CA1123743A - Antinucleating agent in aqueous remineralizing composition comprising calcium, phosphorus, and fluoride - Google Patents
Antinucleating agent in aqueous remineralizing composition comprising calcium, phosphorus, and fluorideInfo
- Publication number
- CA1123743A CA1123743A CA331,247A CA331247A CA1123743A CA 1123743 A CA1123743 A CA 1123743A CA 331247 A CA331247 A CA 331247A CA 1123743 A CA1123743 A CA 1123743A
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- Prior art keywords
- stable aqueous
- aqueous composition
- phosphate
- calcium
- agent
- Prior art date
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Classifications
-
- 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
- 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
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
-
- 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
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8147—Homopolymers or copolymers of acids; Metal or ammonium salts thereof, e.g. crotonic acid, (meth)acrylic acid; Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
Abstract
ABSTRACT
A composition useful for remineralizing sub-surface carious lesions of dental enamel which contains sources of calcium ions and phosphate ions as well as fluoride ions and further includes as an agent to stabilize the composition against precipitation, an antinucleating agent such as ethylene-diamine tetramethylenephosphonic acid or water soluble salt thereof, the pH of the composi-tion being about 5 - 9, preferably close to physiological conditions, such as about 6.8 - 7.5.
A composition useful for remineralizing sub-surface carious lesions of dental enamel which contains sources of calcium ions and phosphate ions as well as fluoride ions and further includes as an agent to stabilize the composition against precipitation, an antinucleating agent such as ethylene-diamine tetramethylenephosphonic acid or water soluble salt thereof, the pH of the composi-tion being about 5 - 9, preferably close to physiological conditions, such as about 6.8 - 7.5.
Description
37~3 I~is invention relates to a stable aqueous composition which is effective to remineralize carious lesions in dental enamel.
It is kr.own that dental caries begin with lesions of so called "white spots", which are demineralized areas below the sur-fa oe of intact dental enamel. If unchecked, surfa oe enamel above a sub-surface lesion eventually collapses, leading to cavitation and subsequent loss of tooth structure.
In order to arrest demineralization, and, indeed, in order to remineralize "white spots" various compositions have been pro-posed. For instan oe, United States Patent No. 3,679,360 to Rubin et al discloses deposition of calcium phosphate frcm a gel onto a tooth surface. This, however, d oe s not reach the sub-surfa oe area where demineralization initially occurs. Further, because of the difficulty of maintaining both calcium ions and phosphate ions avail-able without precipitating a calcium phosphate material, two part kits have been proposed in which a calcium component and a phosphate co~ponent are sequentially applied to the oral cavity as in British Patent No. 1,408,922 to Raff et al and British Patent No. 1,452,125 to Grab~nstetter et al or mixed together shortly before such applica-tion to form a metastable system with temporary stability as in United States Patent 4,080,440 to DiGiulio et al and British Patent No. 1,509,977 to Levine. Another metastable solution has been des-cribed in United States Patent No. 4,097,588 to Levine. Fven this solution, however, is not substantially permanent and precipitation can occur, particularly when fluoride ions are present.
It is an advantage of this invention that a one-part stable aqueous remineralizing solution is suitably prepared 1~.2374~
as a dental mouthrinse and also can be incorporated into other dentifrice compositions such as a dental cream or gel, mouth spray, troche, chewable tablet, lozenge and the like.
Further advantages will be apparent from consideration of the following specification.
In accordance with certain of its aspects, this invention relates to a stable aqueous composition comprising water having dissolved therein a source of calcium ions and a source of phos-phate ions, the amount of calcium ions and phosphate ions being sufficient to effect remineralization of dental enamel; a compound which pro~ides fluoride anticaries agent; and an antinucleating agent selected from the group of acids and orally acceptable water-soluble salts thereof consisting of diamine tetramethylenephosphonic acids of the formula (M2o3PH2c)2N(cH2)nN(cH2po3M2)2~ whe ei integer from 1 to 10, phosphonoacetic acid or salt thereof of the formula M203PCH2COOM, a peroxydiphosphate of the formula M4P208, or an oligomer ~ 3 3 ~ H
a in which M is hydrogen or an orally acceptable cation, Rl,R2,R3, and R4 are independently hydrogen, methyl or ethyl, Y is at least one hydrophilic member of the group consisting of -COOM, -CONH2 and CH20H, X is at least one hydrophobic member of the group consisting of -CN, -COOR, -COOR50R, -CONHR and -COONHR5COR, R is Cl 8 alkyl, R5 is Cl 4 alkylene, a is 0-7 and a + b is about 4-15.
E~
l~;.Z3743 said solution having a pH of about 5 to about 9.
The antinucleating properties of the agents employed in the present invention appear to be effective to prevent precipitate formation from the calcium and phosphate ions of the solution part-icularly with the fluoride ions also present. As described in Ciba Foundation Sy~,posium, "Hard Tissue Growth, Repair and Remineraliza-tion (Elsevier), Associated Scientific Publishers, New York, 1973 in the article by Francis et al, "Chemical Agents in the Control of Calcification Processes in Biological Systems", pages 57-83, part-icularly at pages 75-78, an antinucleating agent (e.g. a diphosphon-ate) can in sufficient quantity at a physiological pH ccmpletely ab-sorb onto a spherical nucleated particle of hydroxyapatite as it forms and entirely block crystal grcwth. In this way, the formation of large insoluble crystals of apatite is prevented and coated small hydroxyapatite crystals of higher water solubility are attained.
It has been found that not all antinucleating agents can successfully stabilize calcium ions and phosphate ions in solution against precipitating to form large insoluble apatite crystals.
For instance, such insoluble crystals form when it is sought to use antinucleating agents such as sodium hexametaphosphate, sodium pyrophosphate, sodium phytate and mellitic acid as well as disodium phosphonoethane-1,2-dicarboxylate, l,l-diphosphonopropane-2,3-dicar-boxylic acid monohydrate, 3-amino-l-hydroxypropane-l,l-diphosphonic acid and imino-diacetic-N-methylene phosphonic acid. Gn the other hand, the antinucleating agents of the present invention sucoess-fully stabilize the calcium ions and phosphate ions against precipi-tation as large insoluble apatite crystals in solution at a 37 ~3 pH between about 5 and abou-t 9. Preferal)ly, the pll is adjusted to about 6.8 to about 7.5, whicll approximates usual human physiological conditions and is optimum for effecting remineralization. Desirably, the antinucleating agent of the invention is present in amount of about 1 to 500 ppm (1 x 10 6M to 1 x 10 3M) of the solution, pref-erably about 25 to 250 ppm (5 x 10 6M to 5 x 10 3M), such as about 225 ppm (5 x 10 4M)~
The antinucleating agent of the invention is desirably a diamine tetramethylenephosphonic acid of the formula (M203P112C)2-N~CH2)nN(C1~2P03M2)2 wherein n is an integer from 1 to 10 and M is hydrogen or an orally acceptable cation such as alkali metal (e.g. sodium or potassium), ammonium or Cl - C18 mono-, di - or trisubstituted ammonium (e.g. mono-, di - or tri-ethanolammonium) salt.
The polyamine polyphosphonic compounds which are most preferred are ethylenediamine tetra(methylenephosphonic acid), (hereinafter EDITEMPA) and its water-soluble orally acceptable salts, (e.g., sodium, potassium, and ammonium and other pharma-ceutically acceptable salts; most preferably the tri-, tetra- or penta-sodium salts), other polyamine polyphosphonic compounds include:
tetramethylenediamine tetra (methylenephosphonic acid), pentamethyl-ene diamine tetra (methylenephosphonic acid), hexamethylenediamine tetra (methylenephosphonic acid) and the water-solub]e salts of these acids, e.g., sodium, potassium, ammonium and other orally acceptable salts.
