WO2015157683A1 - Pâte dentifrice pour la protection et la réparation de l'émail - Google Patents

Pâte dentifrice pour la protection et la réparation de l'émail Download PDF

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Publication number
WO2015157683A1
WO2015157683A1 PCT/US2015/025391 US2015025391W WO2015157683A1 WO 2015157683 A1 WO2015157683 A1 WO 2015157683A1 US 2015025391 W US2015025391 W US 2015025391W WO 2015157683 A1 WO2015157683 A1 WO 2015157683A1
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Prior art keywords
fluoride
toothpastes
enamel
calcium
substantivity
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PCT/US2015/025391
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English (en)
Inventor
William A. Mchale
Dale G. Brown
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Premier Dental Products Company
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Publication date
Priority claimed from US14/251,220 external-priority patent/US9616004B2/en
Application filed by Premier Dental Products Company filed Critical Premier Dental Products Company
Priority to EP15777496.9A priority Critical patent/EP3129000A4/fr
Priority to CN201580031184.0A priority patent/CN106456515A/zh
Priority to JP2016561819A priority patent/JP2017510617A/ja
Priority to CA2945337A priority patent/CA2945337C/fr
Priority to AU2015243225A priority patent/AU2015243225B2/en
Publication of WO2015157683A1 publication Critical patent/WO2015157683A1/fr
Priority to AU2020200179A priority patent/AU2020200179A1/en

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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
    • 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
    • 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
    • A61K8/24—Phosphorous; Compounds thereof
    • 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
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/30—Characterized by the absence of a particular group of ingredients
    • A61K2800/31—Anhydrous

