods of treatment of the present invention include, without limitation : polyhydric alcohols such as glycerin, sorbitol, xylitol or low molecular weight PEGs.
- humectants can prevent hardening of the brushing gels upon exposure to air.
- humectants also function as sweeteners.
- compositions used in the methods of treatment of the present invention including, for example, additional : mouth-feel agents, pH modifying agents, flavorants, sweeteners, antimicrobial (e.g., antibacterial) agents such as those described in U.S. Pat. No. 5,776,435, saliva stimulants, antiinflammatory agents, nutrients, vitamins, proteins, antioxidants, colorants, etc.
- the methods of treatment of the present invention using brushing gels contain ingredients that substantially effect enamel protection factor (EPF) and enamel repair factor (ERF) values, based on bidentate binding of calcium shifting to monodentate binding of calcium in the presence of stannous fluoride.
- EPF enamel protection factor
- EMF enamel repair factor
- Substantivity agents and substantivity enhancers including mixed sodium and calcium salt copolymers of methyl/vinyl/ether/maleic acid; wherein the stannous fluoride, calcium and phosphate components remain unreacted and the pH of the brushing gel when administered to saliva coated enamel is at least about 3.
- the amount of stannous fluoride, used in the methods of treatment of the present invention, where stannous fluoride brushing gels are applied to the toothbrush (dose) is not as important as the concentration of available stannous fluoride in the brushing gel.
- reducing fluoride concentration in brushing products has been reported not to be as effective as regular concentration fluoride products.
- the fluoride dose is important in regard to enamel fluorosis in children under six years of age, due to fluoride brushing gel ingestion. For this reason, reducing the amount of stannous fluoride applied in the methods of treatment of the present invention using brushing gels is a preferred strategy over lowering the dose of stannous fluoride brushing gels intended for use by children under six years of age. While fluoride brushing products have a long history of safety, there is a continuing concern associated with dental fluorosis due to fluoride ingestion in children under age six. Dendrys, J. Am. Dent. Assoc. 2000, 131 (6): 746-755.
- the methods of treatment of the present invention using stannous fluoride brushing gels with their improved efficacy can be used at reduced stannous fluoride levels, and thereby substantially lower the risk of overdosing and the onset of fluorosis, while delivering effective EPF and ERF results.
- plaque have the potential to remineralize even at pH values typically regarded as demineralizing.
- stannous fluoride mouthrinses The ability of the tin ions to inhibit plaque formation has been studied primarily using stannous fluoride mouthrinses. Daily rinsing with a 0.1 percent stannous fluoride solution significantly reduces bacterial accumulation on the teeth.
- stannous ions The action of stannous ions is mediated through their ability to bind to lipotechoic acid on the surface of Gram-positive bacterial. The surface net charge of the organisms is therefore reversed and the adsorption of the cells onto teeth is consequently reduced. Furthermore, the effectiveness of stannous fluoride solution in reducing bacterial adhesion I related to the stability of the stannous ions in aqueous solution and the rate at which they are taken up and retained by specific bacteria. The accumulation of tin in bacteria may alter their metabolism and other physiochemical characteristics.
- the aims of the present work are to determine the rates of growth and dissolution of pure calcium fluoride in aqueous suspensions and possible mechanisms controlling these processes, and to study the properties of the calcium fluoride-like material formed by adding fluoride to systems containing hydroxyapatite crystals and/or dissolved calcium and phosphate, simulating the type of calcium fluoride-like material formed on dental enamel as a result of topical treatment with acidified solutions of high fluoride content.”
- CaF 2 or a CaF 2 -like material/phosphate-contaminated CaF 2 is a major reaction product during topical treatment of dental hard tissues. Recently, evidence has suggested that CaF 2 is formed not only on surfaces but also to some extent in the enamel. The minimum concentration of fluoride required for CaF 2 formation is not well known and may depend on whether calcium is available from plaque fluid or only through dissolution of the dental hard tissue. Furthermore surface adsorption of fluoride to crystals may cause local concentrations necessary for CaF 2 formation. It has been suggested that CaF 2 acts as a pH-controlled reservoir of fluoride. The rate-controlling factor appears to be phosphate, which controls the dissolution rate of CaF 2 at high pH.