Phosphonoacetic acid (hereinafter PAA) and its watèr soluble orally acceptable salts are also desirable antinucleating agents.
They are characterized by the formula M203PC112COOM, wherein M has the meaning indicated above.
-The peroxydiphosphate ~hereinafter PODP) and particularly the alkali metal salts thereof (e.g. potassium or sodium) are likewise desirable antinucleating agents. They are characterized by the formula M4P208 wherein M has the meaning indicated above.
The desirable oligomer antinucleating agents and methods for their preparation are described in United States Patent Nos. 3,646,099 and 3,859,260. They have the formula:
1l IZ R3 R~
M03S - C 1_ 3 C - C- - H
wherein M is hydrogen or a water soluble orally acceptable cation (as indicated above); Rl, R2, R3 and R4 are independently H, methyl or ethyl; Y is at least one hydrophilic member of the group consisting of -COOM, -COHN2 and -CH20H; X is at least one hydrophobic member of the group consisting of -CN, -COOR, -COOR50R, -CONHR and -COONHR5COR, R
is Cl_8 alkyl; R5 is Cl_4 alkylene; a is 0-7; and a + b is about 4-15.
These oligomers are anionic and of relatively low and accurately regulated degree of polymerization, (in contrast to the conventional free radical redox polymerization conducted with an oxidative initiator such as hydrogen, alkyl, or acyl peroxides, persulfates or hydroperoxides in relatively large amounts and a reductive activator such as NaHS03, Na2S204 or ~.Z3743 sodium forn~ldehyde sulfoxylate in relatively low amounts generally added subsequently to the polymerization medium) æe prepared by a reductive poly-merization in which a much larger amount of a bisulfite salt, e.g. NaHS03 (sodium bisulfite, sodium acid sulfite), a reducing agent, is the initiator charge initially with the monamer, and an oxidixing agent is added in smaller amounts as the activator ~lring the polymerizing or oligomerizing process.
Subscript a in the formula represents the numher of moles of hydro-phobic groups, and subscript b the number of moles of hydrophilic groups, in the oligomer molecule. The proportion of X (i.e. the value of a) must be small enough, or even zero, to avoid the production of a too large, sticky and hydrophobic polymer molecule, and will of course be dependent for the most part in any particular instanoe on the identity of the X and Y groups, i.e. the hydrophobic-contaLnLng and hydrophilic aontaining monomeric react-ants. Mixtures of such oligomers may of course also be employed.
Examples of monamers containing hydrophilic Y group are acrylic acid, methacrylic acid, alpha-ethylacrylic acid, betamethylacrylic acid, alpha, beta-dimethylacrylic acid, orally acoeptable salts of these acids, for example those aontaining such cations as alkali metal (e.g. sodium and potassium), ~,.,~nium, Cl l8mono-, di- and tri- substituted ammonium (e.g.
alkanol substituted such as mono-, di~ and tri-ethanolammonium), etc., acryl-amide, methacrylamide, ethacrylamide, and alkyl alcohol and the like.
Examples of monamers aontaining hydrophobic X groups are acryl-onitrile, methacrylonitrile, ethacrylonitrile, methyl and ethyl and octyl acrylate and methacrylate, methoxyethyl acrylate, octaxyethyl methacrylate, ethoxybutyl methacrylate, prapoxymethyl acrylate, N-ethylacrylamide, N-iso-propylacrylamide, N-methylacrylamide, N-propylethacrylamide, vinyl aoetate, propionate and octanoate, diaoetone acrylamide and the like.
The oligamerization is carried out in water in the presen oe of a relatively large amcunt of the bisulfite reducing initiator, expressed in mols of monomer/gram formula weight (gFW) of reducing initiator is about 4 to 15, this ratio determuning the degree of oligamerization.
l~.Z3743 The reductive initiator is preferably a water soluble bisulfite salt (M in the formula), especially aLkali metal such as sodium or potassium, but bisulfite salts containing other orally acoeptable cations of the type referred to above may be employed.
In practice, enough oxidative activator is used to effect 100% con-version of the monamers to oligamers. The amount of such acti~ator, ex-pressed as gFW activator/gFW initiator may range from 0.0001 to 0.1 but usually is from about 0.001 to 0.1. Examples of these oxidative activators are ammonium, sodium potassium persulfate, hydrogen peroxide and other water soluble oxidants oommonly employed in the polymerizatian art.
Following campletion of the oligomerization reaction, any free carboxylic acids groups in the oligamer molecules may, if desired be part-ially or o~mpletely neutralized, preferably at least 60%, by treating the aqueous oligamer solution with a suitable base to convert such groups to their salts with orally acceptable cations as referred to a~ove. These aqueous oligamer solutians have a highly desirable low viscosity, and lcw molecular weight range depending on the monomer units in the oligamer.
It will be understood that the oligamer formula above is not in-tended to depict the actual structure of the oligomer molecule, the brac~eted units of which formula are randamly distributed in the molecule with the -SO3 M group being normally bonded to a terminal carbon atam in the oligamer chain devoid of X and or Y substituents. In the oligamers preferred for use herein, a is zero, Y is -COOM, Rl -R4 are H, and M is alkali metal, e.g.
sodium, b being about 10, as derived from acrylic acid. An oligomer of the formula above in the form of its sodium salt, with a molecular weight of abaut 1,000, containing about 10 acrylic acid monomeric units, is cammerci-ally available under the trade name ND-2 (a product of UniRoyal).
The effective antinucleating agents render the rem meralizing solu-tian stable at normally occurring temperatures, e.g., about 15C-40&. The remineralizing agents can diffuse effectively through an intact enamel sur-faoe in order to act on subsurfaoe lesions.
m e stability provided by the effective antinucleating agents pre-vents spontaneous precipitation on enamel surfa oe s ~m d thereby permits diffu-sion of the remineralizing components to subsurface lesions.
One or more sources of each calcium ions and phosphate ions may be employed. When the source is normally insoluble such as a calcium phosphate, it is solubilized during preparation of the solution, by maintaining an acid pH of about 6 or less (e.g., about 2.5 to 6) during preparation of the remineralizing solution, particularly before the effective antinucleating agent is added.
m e insoluble sources of calcium and phosphate ions may be a single compound such as tricalcium phosphate (which substantially corresponds to hydroxyapatite, Ca5 (P04)30H or 3Ca3 (P04)2Ca (OH)2), bone meal or dicalcium phosphate (dihydrate or anhydrous). In solution, particularly in the pre-sen oe of fluoride ions, formation of hydroxyapatite, fluorohydroxyapatite and fluoroapatite occurs.
Examples of other normally water-soluble or normally water-insol-uble (but soluble at pH of about 6 or less) sources of calcium ion, but not phosphate ion, which can be used in the remineralizing solution of the inven-tion include calcium salts with a oe tate, gluconate, nitrate, stearate, lactate, formate, molybdate, tungstate, sulfate, alkyl sulfonate (e.g., lauryl sulfonate), oleate, tartrate, sorbate, iodate, silicate, aluminate, benzoate, citrate, fumarate, butyrate, isobutyrate, malate, maleate, propion-ate, valerate and the like. Mixtures of such calcium sources with each other or with calcium phosphate may be employed.
