U.S. patent application number 17/308081 was filed with the patent office on 2021-11-11 for oral care compositions comprising monodentate and polydentate ligand.
The applicant listed for this patent is The Procter & Gamble Company. Invention is credited to William Michael Glandorf, Andrew Frederic Groth, Samuel James St. John, Ross Strand.
Application Number | 20210346255 17/308081 |
Document ID | / |
Family ID | 1000005595513 |
Filed Date | 2021-11-11 |
United States Patent
Application |
20210346255 |
Kind Code |
A1 |
Glandorf; William Michael ;
et al. |
November 11, 2021 |
Oral Care Compositions Comprising Monodentate And Polydentate
Ligand
Abstract
Oral care compositions including tin, monodentate ligand, and
polydentate ligand with an optimized molar ratio of tin to
monodentate ligand to polydentate ligand. Oral care compositions
with a tin to monodentate ligand to polydentate molar ratio of from
about 1:0.5:0.5 to about 1:5:5. Oral care compositions including
tin, monocarboxylic acid, and tricarboxylic acid.
Inventors: |
Glandorf; William Michael;
(Mason, OH) ; Groth; Andrew Frederic; (Mason,
OH) ; St. John; Samuel James; (Cincinnati, OH)
; Strand; Ross; (Singapore, SG) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Procter & Gamble Company |
Cincinnati |
OH |
US |
|
|
Family ID: |
1000005595513 |
Appl. No.: |
17/308081 |
Filed: |
May 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
63020032 |
May 5, 2020 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2800/48 20130101;
A61K 8/362 20130101; A61K 2800/74 20130101; A61K 8/06 20130101;
A61K 8/365 20130101; A61K 8/60 20130101; A61K 8/73 20130101; A61K
8/29 20130101; A61K 8/37 20130101; A61K 8/27 20130101; A61Q 11/00
20130101; A61K 8/55 20130101; A61K 8/21 20130101; A61K 8/25
20130101 |
International
Class: |
A61K 8/27 20060101
A61K008/27; A61Q 11/00 20060101 A61Q011/00; A61K 8/06 20060101
A61K008/06; A61K 8/362 20060101 A61K008/362; A61K 8/365 20060101
A61K008/365; A61K 8/55 20060101 A61K008/55; A61K 8/21 20060101
A61K008/21; A61K 8/37 20060101 A61K008/37; A61K 8/25 20060101
A61K008/25; A61K 8/60 20060101 A61K008/60; A61K 8/73 20060101
A61K008/73; A61K 8/29 20060101 A61K008/29 |
Claims
1. An oral care composition comprising: (a) tin; (b) monodentate
ligand; and (c) polydentate ligand, wherein the oral care
composition has a tin to monodentate ligand to polydentate molar
ratio of from about 1:0.5:0.5 to about 1:5:5.
2. The oral care composition of claim 1, wherein the oral care
composition has a tin to monodentate ligand to polydentate molar
ratio of from about 1:1:1 to about 1:5:5.
3. The oral care composition of claim 2, wherein the oral care
composition has a tin to monodentate ligand to polydentate molar
ratio of from about 1:1:1 to about 1:2.5:2.5.
4. The oral care composition of claim 1, wherein the tin comprises
stannous fluoride, stannous chloride, or combinations thereof.
5. The oral care composition of claim 1, wherein the monodentate
ligand comprises a compound comprising a single functional group
capable of chelating tin.
6. The oral care composition of claim 5, wherein the monodentate
ligand comprises carboxylic acid, or a salt thereof.
7. The oral care composition of claim 6, wherein the carboxylic
acid comprises aliphatic carboxylic acid, aromatic carboxylic acid,
sugar acid, salts thereof, or combinations thereof.
8. The oral care composition of claim 7, wherein the sugar acid
comprises aldonic acid, ulsonic acid, uronic acid, aldaric acid,
salts thereof, or combinations thereof.
9. The oral care composition of claim 7, wherein the sugar acid
comprises gluconate.
10. The oral care composition of claim 7, wherein the aliphatic
carboxylic acid comprises linear saturated carboxylic acid, linear
unsaturated carboxylic acid, alpha hydroxy acid, beta hydroxy acid,
gamma hydroxy acid, amino acid, salts thereof, or combinations
thereof.
11. The oral care composition of claim 10, wherein the amino acid
comprises glycine, alanine, valine, isoleucine, tryptophan,
phenylalanine, proline, methionine, leucine, serine, threonine,
tyrosine, asparagine, glutamine, cysteine, citrulline, aspartic
acid, glutamic acid, lysine, arginine, histidine, or combinations
thereof.
12. The oral care composition of claim 10, wherein the alpha
hydroxy acid comprises lactate.
13. The oral care composition of claim 1, wherein the polydentate
ligand comprises a compound comprising at least two functional
groups capable of chelating tin.