- CaF 2 formed at low pH contains less internal phosphate which has been shown to be less soluble. This may be of clinical significance for fluoride applied topically a few times per year.”
- fluorhydroxyapatite The interaction between the fluoride ion and dental hard tissues has been investigated extensively since modern fluoride research started in the 1940s. The chemistry of this process is complicated due to many impurities in hydroxyapatite-like carbonate and magnesium and to a large variety of fluoride concentrations, pH and composition of the agents used in caries prevention. During pH cycling in plaque, fluoride may exchange with hydroxyl in the apatite and a series of solids with intermediate composition and crystallographic properties are formed known as fluorhydroxyapatite.”
- CaF 2 is the major or probably the only reaction product on dental hard tissues from short treatments with relatively concentrated fluoride agents (Cruz et. al., Scand. J. Dent. Res., 1992; 100:154-158). Without doubt, this pH-controlled depot of CaF 2 plays a major role in the cariostatic effect of topical fluoride. CaF 2 has been detected on dental hard tissues weeks and months after a single topical fluoride treatment ⁇ Caries Res., 1991 , 25:21 -26) and is the only logical way to explain that such treatments have a cariostatic effect. By treating enamel samples subjected to topical fluoride treatment with KOH, the cariostatic effect is lost (0gaard, et al., J.
- hydroxyapatite In the presence of low concentrations of fluoride in solution (such as saliva or plaque fluid), hydroxyapatite might be dissolved below the critical pH (for hydroxyapatite), but the released mineral ions could be reprecipitated as fluoroapatite or a mixed fluor- hydroxyapatite. This mechanism prevents the loss of mineral ions, while providing additional protection to mineral crystallites by laying fluoride-rich other layers onto the apatite crystallites.”
- substantivity agent refers to a composition or combination of compositions that, when administered to oral cavity surfaces with biofilm, using the methods of treatment of the present invention enhance the retention of stannous fluoride and calcium to said oral cavity surfaces.
- aqueous-free, brushing gels are attributed to the unique substantivity properties indicated by the brushing gels of the invention.
- preferred substantivity agents for the brushing gels include various aqueous-free emulsions of polydimethylsiloxane/polymers in nonionic surfactants at viscosities of at least about 10,000 cs.
- substantivity agents form mucoadhesive gels in the presence of saliva, which are substantive to biofilm-coated enamel and gradually dissolve under saliva flow, releasing stannous fluoride onto the biofilm on the enamel at a pH of at least about 3; thereby effecting EPF and ERF values of at least about 2.5 and about 200, respectively, using the methods of treatment of the present invention.
- substantivity agents include saliva soluble, aqueous-free emulsions comprised of: polydimethylsiloxane polymers in solid, nonionic surfactants, as described in U.S. Patents: 5,032,387; 5,098,71 1 ; 5,538,667; 5,645,841 ; 5,651 ,959; having the following structural formula:
- liquid nonionic surfactants comprise the continuous phase of the aqueous-free emulsions.
- PDMS polydimethylsiloxane
- Particularly preferred are aqueous-free emulsions with a liquid, nonionic surfactant continuous phase and a discontinuous PDMS phase at viscosities between 1 0,000 cs and 2.5 million cs.
- Solid surfactants, useful as adjuncts to the liquid nonionic surfactant continuous phase are described in detail in U.S. 5,651 ,959. These liquid and liquid/solid nonionic surfactant emulsions form mucoadhesive gels in the presence of saliva.
- Preferred polydimethylsiloxanes are selected from the group consisting of polydimethylsiloxane: at 1 500 cs, at 1 0,000 cs, at 100,000 cs, at 250,000 cs, at 500,000 cs, at 750,000 cs, at 1 .5 million cs, at 2.2 million cs, at 2.5 million cs and combinations thereof.
- copolymers described below are useful as substantivity enhancers; when combined with the aqueous-free, substantivity agents in the methods of treatment of the present invention.
- substantivity enhancers include various linear polymeric, polycarboxylates, such as: copolymers of sodium and calcium salts of methyl/vinyl/ether/maleic acid including those copolymers available commercially as Gantrez® MS-955 polymer, a mixed sodium and calcium salt of methyl/vinyl/ether/maleic acid copolymer; where the cations form salt bridges which cross-link the polymer chains.