Examples of sources of phosphate ion, but not calcium ion, which can be used in the remineralizing solution of the invention include the normally water-soluble or normally water-insoluble (but soluble at pH of about 6 or less) salts including alkali metal (e.g. sodium and potassium), ammonium, magnesium, barium and strontium orthophosphates and acid orthophos-phates, metaphosphates, pyrophosphates, as well as glycerophosphates, "
1~.231743 fructose-6-phosphate, sorbitol-6-phosphate, glucose-l-phosphate, glucose-6-phosphate and the like. Mixtures of such phosphate ~ources with each other or with calcium phosphate may be employed.
Tricalcium phosphate or the other sources of calcium and phosphate which together form hydroxyapatite in solution are employed with the mole ratio of calcium ion to phosphate ion being from about 0.01 to about 100:1, typically about 0.2 to about 5:1, preferably about 1.2 to about 2:1, e.g., about 1.4 to about 1.7:1. A ratio of calcium to phosphate of 1.67:1 corres-ponds to the ratio of calcium to phosphate in dental enamel. The amount of calcium ion and phosphate ion in the composition is sufficient to effect remineralization, there being typically at least about 50 ppm of each calcium ion and phosphate ion. The maxImum amount of calcium ion and phosphate desir-able is that which would not result in precipitate formation. This could vary depending on the ion souroes and the pH conditions. Typically, about 35,000 ppm of calcium ion and about 40,000 ppm of phosphate can be employed and precipitation still avoided.
In the prior art it has been difficult to maintain the solubility of calcium phosphate, particularly in the presence of a fluoride souroe. As previously indicated, this is overcome in the present invention when the effective antinucleating agents are employed. Examples of fluoride ion souroes (including complex fluoride ions) include alkali metal (e.g., sodium potassium and lithium) ammonium, alkaline earth metal (e.g., calcium, barium, strontium, magnesium), aluminum, zinc, stannous, indium, zirconium, copper, nickel, palladium and organonitrogen such as alkylamine (e.g., hexylamine) compounds with fluoride ion souroes. Souroes of fl~loride ions include fluoride, fluorophosphate (including monofluorophosphate, difluorophosphate and polyfluorophosphate), silicofl~loride, fluorozirconate, fluoroborate and fluorostannite. Typical compounds are sodium fluoride, zinc fluoride, stannous fluoride and sodium monofluorophosphate. Sodium fluoride and sodium monofluorophosphate are preferred. me fluoride sour oe oompound is desirably ~.Z37~3 present in amount to provide about 1 ppm to 10,000 ppm (0.0001%-1%) fluoride to the remineralizing composition e.g., about 1 ppm to 1000 ppm (0.001-0.76%) sodium monofluorophosphate, preferably about 5 ppm fluoride. m e amount of the oompound employed should not be sufficient to result in precipitate forma-tion. For instanoe, in the case of a fluoride source of low solubility, such as calcium fluoride, the amount of the compound employed should not exceed 1500 ppm.
The stable remineralizing o~mposition may be prepared by adding controlled amounts of the calcium ion and phosphate ion sources to water and lowering the pH to keep the solution clear. The ion sour oes may be a single material, such as tricalcium phosphate or may be a plurality of materials, such as calcium chloride and sodium dihydrogen orthophosphate. The ratio of calcium ion to phosphate ion may be from about 0.01 to about 100:1, but is desirably about 1.67:1 in order to optimally form hydroxyapatite, for in-stan oe using about 1.5mM calcium ion and 0.9 mM phosphate ion in solution.
A preservative such as sodium benzoate or methyl-4-hydroxybenzoate may be employed to reduoe bacterial yrcwth. An electrolyte salt such as an alkali metal (e.g., sodium or potassium) chloride may be present (e.g. 1 to 1000 ppm) in the stable remineralizing composition to further improve stability and diffusion of remoneralizing material into subsurface lesions.
Acidic materials are used to reduce the pH to about 2-4, typically about 2.8-3.8, in order to maintain clarity of the solution. Typical mate-rials include phosphoric acid, hydrochloric acid and the like.
The pH is then raised to a mildly acid level, such as about 5 to 6.5, e.g. about 6, with basic materials such as sodium hydr~xide, potassium hydroxide, ammonium hydroxide and the like.
me ccm~osition can be stabilized against precipitation by incor-porating therein an effective antinucleating agent, such as ethylene diamine tetramethylenephosphonic acid, pentasodium salt. The antinucleating agent is , 30 added to the solution in amount of about 1 x 10 6M to 1 x 10 4M, typically about 3 x 10 4M (300 ppm) and thoroughly mixed therein.
~.Z3743 The pH can then be maintained or even raised to about 9, with the effective antinucleating agent preventing precipitation of hydroxyapatite.
Preferably it is raised to a physiological pH in the range of about 6.8-7.5, typically about 7 to 7.5. Basic materials of the type indicated may be employed to raise the pH.
A fluoride ion souroe such as sodium fluoride or sodium manofluoro-phosphate is then added in the indicated amcunt and the composition can be diluted to a desired con oentration. In the composition of the present inven~
tion the fluoride does not cause the hydroxyapatite to precipitate.
m us, the composition can be maintained for a lang period of time, remaining effective when brought into CQntaCt with dental material to remineralize sub-surfaoe lesions. The composition can be used as such or incorporated into other dental compositions, such as mouth rinse, dental cream or gel; mDuth spray, troche, chewable tablet, lozenge and the like.
The compoSitiQn of the invention may be applied to dental surfaoes as such, for instance, by rinsing the mouth therewith or it may be incorpor-ated into a mouthwash, dental cream or other dental preparation. When in-coxporated into a mouthwash, the solution is typically about 20-80% by weigh~
of the mouthwash, which mouthwash also includes a non-tQXic lower aliphatic alcohol, such as ethanol, N-propanol or isopropanol. A surface active agent (e.g. about 1-5%) such as sodium lauryl sulfate, sodium N-lauroyl sarcosinate or polyoxyethylene-polyoxypropylene(Pluronic~ material, a flavoring and/or sweetening material or antibacterial agent may also be present.
When incorporated into a dental cream or gel, the solutiQn is typically about 20-60% by weight of the cream or gel; such cream or gel also typically includes about 10-50% of a dentally acoeptable polishing material such as a water insoluble phosphate (e.g. insoluble sodium metaphosphate, hydrated alumina or silica (colloidal, precipitated or crystalline). Prefer-ably polishing materials containing calcium and/or orthophosphate moiety is not employed. The dental cream also generally contains humectant such as ~l.Z37'~3 glycerine, sorbitol, propylene glyeol or polyethylene glyeol 400 and gelling agent sueh as sodium carboxymethyl cellulose or Irish moss. Also, surfaee active agent flavoring and/or sweetening material, antibacterial agent, anti-baeterial preservative, (e.g. sodium benzoate or methyl-4-hydroxy benzoate), silieone material, chlorophyll cc~,pound or ammoniated material may ~e present.
me following examples illustrate the invention but do not limit it.
All parts, amounts and proportions are by weight unless otherwise noted.
A stoek solution of hydroxyapatite (tricalcium phosphate) is pre-pared by adding hydroKyapatite to water to a final concentration of 1.5mMcalcium and O.9mM phosphate. 0.25 grams of sodium benzoate (from 0.05% solu-tion thereof) are then added to the solution to minimize baeterial grc~h.