14. The oral care composition of claim 13, wherein the polydentate
ligand comprises carboxylic acid, phosphate, polyphosphate, salts
thereof, or combinations thereof.
15. The oral care composition of claim 14, wherein the phosphate
comprises phosphate salt, organophosphate, or combinations
thereof.
16. The oral care composition of claim 15, wherein the phosphate
salt comprises orthophosphate, hydrogen phosphate, dihydrogen
phosphate, or combinations thereof.
17. The oral care composition of claim 14, wherein the carboxylic
acid comprises dicarboxylic acid, tricarboxylic acid, salts
thereof, or combinations thereof.
18. The oral care composition of claim 17, wherein the dicarboxylic
acid comprises a compound with the formula
HO.sub.2C--R--CO.sub.2H.
19. The oral care composition of claim 18, wherein R is aliphatic,
aromatic, or combinations thereof.
20. The oral care composition of claim 17, wherein the dicarboxylic
acid comprises oxalic acid, malonic acid, succinic acid, glutaric
acid, adipic acid, pimelic acid, suberic acid, azerlaic acid,
sebacic acid, undecanedioic acid, dodecanedioic acid, brassylic
acid, thapsic acid, japanic acid, phellogenic acid, equisetolic
acid, salts thereof, or combinations thereof.
21. The oral care composition of claim 17, wherein the
tricarboxylic acid comprises citric acid, isocictric acid, aconitic
acid, propane-1,2,3-tricarboxylic acid, trimesic acid, salts
thereof, or combinations thereof.
22. The oral care composition of claim 16, wherein the
polyphosphate comprises pyrophosphate, tripolyphosphate,
tetrapolyphosphate, hexametaphosphate, or combinations thereof.
23. The oral care composition of claim 1, wherein the composition
comprises zinc.
24. The oral care composition of claim 23, wherein the zinc
comprises zinc citrate, zinc lactate, zinc oxide, zinc phosphate,
or combinations thereof.
25. The oral care composition of claim 1, wherein the oral care
composition comprises no added water.
26. The oral care composition of claim 1, wherein the oral care
composition comprises water.
27. The oral care composition of claim 1, wherein the oral care
composition comprises up to 45%, by weight of the composition, of
water.
28. The oral care composition of claim 1, wherein the oral care
composition comprises a dentifrice composition, a unit-dose oral
care composition, an emulsion composition, a leave-on oral care
composition, or combinations thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to oral care compositions
comprising tin, monodentate ligand, and polydentate ligand. The
present invention also relates to improved ligand systems for
stabilizing tin and increasing fluoride uptake and/or soluble
tin.
BACKGROUND OF THE INVENTION
[0002] Oral care compositions have included antimicrobial agents,
such as tin ions, to counter oral bacteria and to prevent and treat
conditions caused by bacteria in the oral cavity, such as formation
of dental plaque and calculus. The formation of dental plaque and
calculus and failure to stop their proliferation are the primary
cause of dental caries, gingivitis, periodontal disease, and tooth
loss. Additionally, tin ions can deposit on surfaces in the oral
cavity to provide protective functions, such as antierosion,
antibacterial, and/or antisensitivity benefits.
[0003] However, tin can be challenging to properly formulate in
oral care compositions due to reactivity between tin and other
components of oral care compositions. Under-stabilizing or
over-stabilizing tin can lead to lower availability of tin ions to
provide the desired benefit. For example, if the tin is
under-stabilized, the tin can react with other components of the
oral care composition, such as silica, water, etc., which can lead
to a lower amount of available tin ions. Additionally, the
remaining under-stabilized tin, when delivered to the oral cavity,
may be hyper-reactive with different oral surfaces, thus impeding
the action of other ingredients or causing excess stain. In
contrast, if the tin is over-stabilized or the chelant-tin
interaction is too strong, tin ions will be tied up when delivered
to the oral cavity, which can also lead to a lower amount of
bioavailable tin ions to produce the desired oral care benefit.
[0004] Thus, the tin-chelant ratio and binding affinity must be
carefully balanced to maximize the amount of available tin ions. As
such, there is a need for oral care compositions comprising a high
amount of available tin ions that are optimally bioavailable for
the desired product benefit.
SUMMARY OF THE INVENTION
[0005] Disclosed herein is an oral care composition comprising (a)
tin; (b) monodentate ligand; and (c) polydentate ligand, wherein
the oral care composition has a tin to monodentate ligand to
polydentate molar ratio of from about 1:0.5:0.5 to about 1:5:5.
[0006] Also disclosed herein is an oral care composition with an
unexpectedly high fluoride uptake and/or unexpectedly high soluble
tin amount.