- m is an integer that provides molecular weight for the polymer between about 60,000 and about 1 ,000,000.
- Preferred are 1 :4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (maleic anhydride) having a molecular weight of about 30,000 to about 1 ,000,000.
- Sodium and calcium salts of carboxymethyl cellulose ether polymers can also be used including sodium and calcium salts of carboxymethyl cellulose ether, hydroxyethyl cellulose ether, sodium cellulose ether, etc.
- stannous fluoride brushing gel samples used in the methods of treatment of the present invention, were prepared, as described below; and subsequently tested for EPF and/or ERF values, as described in Tables 2 through 8 below:
- Example 1 In a stainless steel 1 L mixing vessel, using an overhead stirrer, 26.966 gm of PEG 400 were added along with 82.768 gm of glycerin, and 48.78 gm of 1 .64% stannous fluoride in glycerin. Stirring was begun at a low speed while heating to 80 Q C. Then 2.84 gm of L- 1220/2.5 million PDMS cs (10%) ULTRAMULSION® substantivity agent was added with stirring for 15 minutes. The overhead stirrer speed was increased to medium and 1 .88 gm of Gantrez MS-955 substantivity enhancer was added with stirring for 5 minutes.
- Crodasinic L 1 .42 gm; Sucralose, 0.1 8 gm; and insoluble saccharin, 0.56 gm were added with continued stirring for 10 minutes.
- TEGO betaine CKD 1 .42 gm, was added and stirred for 5 minutes.
- Sipernat 22S 28.3 gm was added with stirring 2 minutes between each addition.
- Sipernat 22S was all added, stirring continued for 15 minutes after which Vanillamint, 1 .32 gm, and Multisensate flavor, 0.1 14 gm, were added with continued stirring for 5 minutes.
- the stirrer was removed and the gel was filled into dispensing tubes. When used as a brushing gel, a pleasant, refreshing mouthfeel and very little metallic taste is perceived.
- Example 2 Using the procedure described in Example 1 , a second brushing gel was formulated without the Gantrez MS-955 substantivity enhancer.
- Another lactic acid solution was prepared by diluting two moles lactic acid to 2000 ml with distilled water.
- the solution of lactic acid and sodium hydroxide was placed in a 4000 ml beaker, and pH electrodes placed in the solution.
- the 1 .0 M lactic acid solution was used to adjust the pH of the buffered solution to 4.5.
- the 1 .0 M buffer was diluted by a factor of 10 with distilled water.
- the test was performed using preheated (37 °C) tooth sets and lactate buffer.
- the deprotected tooth sets were mounted on 1 /4 inch diameter acrylic rods with molten red boxing wax.
- Multiplaced stirrers were used for treatments and the etches. All slurries and solutions were pre-heated to 37 °C. The actual treatments and etches were carried out on the bench top with the preheated solutions.
- Plastic specimen containers 120 ml) were used for the etching procedure. A 1/4 inch hole was drilled in each container lid to accommodate the plastic rod to which the tooth sets were mounted.
- a 40 ml portion of 0.1 M lactic acid buffer was placed in each container along with a one-inch magnetic stirring bar.
- the rod of the first tooth set was pushed through the hole in the lid, placed in the first container and adjusted so that all enamel surfaces were immersed into the buffer solution.
- the container was then placed on the first magnetic stirrer and stirring was begun. The timer was started at this time. At 30-second intervals the other tooth sets were started in the same manner.
- the first set was stopped and the lid and tooth set immediately removed from the container and placed in a tray of distilled water to terminate etching.
- the other sets were similarly removed at 30 second intervals in the same order that they were initiated and the lactate buffer solutions was retained for phosphorus analysis.
- the tooth sets were placed back in the 37 °C water bath in preparation for the fluoride treatment step.
- the treatments were performed using slurries of the fluoride brushing products.
- the slurries consisted of 1 part fluoride brushing product and 3 parts preheated (37 Q C) distilled water (9g :27ml). Each slurry was mixed for exactly one minute after adding the water.
- the slurries were NOT prepared ahead of time. They were NOT centrifuged. All tooth sets were treated at the same time (one for each fluoride brushing product).
- the treatment procedure was similar to the etching procedure with the exception of the slurry in place of the acid.