Phosphorie aeid is then added to 500 ml of the stoek solution to produoe a elear solution at pH 3, after whieh the pH is raised to 6 with l N
- potassium hydroxide. Next EDITEMPA is added and mixed into the solution to a concentration of l x lO M thereof, following whieh additional potassium hydroxide is added to produoe a pH of 7. Sodium monofluorophosphate is then added to a eon oentration of 5 ppm fluoride in the stock solution following whieh sodium ehloride is added to give an electrolyte concentration of 50mM
and additional water is added to l liter.
The solution thus formed remains stable and elear upon storage. A
similæ solution without EDITEMPA and without fluoride containing oompound results in precipitation by lO seconds from the time of the final pH rise.
When the fluoride eontaining compound is present and EDITEMPA absent, pre-eipitation also oeeurs by lO seconds from the time of the final pH rise.
The solution remains elear when just sodium ehloride is omitted.
Example 1 with EDITEMPA and sodium monofluorophosphate is repeated using dicaleium phosphate dihydrate in place of hydroxyapatite to give a final eon oentration of 60 ppm ealeium and 400 ppm phosphate in the stoek solution. The solution remains stable and clear.
~.Z3~ 3 Example l with EDITEMPA and sodium monofluorophosphate is repeated exoept that in plaoe of hydroxyapatite, calcium chloride and sodium phosphate are each added to water to form the stock solution with a final concentration of 60 ppm calcium and 400 ppm phosphate. me solution remains stable and clear.
Each of Example l, 2 and 3 are repeated except that in place of EDITEMPA, there is separately employed PAA (concentration 5 x 10 M); PODP
(conoentration 5 x 10 M); UniRcyal Oligo~er NL-2 (concentration 5 x 10 M).
All solutions remain stable and clear.
100 parts of each solution of Examples 1-4 are incorporated into 100 parts of the following mouthwash:
PAgrS
Ethanol 6 Pluronic *F-10 8 (polyoxyethylene-polyoxypropylene) 2 Glyoe rine 15 Benzoic acid 0.01 Sodium Saccharin 0.02 Flavor 0-075 Sodium benzoate 0.500 Color 0.0006 Water Q.S. to 100 * Trademark 37~
1 part of each solution of Examples 1-4 is mixed into 9 parts of the follcwing dental cream formulation:
PA:grS
Glycerine 10 Sorbitol 17 Water 13.70 Sodium benzoate 0.50 Sodium saccharin 0.20 Sodium carboxymethyl oe llulose 1.10 Precipitated silica 45.00 Sodium lauryl sulfate 1.50 Flavor 1.00 me solutions of Examples 1-4, the mouthwash of Example 5 and the dental cream of Example 6 containing antinucleating agent all effectively remineralize sub-surfaoe dental lesions when applied to dental surfaces in the oral cavity in a regimen manner.
It will be apparent to one skilled in the art that various modifica-tions of the foregoing Examples may be made thereto.
It is kr.own that dental caries begin with lesions of so called "white spots", which are demineralized areas below the sur-fa oe of intact dental enamel. If unchecked, surfa oe enamel above a sub-surface lesion eventually collapses, leading to cavitation and subsequent loss of tooth structure.
In order to arrest demineralization, and, indeed, in order to remineralize "white spots" various compositions have been pro-posed. For instan oe, United States Patent No. 3,679,360 to Rubin et al discloses deposition of calcium phosphate frcm a gel onto a tooth surface. This, however, d oe s not reach the sub-surfa oe area where demineralization initially occurs. Further, because of the difficulty of maintaining both calcium ions and phosphate ions avail-able without precipitating a calcium phosphate material, two part kits have been proposed in which a calcium component and a phosphate co~ponent are sequentially applied to the oral cavity as in British Patent No. 1,408,922 to Raff et al and British Patent No. 1,452,125 to Grab~nstetter et al or mixed together shortly before such applica-tion to form a metastable system with temporary stability as in United States Patent 4,080,440 to DiGiulio et al and British Patent No. 1,509,977 to Levine. Another metastable solution has been des-cribed in United States Patent No. 4,097,588 to Levine. Fven this solution, however, is not substantially permanent and precipitation can occur, particularly when fluoride ions are present.
It is an advantage of this invention that a one-part stable aqueous remineralizing solution is suitably prepared 1~.2374~
as a dental mouthrinse and also can be incorporated into other dentifrice compositions such as a dental cream or gel, mouth spray, troche, chewable tablet, lozenge and the like.
Further advantages will be apparent from consideration of the following specification.
In accordance with certain of its aspects, this invention relates to a stable aqueous composition comprising water having dissolved therein a source of calcium ions and a source of phos-phate ions, the amount of calcium ions and phosphate ions being sufficient to effect remineralization of dental enamel; a compound which pro~ides fluoride anticaries agent; and an antinucleating agent selected from the group of acids and orally acceptable water-soluble salts thereof consisting of diamine tetramethylenephosphonic acids of the formula (M2o3PH2c)2N(cH2)nN(cH2po3M2)2~ whe ei integer from 1 to 10, phosphonoacetic acid or salt thereof of the formula M203PCH2COOM, a peroxydiphosphate of the formula M4P208, or an oligomer ~ 3 3 ~ H
a in which M is hydrogen or an orally acceptable cation, Rl,R2,R3, and R4 are independently hydrogen, methyl or ethyl, Y is at least one hydrophilic member of the group consisting of -COOM, -CONH2 and CH20H, X is at least one hydrophobic member of the group consisting of -CN, -COOR, -COOR50R, -CONHR and -COONHR5COR, R is Cl 8 alkyl, R5 is Cl 4 alkylene, a is 0-7 and a + b is about 4-15.
E~
l~;.Z3743 said solution having a pH of about 5 to about 9.
The antinucleating properties of the agents employed in the present invention appear to be effective to prevent precipitate formation from the calcium and phosphate ions of the solution part-icularly with the fluoride ions also present. As described in Ciba Foundation Sy~,posium, "Hard Tissue Growth, Repair and Remineraliza-tion (Elsevier), Associated Scientific Publishers, New York, 1973 in the article by Francis et al, "Chemical Agents in the Control of Calcification Processes in Biological Systems", pages 57-83, part-icularly at pages 75-78, an antinucleating agent (e.g. a diphosphon-ate) can in sufficient quantity at a physiological pH ccmpletely ab-sorb onto a spherical nucleated particle of hydroxyapatite as it forms and entirely block crystal grcwth. In this way, the formation of large insoluble crystals of apatite is prevented and coated small hydroxyapatite crystals of higher water solubility are attained.
It has been found that not all antinucleating agents can successfully stabilize calcium ions and phosphate ions in solution against precipitating to form large insoluble apatite crystals.
For instance, such insoluble crystals form when it is sought to use antinucleating agents such as sodium hexametaphosphate, sodium pyrophosphate, sodium phytate and mellitic acid as well as disodium phosphonoethane-1,2-dicarboxylate, l,l-diphosphonopropane-2,3-dicar-boxylic acid monohydrate, 3-amino-l-hydroxypropane-l,l-diphosphonic acid and imino-diacetic-N-methylene phosphonic acid. Gn the other hand, the antinucleating agents of the present invention sucoess-fully stabilize the calcium ions and phosphate ions against precipi-tation as large insoluble apatite crystals in solution at a 37 ~3 pH between about 5 and abou-t 9. Preferal)ly, the pll is adjusted to about 6.8 to about 7.5, whicll approximates usual human physiological conditions and is optimum for effecting remineralization. Desirably, the antinucleating agent of the invention is present in amount of about 1 to 500 ppm (1 x 10 6M to 1 x 10 3M) of the solution, pref-erably about 25 to 250 ppm (5 x 10 6M to 5 x 10 3M), such as about 225 ppm (5 x 10 4M)~
The antinucleating agent of the invention is desirably a diamine tetramethylenephosphonic acid of the formula (M203P112C)2-N~CH2)nN(C1~2P03M2)2 wherein n is an integer from 1 to 10 and M is hydrogen or an orally acceptable cation such as alkali metal (e.g. sodium or potassium), ammonium or Cl - C18 mono-, di - or trisubstituted ammonium (e.g. mono-, di - or tri-ethanolammonium) salt.