Definitions

  • the present invention is directed to advances in enamel protectant and enamel repair, aqueous-free, stannous fluoride, toothpastes; 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 for the toothpastes of the present invention comprise: stannous fluoride and calcium in aqueous-free, substantivity agents.
  • Dentifrices Dentifrices containing 850 to 1 , 150 ppm theoretical total
  • Fluoride dentifrices have been shown in numerous clinical trials to be effective anticaries agents [Stookey, J. Dent. Res. 1 990, 69(Special Issue): 805-81 2] 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 toothpastes 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 1500 ppm fluoride, the maximum level provided for 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, 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 are generally applied professionally, at a frequency of about once every six months with the target audience comprising primarily children.
  • 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 (ERF) 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.
  • Teepaste is defined as: an abrasive-based paste suitable for administration of stannous fluoride to enamel surfaces by brushing with a toothbrush.
  • “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.
  • Nonionic surfactant is defined as: a 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.
  • Emsion continuous phase is defined as: an emulsion component that surrounds discontinuous phase component.
  • the present invention is directed to aqueous-free, toothpaste compositions and associated methods for treatment and methods of manufacture, wherein the toothpastes contain stannous fluoride from between 850 and about 1500 ppm fluoride, in an aqueous-free, substantivity agent.
  • the toothpastes of the present invention protect and repair enamel more effectively than toothpastes and toothpaste compositions containing comparable or substantially higher levels of fluoride, as indicated by comparative EPF and ERF values reported herein.
  • stannous fluoride at fluoride levels from between about 850 and about 1 500 ppm fluoride and calcium ;
  • the enamel protectant and enamel repair, toothpaste compositions of the present invention when brushed onto enamel, form substantive, mucoadhesive gels on enamel in the presence of saliva; which mucoadhesive gels gradually release the stannous fluoride 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 risks associated with elevated fluoride levels.
  • FIG. 1 of the Drawings summarizes comparative, in vitro, enamel protectant factor (EPF) values for enamel treated with a toothpaste of the present invention with stannous fluoride at 1 150 ppm fluoride; compared with : (a) an Rx 5000 ppm, sodium fluoride toothpaste, and (b) an OTC, 900 ppm, stannous fluoride toothpaste.
  • EPF enamel protectant factor
  • FIGS 2 through 5 of the Drawings illustrate enamel repair factor (ERF) values for toothpastes of the present invention with compositions, as described in Examples 1 through 5, with stannous fluoride at: 1 100, 1 148 and 1 150 ppm stannous fluoride 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 2 through 5 present ERF values for toothpastes of the present invention comprising compositions, as described in Examples 1 through 5.
  • These toothpastes of the present invention contain stannous fluoride at levels of: 1 100, 1 148 and 1 1 50 ppm stannous fluoride, compared with: (a) a 900 ppm sodium fluoride toothpaste, and (b) an 1 1 00 ppm stannous fluoride toothpaste, (c) a 5000 ppm sodium fluoride toothpaste or (d) a 900 ppm fluoride toothpaste.
  • Figures 2 through 5 of the Drawings illustrate enamel repair factor (ERF) for toothpastes of the present invention with compositions as described in Examples 1 through 5.
  • ERP enamel repair factor
  • These toothpastes of the present invention contain stannous fluoride at levels of: 1 1 00, 1 148 and 1 150 ppm stannous fluoride compared with 1 000 ppm stannous fluoride toothpaste, 900 ppm sodium fluoride toothpaste and 5000 ppm sodium fluoride toothpaste.
  • Aqueous-free, stannous fluoride, toothpastes of the present invention 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 onto enamel surfaces with biofilm as they dissolve. This gradual dissolution feature of these mucoadhesive gels minimizes saliva "wash-out" of enamel protectant and enamel repair ingredients by gradually releasing these ingredients onto enamel surfaces with biofilm.
  • the substantivity agents of the present invention extend the duration of enamel protectant and enamel repair treatments and support cation bridging associated with microbial fluoride binding, thereby enhancing the EPF and ERF values of various toothpastes of the present invention, while simultaneously reducing the level of fluoride required to achieve the unexpected increases in EPF and ERF values.
  • calcium and phosphate components are included in the toothpastes. These are described by Ming Tung in U.S. Patents: 5,037,639; 5,268,1 67; 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® M955 available from International Specialty Products, Wayne, NJ, USA.
  • the aqueous-free, substantivity agents 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.
  • this mucoadhesive, substantivity agent is totally dissolved by saliva, releasing the balance of unreacted enamel protectant and enamel repair ingredients onto saliva and biofilm coated, enamel surfaces.
  • Aqueous-free, toothpastes of the present invention contain enamel protectant and enamel repair ingredients, suitable for protecting and repairing dental enamel ; wherein : said aqueous-free, toothpastes inhibit premature reaction of the enamel protectant and enamel repair ingredients;
  • the enamel protectant and enamel repair ingredients are introduced onto enamel with biofilm via saliva that solubilizes substantivity agents that are substantive to: enamel, dentin, biofilm and pellicle; the enamel protectant and enamel repair ingredients contained in the 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; and
  • saliva soluble, aqueous-free emulsions used as substantivity agents include those emulsions that are comprised of polydimethylsiloxane polymers in 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:
  • aqueous-free, saliva soluble emulsions for use as substantivity agents of the present invention include aqueous-free emulsions comprising a nonionic surfactant continuous phase and a discontinuous phase of polydimethylsiloxane (PDMS) at viscosities ranging from between about 1500 cs and about 2.5 million cs.
  • aqueous-free emulsions include a nonionic surfactant continuous phase and a discontinuous phase PDMS at viscosities between 1 0,000 cs and 2.5 million cs.
  • 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.