- a 30 ml portion of the preheated fluoride brushing slurry was added to the first tooth set, the teeth were immersed in the slurry and the container placed on the first stirrer.
- the stirrer and timer were started. At 90-second intervals (to allow time for stirring), the other tooth sets were started in the same manner. At the end of the five minutes of treatment, the first set was stopped, the tooth set removed and rinsed well with distilled water. The other sets were removed at 90-second intervals and rinsed well. The treatment fluoride brushing slurries were discarded.
- a second acid exposure was then performed by the same method as the pre-treatment etch and the lactate buffer solutions were again retained for phosphorus analysis.
- the pre and post-treatment solutions were analyzed using a Klett-Summerson Photoelectric Colorimeter.
- the tooth sets were deprotected and the procedure repeated additional times so that each fluoride brushing product was treated and assayed on each tooth set.
- the treatment design was a Latin Square design so that no treatment followed another treatment consistently.
- the percent of enamel solubility reduction was computed as the difference between the amount of phosphorus in the pre and post acidic solutions, divided by the amount of phosphorus in the pre solution and multiplied by 100.
- Placebo (deionized water)
- Positive control 1 Crest® PRO-HEALTH® Toothpaste with stannous fluoride @ 1 100 ppm fluoride
- Positive control 2 ClinPro® 5000 Toothpaste with sodium fluoride at 5000 ppm fluoride
- Test Gel with stannous fluoride at 970 ppm fluoride composition as described hereinafter in Example 1 was used in a method of treatment of the present invention.
- the deionized water negative control was not effective in reducing enamel solubility.
- the positive fluoride containing controls and the test gel were significantly more effective than the deionized water negative control.
- the Clinpro 5000® toothpaste was significantly more effective than the negative control.
- the method of treatment of the present invention using the Test Gel was significantly more effective than the other two positive controls in reducing enamel solubility. The results are shown in Table 2 below:
- the fluoride uptake was established by analyzing fluoride and calcium levels of enamel pre-treatment and enamel post-treatment to determine the change in enamel fluoride attributed to treatment with fluoride containing brushing products.
- Each enamel specimen was then etched by immersion into 0.5 ml of 1 M HCI0 4 for 15 seconds. Throughout the etch period, the etch solutions were continuously agitated. A sample of each solution was then buffered with TISAB(fluoride ion probe buffer) to a pH of 5.2 (0.25 ml sample, 0.5 ml TISAB and 0.25 ml 1 N NaOH) and the fluoride content of the solution determined by comparison to a similarly prepared standard curve (1 ml std + 1 ml TISAB). For use in depth of each calculation, the Ca content of the etch solution was determined by taking 50 ⁇ and analyzing for Ca by atomic absorption (0.05 ml qs to 5 ml). These data was the indigenous fluoride level of each specimen prior to treatment.
- the treatments were performed using slurries of the various fluoride containing brushing products.
- the flurries consisted of 1 part fluoride containing brushing product and 3 parts distilled water (9g:27ml). Each slurry was mixed for exactly one minute after adding the water. The slurries were NOT prepared ahead of time. They were NOT centrifuged. The 12 specimens of each group were then immersed into 25 ml of their assigned slurry with constant stirring (350 rpm) for 30 minutes. Following treatment, the specimens were rinsed with distilled water. One layer of enamel was then removed from each specimen and analyzed for fluoride and calcium as outlined above (i.e. 15 second etch). The pretreatment fluoride (indigenous) level of each specimen was then subtracted from post treatment, fluoride value to determine the change in enamel fluoride due to the last treatment.
- Test Products The test fluoride containing brushing products were coded as follows:
- a method of treatment of the 47 ⁇ 5 3003 ⁇ 212 2956 ⁇ 212 13.36 ⁇ 0.26 300 present invention using a Brushing
- the anchor stirrer was increased to medium speed and Gantrez MS-955, 47 gm, was added with stirring and homogenizing for 5 minutes.
- Crodasinic L 35.5 gm
- TEGO Betaine CKD 35.5 gm
- Micronized (20 micron D50) calcium fumarate, anhydrous, 71 gm was added with stirring for 5 minutes.
- Micronized (20 micron) sodium phosphate monobasic, anhydrous, 15.3 gm was added with stirring for 5 minutes.