The polyamine polyphosphonic compounds which are most preferred are ethylenediamine tetra(methylenephosphonic acid), (hereinafter EDITEMPA) and its water-soluble orally acceptable salts, (e.g., sodium, potassium, and ammonium and other pharma-ceutically acceptable salts; most preferably the tri-, tetra- or penta-sodium salts), other polyamine polyphosphonic compounds include:
tetramethylenediamine tetra (methylenephosphonic acid), pentamethyl-ene diamine tetra (methylenephosphonic acid), hexamethylenediamine tetra (methylenephosphonic acid) and the water-solub]e salts of these acids, e.g., sodium, potassium, ammonium and other orally acceptable salts.
Phosphonoacetic acid (hereinafter PAA) and its watèr soluble orally acceptable salts are also desirable antinucleating agents.
They are characterized by the formula M203PC112COOM, wherein M has the meaning indicated above.
-The peroxydiphosphate ~hereinafter PODP) and particularly the alkali metal salts thereof (e.g. potassium or sodium) are likewise desirable antinucleating agents. They are characterized by the formula M4P208 wherein M has the meaning indicated above.
The desirable oligomer antinucleating agents and methods for their preparation are described in United States Patent Nos. 3,646,099 and 3,859,260. They have the formula:
1l IZ R3 R~
M03S - C 1_ 3 C - C- - H
wherein M is hydrogen or a water soluble orally acceptable cation (as indicated above); Rl, R2, R3 and R4 are independently H, methyl or ethyl; Y is at least one hydrophilic member of the group consisting of -COOM, -COHN2 and -CH20H; X is at least one hydrophobic member of the group consisting of -CN, -COOR, -COOR50R, -CONHR and -COONHR5COR, R
is Cl_8 alkyl; R5 is Cl_4 alkylene; a is 0-7; and a + b is about 4-15.
These oligomers are anionic and of relatively low and accurately regulated degree of polymerization, (in contrast to the conventional free radical redox polymerization conducted with an oxidative initiator such as hydrogen, alkyl, or acyl peroxides, persulfates or hydroperoxides in relatively large amounts and a reductive activator such as NaHS03, Na2S204 or ~.Z3743 sodium forn~ldehyde sulfoxylate in relatively low amounts generally added subsequently to the polymerization medium) æe prepared by a reductive poly-merization in which a much larger amount of a bisulfite salt, e.g. NaHS03 (sodium bisulfite, sodium acid sulfite), a reducing agent, is the initiator charge initially with the monamer, and an oxidixing agent is added in smaller amounts as the activator ~lring the polymerizing or oligomerizing process.
Subscript a in the formula represents the numher of moles of hydro-phobic groups, and subscript b the number of moles of hydrophilic groups, in the oligomer molecule. The proportion of X (i.e. the value of a) must be small enough, or even zero, to avoid the production of a too large, sticky and hydrophobic polymer molecule, and will of course be dependent for the most part in any particular instanoe on the identity of the X and Y groups, i.e. the hydrophobic-contaLnLng and hydrophilic aontaining monomeric react-ants. Mixtures of such oligomers may of course also be employed.
Examples of monamers containing hydrophilic Y group are acrylic acid, methacrylic acid, alpha-ethylacrylic acid, betamethylacrylic acid, alpha, beta-dimethylacrylic acid, orally acoeptable salts of these acids, for example those aontaining such cations as alkali metal (e.g. sodium and potassium), ~,.,~nium, Cl l8mono-, di- and tri- substituted ammonium (e.g.
alkanol substituted such as mono-, di~ and tri-ethanolammonium), etc., acryl-amide, methacrylamide, ethacrylamide, and alkyl alcohol and the like.
Examples of monamers aontaining hydrophobic X groups are acryl-onitrile, methacrylonitrile, ethacrylonitrile, methyl and ethyl and octyl acrylate and methacrylate, methoxyethyl acrylate, octaxyethyl methacrylate, ethoxybutyl methacrylate, prapoxymethyl acrylate, N-ethylacrylamide, N-iso-propylacrylamide, N-methylacrylamide, N-propylethacrylamide, vinyl aoetate, propionate and octanoate, diaoetone acrylamide and the like.
The oligamerization is carried out in water in the presen oe of a relatively large amcunt of the bisulfite reducing initiator, expressed in mols of monomer/gram formula weight (gFW) of reducing initiator is about 4 to 15, this ratio determuning the degree of oligamerization.
l~.Z3743 The reductive initiator is preferably a water soluble bisulfite salt (M in the formula), especially aLkali metal such as sodium or potassium, but bisulfite salts containing other orally acoeptable cations of the type referred to above may be employed.
In practice, enough oxidative activator is used to effect 100% con-version of the monamers to oligamers. The amount of such acti~ator, ex-pressed as gFW activator/gFW initiator may range from 0.0001 to 0.1 but usually is from about 0.001 to 0.1. Examples of these oxidative activators are ammonium, sodium potassium persulfate, hydrogen peroxide and other water soluble oxidants oommonly employed in the polymerizatian art.
Following campletion of the oligomerization reaction, any free carboxylic acids groups in the oligamer molecules may, if desired be part-ially or o~mpletely neutralized, preferably at least 60%, by treating the aqueous oligamer solution with a suitable base to convert such groups to their salts with orally acceptable cations as referred to a~ove. These aqueous oligamer solutians have a highly desirable low viscosity, and lcw molecular weight range depending on the monomer units in the oligamer.
It will be understood that the oligamer formula above is not in-tended to depict the actual structure of the oligomer molecule, the brac~eted units of which formula are randamly distributed in the molecule with the -SO3 M group being normally bonded to a terminal carbon atam in the oligamer chain devoid of X and or Y substituents. In the oligamers preferred for use herein, a is zero, Y is -COOM, Rl -R4 are H, and M is alkali metal, e.g.
sodium, b being about 10, as derived from acrylic acid. An oligomer of the formula above in the form of its sodium salt, with a molecular weight of abaut 1,000, containing about 10 acrylic acid monomeric units, is cammerci-ally available under the trade name ND-2 (a product of UniRoyal).
The effective antinucleating agents render the rem meralizing solu-tian stable at normally occurring temperatures, e.g., about 15C-40&. The remineralizing agents can diffuse effectively through an intact enamel sur-faoe in order to act on subsurfaoe lesions.
m e stability provided by the effective antinucleating agents pre-vents spontaneous precipitation on enamel surfa oe s ~m d thereby permits diffu-sion of the remineralizing components to subsurface lesions.
One or more sources of each calcium ions and phosphate ions may be employed. When the source is normally insoluble such as a calcium phosphate, it is solubilized during preparation of the solution, by maintaining an acid pH of about 6 or less (e.g., about 2.5 to 6) during preparation of the remineralizing solution, particularly before the effective antinucleating agent is added.
m e insoluble sources of calcium and phosphate ions may be a single compound such as tricalcium phosphate (which substantially corresponds to hydroxyapatite, Ca5 (P04)30H or 3Ca3 (P04)2Ca (OH)2), bone meal or dicalcium phosphate (dihydrate or anhydrous). In solution, particularly in the pre-sen oe of fluoride ions, formation of hydroxyapatite, fluorohydroxyapatite and fluoroapatite occurs.