  • Foam modulators are useful in the present invention. These include, without limitation: materials operable to control amount, thickness or stability of foam generated by the composition (e.g., dentifrice 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
  • Humectants useful for the present invention include, without limitation : polyhydric alcohols such as glycerin, sorbitol, xylitol or low molecular weight PEGs.
  • humectants can prevent hardening of the toothpastes upon exposure to air.
  • humectants also function as sweeteners.
  • compositions including, for example, additional: mouth-feel agents, pH modifying agents, flavorants, sweeteners, additional anticalculus and Antiplaque agents, abrasives, polishing agents, antimicrobial (e.g. antibacterial) agents such as those described in U.S. Pat. No. 5,776,435, saliva stimulants, anti-inflammatory agents, H2 antagonists, nutrients, vitamins, proteins, antioxidants, colorants, or additional active materials useful for the prevention or treatment of a condition or disorder of hard or soft tissue of the oral cavity, the prevention or treatment of a physiological disorder or condition, or to provide a cosmetic benefit
  • additional: mouth-feel agents, pH modifying agents, flavorants, sweeteners, additional anticalculus and Antiplaque agents, abrasives, polishing agents, antimicrobial (e.g. antibacterial) agents such as those described in U.S. Pat. No. 5,776,435, saliva stimulants, anti-inflammatory agents, H2 antagonists, nutrients, vitamins, proteins, antioxidants, colorants, or additional active materials useful for the prevention
  • the toothpastes of the present invention contain ingredients that substantially effect enamel protection factor (EPF) and enamel repair factor (ERF) values. These include:
  • Substantivity agents and substantivity enhancers including: mixed sodium and calcium salt copolymers of methyl/vinyl/ether/maleic acid;
  • stannous fluoride, calcium and phosphate components remain unreacted and the pH of the toothpaste when administered to saliva coated enamel is at least about 4.
  • the amount of stannous fluoride in the toothpastes of the present invention, applied to the toothbrush (dose) is not as important as the concentration of available stannous fluoride in the toothpaste.
  • reducing fluoride concentration in brushing products has been reported not to be as effective as regular concentration fluoride products.
  • the extraordinary EPF and ERF values of the toothpastes of the present invention allow for reducing stannous fluoride concentrations while effecting acceptable fluoride protection and uptake results.
  • the fluoride dose is important in regard to enamel fluorosis in children under six years of age, due to fluoride toothpaste ingestion. For this reason, reducing the amount of stannous fluoride applied with the toothpastes of the present invention is a preferred strategy over lowering the dose of stannous fluoride toothpastes of the invention intended for use by children under six years of age.
  • Stannous fluoride toothpastes of the present invention 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 has the potential to remineralize even at pH values typically regarded as demineralizing.
  • 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.”
  • CaF2 or a CaF2-like material/phosphate-contaminated CaF2 is a major reaction product during topical treatment of dental hard tissues. Recently, evidence has suggested that CaF2 is formed not only on surfaces but also to some extent in the enamel. The minimum concentration of fluoride required for CaF2 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 CaF2 formation. It has been suggested that CaF2 acts as a pH-controlled reservoir of fluoride. The rate-controlling factor appears to be phosphate, which controls the dissolution rate of CaF2 at high pH.
  • CaF2 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.”
  • CaF2 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., 1 992; 100:1 54-158). Without doubt, this pH-controlled depot of CaF2 plays a major role in the cariostatic effect of topical fluoride. CaF2 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, enhance the retention of stannous fluoride and calcium to said biofilm containing oral cavity surfaces.
  • aqueous-free, stannous fluoride toothpastes of the present invention are attributed to the unique substantivity properties indicated by the toothpastes of the invention.
  • preferred substantivity agents for the stannous fluoride toothpastes of the present invention 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.
  • substantivity agents include saliva soluble, aqueous-free emulsions comprised of:
  • PDMS polydimethylsiloxane
  • 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 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 500,000.
  • 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.
  • Example 1 The following stannous fluoride toothpaste samples were prepared, as described below, and subsequently tested for EPF and/or ERF values, as described in Tables 1 through 8 and Figures 1 through 5 below:
  • Example 1 The following stannous fluoride toothpaste samples were prepared, as described below, and subsequently tested for EPF and/or ERF values, as described in Tables 1 through 8 and Figures 1 through 5 below:
  • a 5 liter Ross/Olsa vacuum mixer kettle with internal homogenizer was heated to 60 degrees C while the vessel was charged with 592.225 gm of anhydrous glycerin.
  • Crodasinic L, 53.5 gm and TEGO betaine, 53.5 were added and homogenized at 1500 RPM for 10 minutes under vacuum.
  • 942.1 gm of PEG 400 was added along with ULTRAMULSION® [poloxamer 407 (80%)] and 2.5 million cs polydimethylsiloxane (20%), 64.5 gm, with homogenizer speed at 1500 rpm for 10 minutes.
  • Additional glycerin 592.225 gm, was added along with acesulfame K, 21 .0 gm, titanium dioxide, 53.5 gm, calcium sulfate, 97.0 gm, micronized (20 micron) sodium phosphate monobasic, 17.4 gm, and Gantrez MS-955, 1 07.5 gm.
  • the homogenizer at 1500 rpm was begun and continued for 15 minutes under vacuum. The contents were cooled to 25 degrees C and 1 .64% stannous fluoride in glycerin, 1443.5 gm, was added to the kettle.
  • the homogenizer was set at 1000 rpm under vacuum for 10 minutes and stopped.
  • Example 2 In a stainless steel 500 ml_ mixing vessel, using an overhead stirrer, 34.26 gm of PEG 400 were added along with 49.406 gm of glycerin, and 57.74 gm of 1 .64% stannous fluoride in glycerin. Stirring was begun at a low speed while heating to 80 Q C. Then 2.58 gm of poloxamer 407/2.5 million cs (10%) ULTRAMULSION® substantivity agent was added with stirring for 15 minutes. The overhead stirrer speed was increased to medium and 4.3 gm of Gantrez MS-955 substantivity enhancer was added with stirring for 5 minutes.
  • Crodasinic L 2.14 gm; Sucralose, 0.344 gm; and acesulfame K, 1 .074 gm were added with continued stirring for 10 minutes.
  • TEGO betaine CKD 2.14 gm, was added and stirred for 5 minutes.