- Sident 22S, 707.5 gm was added in increments at 2 minutes between additions until all was added. Stirring was continued for 15 minutes.
- the vessel was cooled to ambient temperature over 15 minutes.
- the contents were dispensed into tubes for use.
- the brushing gel was pleasant testing with no stannous fluoride aftertaste.
- Stannous fluoride stability testing was performed on the product. Discussion of EPF and ERF values established by in vitro testing
- the ERF values, reported in Table 3 and Fig. 2 for using Crest® PRO- HEALTH® and Clinpro 5000® toothpastes are 170 and 65 respectively, compared to an ERF for the methods of treatment of the present invention using a stannous fluoride brushing gel of 300.
- the ERF values reported in Table 7 and Fig. 6 of the Drawings for Crest® PRO-HEALTH® toothpaste is 210 compared to an ERF for the methods of treatment of the present invention using a Stannous Fluoride Brushing Gel, 1070.
- a drop in pH follows exposure of plaque to sucrose which removes some anionic groups by neutralization, thereby liberating calcium and fluoride (as CaF + ) at the very sites where these moieties can do the most good.
- Stannous fluoride produces a marked reduction in calcium binding affinity accompanied by an approximate doubling of the calcium binding capacity.
- divalent cation binding to plaque is bidentate.
- Fluoride competes with macromolecular anionic groups, causing binding to become monodentate. Release of fluoride formed by calcium bridging, is accompanied by release of calcium, which potentiates the cariostatic effect of fluoride.
- fluoride binding produces a marked reduction in calcium binding affinity, along with a doubling of calcium binding capacity. This indicates that calcium binding changes from bidentate to monodentate. This shift from bidentate to monodentate is a consequence of fluoride replacing anionic group as one of the calcium ligends.
- the anionic groups to which calcium is no longer bound are then free to bind a CaF + ion pair, resulting in a doubling of the calcium binding capacity. Release of fluoride, bound by calcium bridging into plaque fluid, may be accompanied by a release of calcium which will potentiate the cariostatic effect of fluoride.
- CaF + is taken up by hydroxyapatite and is responsible for the EPF and ERF in vitro data reported for the methods of treatment of the present invention.
- the ERF values reported in Tables 3 through 8 and Figures 2 through 6 of the Drawings suggest that the CaF + moiety is incorporated into the hydroxyapatite lattice during remineralization methods of treatment of the present invention.
- the methods of treatment of the present invention using brushing gels set a new, oral care standard for Enamel Protection and Enamel Repair, while dramatically reducing exposure to elevated fluoride levels in various fluoride varnishes, gels and toothpastes.
Abstract
Description
Claims
Priority Applications (5)
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JP2016561820A JP2017510618A (en) | 2012-10-12 | 2015-04-10 | How to protect and repair enamel |
CA2945330A CA2945330C (en) | 2014-04-11 | 2015-04-10 | Methods for protecting and repairing enamel |
AU2015243217A AU2015243217A1 (en) | 2014-04-11 | 2015-04-10 | Methods for protecting and repairing enamel |
EP15776096.8A EP3128999A4 (en) | 2014-04-11 | 2015-04-10 | Methods for protecting and repairing enamel |
CN201580031104.1A CN106456514A (en) | 2014-04-11 | 2015-04-10 | Methods for protecting and repairing enamel |
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US14/251,104 US9604078B2 (en) | 2012-10-12 | 2014-04-11 | Methods for protecting and reparing enamel |
US14/251,104 | 2014-04-11 |
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EP (1) | EP3128999A4 (en) |
CN (1) | CN106456514A (en) |
AU (1) | AU2015243217A1 (en) |
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- 2015-04-10 WO PCT/US2015/025375 patent/WO2015157675A1/en active Application Filing
- 2015-04-10 CN CN201580031104.1A patent/CN106456514A/en active Pending
- 2015-04-10 AU AU2015243217A patent/AU2015243217A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
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AU2015243217A1 (en) | 2016-11-03 |
CA2945330C (en) | 2023-04-18 |
CN106456514A (en) | 2017-02-22 |
EP3128999A4 (en) | 2017-11-22 |
CA2945330A1 (en) | 2015-10-15 |
EP3128999A1 (en) | 2017-02-15 |
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