Examples of other normally water-soluble or normally water-insol-uble (but soluble at pH of about 6 or less) sources of calcium ion, but not phosphate ion, which can be used in the remineralizing solution of the inven-tion include calcium salts with a oe tate, gluconate, nitrate, stearate, lactate, formate, molybdate, tungstate, sulfate, alkyl sulfonate (e.g., lauryl sulfonate), oleate, tartrate, sorbate, iodate, silicate, aluminate, benzoate, citrate, fumarate, butyrate, isobutyrate, malate, maleate, propion-ate, valerate and the like. Mixtures of such calcium sources with each other or with calcium phosphate may be employed.
Examples of sources of phosphate ion, but not calcium ion, which can be used in the remineralizing solution of the invention include the normally water-soluble or normally water-insoluble (but soluble at pH of about 6 or less) salts including alkali metal (e.g. sodium and potassium), ammonium, magnesium, barium and strontium orthophosphates and acid orthophos-phates, metaphosphates, pyrophosphates, as well as glycerophosphates, "
1~.231743 fructose-6-phosphate, sorbitol-6-phosphate, glucose-l-phosphate, glucose-6-phosphate and the like. Mixtures of such phosphate ~ources with each other or with calcium phosphate may be employed.
Tricalcium phosphate or the other sources of calcium and phosphate which together form hydroxyapatite in solution are employed with the mole ratio of calcium ion to phosphate ion being from about 0.01 to about 100:1, typically about 0.2 to about 5:1, preferably about 1.2 to about 2:1, e.g., about 1.4 to about 1.7:1. A ratio of calcium to phosphate of 1.67:1 corres-ponds to the ratio of calcium to phosphate in dental enamel. The amount of calcium ion and phosphate ion in the composition is sufficient to effect remineralization, there being typically at least about 50 ppm of each calcium ion and phosphate ion. The maxImum amount of calcium ion and phosphate desir-able is that which would not result in precipitate formation. This could vary depending on the ion souroes and the pH conditions. Typically, about 35,000 ppm of calcium ion and about 40,000 ppm of phosphate can be employed and precipitation still avoided.
In the prior art it has been difficult to maintain the solubility of calcium phosphate, particularly in the presence of a fluoride souroe. As previously indicated, this is overcome in the present invention when the effective antinucleating agents are employed. Examples of fluoride ion souroes (including complex fluoride ions) include alkali metal (e.g., sodium potassium and lithium) ammonium, alkaline earth metal (e.g., calcium, barium, strontium, magnesium), aluminum, zinc, stannous, indium, zirconium, copper, nickel, palladium and organonitrogen such as alkylamine (e.g., hexylamine) compounds with fluoride ion souroes. Souroes of fl~loride ions include fluoride, fluorophosphate (including monofluorophosphate, difluorophosphate and polyfluorophosphate), silicofl~loride, fluorozirconate, fluoroborate and fluorostannite. Typical compounds are sodium fluoride, zinc fluoride, stannous fluoride and sodium monofluorophosphate. Sodium fluoride and sodium monofluorophosphate are preferred. me fluoride sour oe oompound is desirably ~.Z37~3 present in amount to provide about 1 ppm to 10,000 ppm (0.0001%-1%) fluoride to the remineralizing composition e.g., about 1 ppm to 1000 ppm (0.001-0.76%) sodium monofluorophosphate, preferably about 5 ppm fluoride. m e amount of the oompound employed should not be sufficient to result in precipitate forma-tion. For instanoe, in the case of a fluoride source of low solubility, such as calcium fluoride, the amount of the compound employed should not exceed 1500 ppm.
The stable remineralizing o~mposition may be prepared by adding controlled amounts of the calcium ion and phosphate ion sources to water and lowering the pH to keep the solution clear. The ion sour oes may be a single material, such as tricalcium phosphate or may be a plurality of materials, such as calcium chloride and sodium dihydrogen orthophosphate. The ratio of calcium ion to phosphate ion may be from about 0.01 to about 100:1, but is desirably about 1.67:1 in order to optimally form hydroxyapatite, for in-stan oe using about 1.5mM calcium ion and 0.9 mM phosphate ion in solution.
A preservative such as sodium benzoate or methyl-4-hydroxybenzoate may be employed to reduoe bacterial yrcwth. An electrolyte salt such as an alkali metal (e.g., sodium or potassium) chloride may be present (e.g. 1 to 1000 ppm) in the stable remineralizing composition to further improve stability and diffusion of remoneralizing material into subsurface lesions.
Acidic materials are used to reduce the pH to about 2-4, typically about 2.8-3.8, in order to maintain clarity of the solution. Typical mate-rials include phosphoric acid, hydrochloric acid and the like.
The pH is then raised to a mildly acid level, such as about 5 to 6.5, e.g. about 6, with basic materials such as sodium hydr~xide, potassium hydroxide, ammonium hydroxide and the like.
me ccm~osition can be stabilized against precipitation by incor-porating therein an effective antinucleating agent, such as ethylene diamine tetramethylenephosphonic acid, pentasodium salt. The antinucleating agent is , 30 added to the solution in amount of about 1 x 10 6M to 1 x 10 4M, typically about 3 x 10 4M (300 ppm) and thoroughly mixed therein.
~.Z3743 The pH can then be maintained or even raised to about 9, with the effective antinucleating agent preventing precipitation of hydroxyapatite.
Preferably it is raised to a physiological pH in the range of about 6.8-7.5, typically about 7 to 7.5. Basic materials of the type indicated may be employed to raise the pH.
A fluoride ion souroe such as sodium fluoride or sodium manofluoro-phosphate is then added in the indicated amcunt and the composition can be diluted to a desired con oentration. In the composition of the present inven~
tion the fluoride does not cause the hydroxyapatite to precipitate.
m us, the composition can be maintained for a lang period of time, remaining effective when brought into CQntaCt with dental material to remineralize sub-surfaoe lesions. The composition can be used as such or incorporated into other dental compositions, such as mouth rinse, dental cream or gel; mDuth spray, troche, chewable tablet, lozenge and the like.
The compoSitiQn of the invention may be applied to dental surfaoes as such, for instance, by rinsing the mouth therewith or it may be incorpor-ated into a mouthwash, dental cream or other dental preparation. When in-coxporated into a mouthwash, the solution is typically about 20-80% by weigh~
of the mouthwash, which mouthwash also includes a non-tQXic lower aliphatic alcohol, such as ethanol, N-propanol or isopropanol. A surface active agent (e.g. about 1-5%) such as sodium lauryl sulfate, sodium N-lauroyl sarcosinate or polyoxyethylene-polyoxypropylene(Pluronic~ material, a flavoring and/or sweetening material or antibacterial agent may also be present.
When incorporated into a dental cream or gel, the solutiQn is typically about 20-60% by weight of the cream or gel; such cream or gel also typically includes about 10-50% of a dentally acoeptable polishing material such as a water insoluble phosphate (e.g. insoluble sodium metaphosphate, hydrated alumina or silica (colloidal, precipitated or crystalline). Prefer-ably polishing materials containing calcium and/or orthophosphate moiety is not employed. The dental cream also generally contains humectant such as ~l.Z37'~3 glycerine, sorbitol, propylene glyeol or polyethylene glyeol 400 and gelling agent sueh as sodium carboxymethyl cellulose or Irish moss. Also, surfaee active agent flavoring and/or sweetening material, antibacterial agent, anti-baeterial preservative, (e.g. sodium benzoate or methyl-4-hydroxy benzoate), silieone material, chlorophyll cc~,pound or ammoniated material may ~e present.
me following examples illustrate the invention but do not limit it.