  • Sident 22S 26.0 gm was added with stirring 2 minutes between each addition.
  • the stirrer was removed and the toothpaste was added to dispensing tubes. When used as a toothpaste, a pleasant, refreshing mouthfeel and very little metallic taste is perceived.
  • Crodasinic L 2.14 gm; Sucralose, 0.344 gm; and acesulfame K, 1 .074 gm were added with continued stirring for 10 minutes.
  • TEGO betaine CKD 2.14 gm, was added and stirred for 5 minutes.
  • Sident 22S 26.0 gm was added with stirring 2 minutes between each addition.
  • the stirrer was removed and the toothpaste was added to dispensing tubes. When used as a toothpaste, a pleasant, refreshing mouthfeel and very little metallic taste is perceived.
  • Crodasinic L 2.14 gm; Sucralose, 0.344 gm; and acesulfame K, 1 .074 gm were added with continued stirring for 10 minutes.
  • TEGO betaine CKD 2.14 gm, was added and stirred for 5 minutes.
  • Sident 22S 26.0 gm was added with stirring 2 minutes between each addition.
  • Example 5 A 5 liter Ross/Olsa vacuum mixer with internal homogenizer was heated to 80 degrees C while the vessel was charged with 942.1 gm of PEG 400, 1 184.45 gm of anhydrous glycerin and 1443.5 gm of 1 .64% stannous fluoride/glycerin. Anchor stirring at slow speed was begun and continued for 7 minutes.
  • ULTRAMULSION® polyoxamer 407 (80%)] and 2.5 million cs polydimethylsiloxane (20%), 64.5gm, was added with homogenizer speed adjusted to 2500 rpm for 1 5 minutes.
  • the anchor stirrer was increased to medium speed and Gantrez MS-955, 107.5 gm, was added with stirring and homogenizing for 5 minutes.
  • Crodasinic L 53.5 gm, was added with continued stirring for 5 minutes.
  • TEGO Betaine CKD 53.5 gm, was added and stirring continued for 5 minutes.
  • Micronized (20 micron) sodium phosphate monobasic, anhydrous, 1 7.4 gm was added with stirring for 5 minutes.
  • Sident 22S 650 gm, was added in increments at 2 minutes between additions until all was added. Stirring was continued for 1 5 minutes.
  • 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 1 0 with distilled water.
  • 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.
  • 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 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.
  • the deionized water negative control was not effective in reducing enamel solubility.
  • the positive fluoride containing controls and the test toothpaste were significantly more effective than the deionized water negative control.
  • the Clinpro 5000® toothpaste was slightly, significantly more effective than the negative control.
  • the test toothpaste was dramatically superior to the two positive controls (by a factor of 10).
  • test procedure was identical to the procedure identified as Procedure 40 in the FDA anticaries Monograph, except the lesions were formed using a solution comprising 0.1 M lactic acid and 0.2% Carbopol 907, wherein the solution was saturated with HAP(hydroxyapatite) at a pH of 5.0.
  • 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 HCI04 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.
  • TISAB fluoride ion probe buffer
  • the specimens were once again ground and polished as described above. An incipient lesion was formed in each enamel specimen by immersion into a 0.1 M lactic acid/0.2% Carbopol 907 solution for 24 hours at room temperature. These specimens were then rinsed well with distilled water and stored in a humid environment until used. 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 1 2 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. 1 5 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 fluoride containing toothpastes were coded as follows: 1 .
  • test fluoride containing toothpastes were coded as follows:
  • Test Toothpaste (stannous 47 + 5 4857 ⁇ 338 481 5 ⁇ 338 13.36 ⁇ 0.26 420 fluoride at 1 148 ppm fluoride)
  • Test Toothpaste (stannous 52+6 1948+68 1 902+70 15.28 ⁇ 0.56 166 fluoride at 1 148 ppm fluoride)
  • EPF at least about 1 .8
  • ERF at least about 140
  • EPF at least about 2.2
  • ERF at least about 1 80
  • EPF at least about 2.4
  • ERF at least about 1 65
  • Preferred, stannous fluoride toothpastes of the present invention show substantial improvement in EPF and ERF values compared to commercial toothpastes at various fluoride loads as reported in Tables 2 and 8 and Figs. 1 and 5 of the Drawings.
  • ERF values reported in Table 2 and Fig. 2 for Ml Paste Plus, OTC Stannous Fluoride paste and Clinpro 5000® Toothpaste are 31 , 34 and 50, respectively, compared to an ERF for the stannous fluoride toothpaste of the present invention described in Example 1 of 540.
  • This 1 0X plus improvement in ERF value over commercial toothpastes represents a major advance in fluoride uptake and enamel hardening effectiveness.
  • Such an advantage in enamel hardening efficiency is particularly critical to patients experiencing: rampant caries, coronal caries, cancer therapy treatments, mucositis treatments, immune deficiency treatments, bone marrow transplants, etc.
  • Stable fluoride in the toothpastes of the present invention produces marked reduction in calcium binding affinity and approximately doubles calcium binding capacity. In the absence of fluoride, calcium binding to biofilm is bidentate. Stable fluoride in the toothpastes of the present invention compete with biofilm causing calcium binding to biofilm to become monodentate. This allows the binding of about double the quantity of calcium and of CaF+ bound to biofilm. Release of fluoride bound by calcium bridging into biofilm fluid as a result of fluoride clearance into saliva will be accompanied by a corresponding release of calcium which, in turn, potentiates the cariostatic effect of fluoride as indicated in the in vitro testing described in Tables 2 through 8 and Figs. 1 through 5 of the Drawings.
  • At least some of the stable fluoride present in the toothpastes of the present invention is bound to calcium ions (sourced from various calcium salts in the present invention and/or calcium present in the copolymer substantivity enhancer, such as Gantrez® MS- 955). These calcium ions, in turn, are bound to biofilm associated with enamel.
  • 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.
  • the effectiveness of the toothpastes of the present invention depends on three factors: substantivity of the formulation to biofilm,
  • 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 an 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 compositions of the present invention.
  • the ERF values reported in Tables 2 through 8 and Figures 2 through 5 of the Drawings suggest that the CaF+ moiety is incorporated into the hydroxyapatite lattice during remineralization.
  • the toothpastes of the present invention set a new, oral care STANDARD for Enamel Protection and Enamel Repair, while dramatically reducing exposure to elevated levels in various fluoride varnishes, gels and toothpastes.