All parts, amounts and proportions are by weight unless otherwise noted.
A stoek solution of hydroxyapatite (tricalcium phosphate) is pre-pared by adding hydroKyapatite to water to a final concentration of 1.5mMcalcium and O.9mM phosphate. 0.25 grams of sodium benzoate (from 0.05% solu-tion thereof) are then added to the solution to minimize baeterial grc~h.
Phosphorie aeid is then added to 500 ml of the stoek solution to produoe a elear solution at pH 3, after whieh the pH is raised to 6 with l N
- potassium hydroxide. Next EDITEMPA is added and mixed into the solution to a concentration of l x lO M thereof, following whieh additional potassium hydroxide is added to produoe a pH of 7. Sodium monofluorophosphate is then added to a eon oentration of 5 ppm fluoride in the stock solution following whieh sodium ehloride is added to give an electrolyte concentration of 50mM
and additional water is added to l liter.
The solution thus formed remains stable and elear upon storage. A
similæ solution without EDITEMPA and without fluoride containing oompound results in precipitation by lO seconds from the time of the final pH rise.
When the fluoride eontaining compound is present and EDITEMPA absent, pre-eipitation also oeeurs by lO seconds from the time of the final pH rise.
The solution remains elear when just sodium ehloride is omitted.
Example 1 with EDITEMPA and sodium monofluorophosphate is repeated using dicaleium phosphate dihydrate in place of hydroxyapatite to give a final eon oentration of 60 ppm ealeium and 400 ppm phosphate in the stoek solution. The solution remains stable and clear.
~.Z3~ 3 Example l with EDITEMPA and sodium monofluorophosphate is repeated exoept that in plaoe of hydroxyapatite, calcium chloride and sodium phosphate are each added to water to form the stock solution with a final concentration of 60 ppm calcium and 400 ppm phosphate. me solution remains stable and clear.
Each of Example l, 2 and 3 are repeated except that in place of EDITEMPA, there is separately employed PAA (concentration 5 x 10 M); PODP
(conoentration 5 x 10 M); UniRcyal Oligo~er NL-2 (concentration 5 x 10 M).
All solutions remain stable and clear.
100 parts of each solution of Examples 1-4 are incorporated into 100 parts of the following mouthwash:
PAgrS
Ethanol 6 Pluronic *F-10 8 (polyoxyethylene-polyoxypropylene) 2 Glyoe rine 15 Benzoic acid 0.01 Sodium Saccharin 0.02 Flavor 0-075 Sodium benzoate 0.500 Color 0.0006 Water Q.S. to 100 * Trademark 37~
1 part of each solution of Examples 1-4 is mixed into 9 parts of the follcwing dental cream formulation:
PA:grS
Glycerine 10 Sorbitol 17 Water 13.70 Sodium benzoate 0.50 Sodium saccharin 0.20 Sodium carboxymethyl oe llulose 1.10 Precipitated silica 45.00 Sodium lauryl sulfate 1.50 Flavor 1.00 me solutions of Examples 1-4, the mouthwash of Example 5 and the dental cream of Example 6 containing antinucleating agent all effectively remineralize sub-surfaoe dental lesions when applied to dental surfaces in the oral cavity in a regimen manner.
It will be apparent to one skilled in the art that various modifica-tions of the foregoing Examples may be made thereto.
Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A stable aqueous composition comprising water having dissolved therein a source of calcium ions and a source of phosphate ions, the amount of calcium ions and phosphate ions being sufficient to effect remineraliza-tion of dental enamel; a compound which provides fluoride anticaries agent;
and an antinucleating agent selected from the group of acids and orally acceptable water-soluble salts thereof consisting of diamine tetramethylene-phosphonic acids of the formula (M203PH2C)2N(CH2)nN(CH2PO3M2)2, wherein n is an integer from 1 to 10, phosphonoacetic acid or salt thereof of the formula M203PCH2COOM, a peroxydiphosphate of the formula M4P208, or an oligomer in which M is hydrogen or an orally acceptable cation, R1, R2, R3, and R4 are independently hydrogen, methyl or ethyl, Y is at least one hydrophilic member of the group consisting of -COOM, -CONH2 and CH2OH, X is at least one hydro-phobic member of the group consisting of -CN, -COOR, -COOR5OR, -CONHR and -COONHR5COR, R is C1-8alkyl, R5 is C1-4 alkylene, a is 0-7 and a+b is about 4-15, said solution having a pH of about 5 to 9.
and an antinucleating agent selected from the group of acids and orally acceptable water-soluble salts thereof consisting of diamine tetramethylene-phosphonic acids of the formula (M203PH2C)2N(CH2)nN(CH2PO3M2)2, wherein n is an integer from 1 to 10, phosphonoacetic acid or salt thereof of the formula M203PCH2COOM, a peroxydiphosphate of the formula M4P208, or an oligomer in which M is hydrogen or an orally acceptable cation, R1, R2, R3, and R4 are independently hydrogen, methyl or ethyl, Y is at least one hydrophilic member of the group consisting of -COOM, -CONH2 and CH2OH, X is at least one hydro-phobic member of the group consisting of -CN, -COOR, -COOR5OR, -CONHR and -COONHR5COR, R is C1-8alkyl, R5 is C1-4 alkylene, a is 0-7 and a+b is about 4-15, said solution having a pH of about 5 to 9.
2. The stable aqueous composition claimed in Claim 1 wherein the pH
of said solution is about 6.8 to about 7.5.
of said solution is about 6.8 to about 7.5.
3. The stable aqueous composition claimed in Claim 1 wherein said antinucleating agent is present in an amount of about 1 to 500 ppm.
4. The stable aqueous composition claimed in Claim 1 wherein said antinucleating agent is said diamine tetramethylenephosphonic acid or orally acceptable salt thereof.
5. The stable aqueous composition claimed in Claim 1 wherein said antinucleating agent is ethylene diamine tetramethylenephosphonic acid or orally acceptable salt thereof.
6. The stable aqueous composition claimed in Claim 1 wherein said antinucleating agent is said phosphonacetic acid or orally acceptable salt thereof.
7. The stable aqueous composition claimed in Claim 1 wherein said antinucleating agent is said an orally acceptable peroxydiphosphate.
8. The stable aqueous composition claimed in Claim 1 wherein said antinucleating agent is said oligomer or orally acceptable salt thereof.
9. The stable aqueous composition claimed in Claim 1 wherein an electrolyte salt is present.
10. The stable aqueous composition claimed in Claim 1 wherein the mole ratio of calcium to phosphate is from about 0.01 to about 100:1 and at least about 50 ppm of each of calcium and phosphate is present.
11. The stable aqueous composition claimed in Claim 10 wherein said source of calcium ions and of phosphate ions is hydroxyapatite and the mole ratio of calcium to phosphate is about 1.67 to 1.
12. The stable aqueous composition claimed in Claim 1 wherein said source of calcium ions and of phosphate ions is dicalcium phosphate.
13. The stable aqueous composition claimed in Claim 1 wherein said source of calcium ions is calcium chloride and said source of phosphate ions is disodium phosphate.
14. The stable aqueous composition claimed in Claim 1 wherein said com-pound which provides fluoride anticaries agent provides about 1 ppm to about 1000 ppm.