Abstract

L'invention concerne des pâtes dentifrice pratiquement anhydres, pour la protection de l'émail et la réparation de l'émail, contenant : du fluorure stanneux, du calcium et un agent de substantivité comprenant : une émulsion de polydiméthylsiloxane dans un tensioactif non ionique, où (a) la substantivité dudit fluorure stanneux et dudit calcium dans le biofilm présent sur l'émail est renforcée grâce à un déplacement de la liaison du calcium, d'un état bidenté à un état monodenté, en présence de fluorure stanneux ; et (b) ladite pâte dentifrice présente des valeurs sensiblement améliorées du facteur de protection de l'émail (EPF) et du facteur de réparation de l'émail (ERF) par comparaison avec des traitements de brossage au fluorure présentant des niveaux de fluorure comparables ou plus élevés.
PCT/US2015/025391 2012-10-12 2015-04-10 Pâte dentifrice pour la protection et la réparation de l'émail WO2015157683A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP15777496.9A EP3129000A4 (fr) 2014-04-11 2015-04-10 Pâte dentifrice pour la protection et la réparation de l'émail
CN201580031184.0A CN106456515A (zh) 2014-04-11 2015-04-10 牙釉质保护和修复牙膏
JP2016561819A JP2017510617A (ja) 2012-10-12 2015-04-10 エナメル質の保護及び修復練り歯磨き
CA2945337A CA2945337C (fr) 2014-04-11 2015-04-10 Pate dentifrice pour la protection et la reparation de l'email
AU2015243225A AU2015243225B2 (en) 2014-04-11 2015-04-10 Enamel protectant and repair toothpaste
AU2020200179A AU2020200179A1 (en) 2014-04-11 2020-01-09 Enamel protectant and repair toothpaste

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/251,220 US9616004B2 (en) 2012-10-12 2014-04-11 Enamel protectant and repair toothpaste
US14/251,220 2014-04-11

Publications (1)

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WO2015157683A1 true WO2015157683A1 (fr) 2015-10-15

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CN (1) CN106456515A (fr)
AU (2) AU2015243225B2 (fr)
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US20030165442A1 (en) * 1999-11-12 2003-09-04 The Procter & Gamble Company Method of protecting teeth against erosion
US20040126335A1 (en) * 1999-11-12 2004-07-01 The Procter & Gamble Company Method of enhancing fluoridation and mineralization of teeth
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Publication number Publication date
CA2945337C (fr) 2023-04-18
CN106456515A (zh) 2017-02-22
CA2945337A1 (fr) 2015-10-15
EP3129000A4 (fr) 2017-11-29
AU2020200179A1 (en) 2020-01-30
AU2015243225B2 (en) 2019-10-10
EP3129000A1 (fr) 2017-02-15
AU2015243225A1 (en) 2016-10-27

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