15. The stable aqueous composition claimed in Claim 14 wherein said com-pound which provides fluoride anticaries agent is sodium monofluorophosphate.
16. A mouthwash comprising a non-toxic lower aliphatic alcohol carrier and incorporated therein the stable aqueous remineralizing solution claimed in Claim 1.
17. A dental cream or gel comprising water, a humectant, a gelling agent and a dentally acceptable polishing material and the stable aqueous composition claimed in Claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US951,893 | 1978-10-13 | ||
| US05/951,893 US4183915A (en) | 1978-10-13 | 1978-10-13 | Stable solution for dental remineralization |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1123743A true CA1123743A (en) | 1982-05-18 |
Family
ID=25492286
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA331,247A Expired CA1123743A (en) | 1978-10-13 | 1979-07-05 | Antinucleating agent in aqueous remineralizing composition comprising calcium, phosphorus, and fluoride |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4183915A (en) |
| JP (1) | JPS5553212A (en) |
| AR (1) | AR226819A1 (en) |
| AT (1) | AT369986B (en) |
| AU (1) | AU522979B2 (en) |
| BE (1) | BE877516A (en) |
| CA (1) | CA1123743A (en) |
| CH (1) | CH642535A5 (en) |
| DE (1) | DE2925926A1 (en) |
| DK (1) | DK276679A (en) |
| FR (1) | FR2438478A1 (en) |
| GB (1) | GB2031725B (en) |
| IT (1) | IT1117784B (en) |
| MY (1) | MY8600529A (en) |
| NL (1) | NL7905276A (en) |
| NO (1) | NO152585C (en) |
| NZ (1) | NZ190747A (en) |
| PH (1) | PH15445A (en) |
| PT (1) | PT69863A (en) |
| SE (1) | SE444262B (en) |
| ZA (1) | ZA792890B (en) |
Families Citing this family (69)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4405600A (en) * | 1979-06-07 | 1983-09-20 | University Patents, Inc. | Methods and materials for prevention of carious degradation of teeth |
| US4283385A (en) * | 1980-05-09 | 1981-08-11 | Richardson-Merrell Inc. | Dentifrices with improved soluble fluoride availability |
| US4348381A (en) * | 1981-05-06 | 1982-09-07 | Colgate-Palmolive Company | Dental remineralization composition |
| US4606912A (en) * | 1981-07-22 | 1986-08-19 | Caries Research Group Of Rochester, Inc. | Method of making a clear, stable aqueous mouthwash solution and the solution made by that method for the enhancement of cells of the oral cavity and the remineralization of teeth |
| US4532124A (en) * | 1981-08-19 | 1985-07-30 | Development Finance Corporation Of New Zealand | Dental rinse |
| US4419342A (en) * | 1982-03-10 | 1983-12-06 | Colgate-Palmolive Company | Dentifrice preparation |
| GR77131B (en) * | 1982-03-10 | 1984-09-07 | Procter & Gamble | |
| ZA831878B (en) * | 1982-03-24 | 1984-11-28 | Colgate Palmolive Co | Peroxydiphosphate toothpaste composition |
| US4537765A (en) * | 1982-03-24 | 1985-08-27 | Colgate-Palmolive Company | Peroxydiphosphate toothpaste composition |
| US4610873A (en) * | 1982-09-08 | 1986-09-09 | Caries Research Group Of Rochester, Inc. | Composition and method for making a clear aqueous solution free of calcium phosphate crystals |
| US4556561A (en) * | 1983-03-25 | 1985-12-03 | American Dental Association Health Foundation | Compositions and methods for topically fluoridating and/or mineralizing dental tissue |
| US4436721A (en) | 1983-06-08 | 1984-03-13 | Colgate-Palmolive Company | Oral composition having mole ratio of tetra (methylene phosphonate) to alkali metal fluoride of at least 1.4:1 |
| US4672032A (en) * | 1983-11-09 | 1987-06-09 | University Of Southern California | Dental enamel production |
| US4569838A (en) * | 1983-12-23 | 1986-02-11 | Colgate-Palmolive Company | Dentifrice |
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-
1978
- 1978-10-13 US US05/951,893 patent/US4183915A/en not_active Expired - Lifetime
-
1979
- 1979-06-11 ZA ZA792890A patent/ZA792890B/en unknown
- 1979-06-12 NO NO791961A patent/NO152585C/en unknown
- 1979-06-15 NZ NZ190747A patent/NZ190747A/en unknown
- 1979-06-22 AU AU48300/79A patent/AU522979B2/en not_active Ceased
- 1979-06-27 DE DE19792925926 patent/DE2925926A1/en active Granted
- 1979-06-29 DK DK276679A patent/DK276679A/en not_active Application Discontinuation
- 1979-07-02 PT PT69863A patent/PT69863A/en unknown
- 1979-07-02 FR FR7917140A patent/FR2438478A1/en active Granted
- 1979-07-02 IT IT49601/79A patent/IT1117784B/en active
- 1979-07-02 PH PH22732A patent/PH15445A/en unknown
- 1979-07-03 SE SE7905790A patent/SE444262B/en not_active IP Right Cessation
- 1979-07-04 AT AT0465679A patent/AT369986B/en not_active IP Right Cessation
- 1979-07-04 GB GB7923231A patent/GB2031725B/en not_active Expired
- 1979-07-05 BE BE0/196155A patent/BE877516A/en not_active IP Right Cessation
- 1979-07-05 JP JP8550879A patent/JPS5553212A/en active Granted
- 1979-07-05 CA CA331,247A patent/CA1123743A/en not_active Expired
- 1979-07-05 CH CH631679A patent/CH642535A5/en not_active IP Right Cessation
- 1979-07-05 AR AR277204A patent/AR226819A1/en active
- 1979-07-05 NL NL7905276A patent/NL7905276A/en not_active Application Discontinuation
-
1986
- 1986-12-30 MY MY529/86A patent/MY8600529A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2438478A1 (en) | 1980-05-09 |
| AT369986B (en) | 1983-02-25 |
| DE2925926C2 (en) | 1989-08-03 |
| NZ190747A (en) | 1981-11-19 |
| NO791961L (en) | 1980-04-15 |
| IT7949601A0 (en) | 1979-07-02 |
| JPS5553212A (en) | 1980-04-18 |
| NL7905276A (en) | 1980-04-15 |
| AU4830079A (en) | 1980-04-17 |
| SE444262B (en) | 1986-04-07 |
| CH642535A5 (en) | 1984-04-30 |
| DE2925926A1 (en) | 1980-04-30 |
| ATA465679A (en) | 1982-07-15 |
| GB2031725B (en) | 1983-03-02 |
| NO152585C (en) | 1985-10-23 |
| DK276679A (en) | 1980-04-14 |
| PH15445A (en) | 1983-01-18 |
| FR2438478B1 (en) | 1984-11-30 |
| GB2031725A (en) | 1980-04-30 |
| IT1117784B (en) | 1986-02-24 |
| SE7905790L (en) | 1980-04-14 |
| US4183915A (en) | 1980-01-15 |
| AR226819A1 (en) | 1982-08-31 |
| PT69863A (en) | 1979-08-01 |
| MY8600529A (en) | 1986-12-31 |
| JPS6347685B2 (en) | 1988-09-26 |
| NO152585B (en) | 1985-07-15 |
| BE877516A (en) | 1979-11-05 |
| AU522979B2 (en) | 1982-07-08 |
| ZA792890B (en) | 1981-01-28 |
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