[0007] Also disclosed herein is an oral care composition comprising
(a) tin; (b) monodentate ligand, the monodentate ligand comprising
carboxylic acid; and (c) polydentate ligand, the polydentate ligand
comprising dicarboxylic acid, tricarboxylic acid, or combinations
thereof, wherein the oral care composition has a tin to monodentate
ligand to polydentate molar ratio of from about 1:0.5:0.5 to about
1:5:5.
[0008] Also disclosed herein is an oral care composition comprising
(a) tin; (b) monodentate ligand, the monodentate ligand comprising
carboxylic acid; and (c) polydentate ligand, the polydentate ligand
comprising polyphosphate, wherein the oral care composition has a
tin to monodentate ligand to polydentate molar ratio of from about
1:1:1 to about 1:5:5.
[0009] Also disclosed herein is an oral care composition comprising
(a) stannous fluoride; (b) monodentate ligand; (c) polydentate
ligand, wherein the oral care composition has a tin to monodentate
ligand to polydentate molar ratio of from about 1:0.5:0.75 to about
1:5:5.
[0010] Also disclosed herein is an oral care composition comprising
(a) tin; (b) monodentate ligand; and (c) polydentate ligand,
wherein the oral care composition has a tin to monodentate ligand
to polydentate molar ratio of from about 1:0.5:0.5 to about 1:5:5
and the composition is free of phytic acid.
[0011] Also disclosed herein is an oral care composition comprising
(a) tin; (b) monodentate ligand; and (c) polydentate ligand,
wherein the oral care composition has a tin to monodentate ligand
to polydentate molar ratio of from about 1:0.5:0.5 to about 1:5:5
and the composition has a pH of greater than about 6.
[0012] Also disclosed herein is an oral care composition comprising
(a) tin; (b) monodentate ligand; (c) polydentate ligand; and (d)
thickening agent comprising xanthan gum, wherein the oral care
composition has a tin to monodentate ligand to polydentate molar
ratio of from about 1:0.5:0.5 to about 1:5:5.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 displays the change in pH of an acid challenge after
hydroxyapatite powder treated with a variety of oral care
compositions was introduced to the acid challenge.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention is directed to oral care compositions
with a tin-chelant and/or tin-ligand ratio that results in an
optimally bioavailable and shelf-stable composition. Thus, the
present invention provides efficacious oral hard tissue solubility
reduction benefits and fluoride uptake benefits while
simultaneously improving soluble tin throughout the shelf-life of
the oral care composition. Such an achievement was realized with
the discovery of optimum ratios of metal to monodentate ligand and
metal to polydentate ligand that produces the desired stability and
reactivity results.
[0015] The chelate effect postulates that complexes of polydentate
ligands with a metal are more stable than the dentate-normalized
equivalent of the monodentate-ligand-stabilized metal complex
(e.g., 1 mole of a bidentate ligand in comparison to 2 moles of a
similarly structured monodentate ligand) because of a reduction in
molar entropy of the bidentate chelate with respect to the
monodentate complex.
[0016] While not wishing to be bound by theory, in the cases of
metals forming complexes in mixed polydentate/monodentate
solutions, configurational restrictions in bonding geometries often
result when using conventional stabilizers (e.g., citrate anion)
that thusly favor the formation of metal-monodentate-polydentate
complexes. Consider the case of stannous metal ion being chelated
by citrate anion. Sn.sup.2+ prefers a tetrahedral bonding geometry.
The tridentate citrate anion can only occupy two of the four
coordinating sites with stannous in this geometry because of steric
restrictions. A monodentate ligand (e.g., gluconate) can thus
participate in the complex at a third coordination site. The excess
electron density (one electron from each of the three coordinating
carboxylate anions minus the 2+ formal tin valency) is then
distributed within the Sn bonding orbitals to the fourth
coordination site that can acquire a hydrogen-bonded water or
hydronium ion when in solution.
[0017] While not wishing to be bound by theory, if instead in the
previous example, the molar ratio of citrate were increased from 1
to 2 and no monodentate ligand were present, the metal chelate
would be over-stabilized resulting in a reduction of Sn
bioavailability and a loss of oral care benefits. This is a direct
result of the chelate effect. Additionally, the metal complex is
under-stabilized if too little of the polydentate ligand is used in
either the mixed- or polydentate-only cases also resulting in a
loss of oral care benefits. Because of the unique properties of
stannous ion in solution (tetrahedral bonding geometry with 2+
formal valence) and in the presence of mixed mono/polydentate
ligands, Sn.sup.2+ prefers mixed-dentate complexes. This is
because, although two polydentate ligands can form a chelate
complex, the resulting distribution of electron density is not
favored thus providing an enthalpic penalty to formation of the
complex.
[0018] Finally, in the case of monodentate-only stabilized metal
complexes, there is no chelate effect and the stabilizing ligands
can easily be replaced by chemical moieties with higher binding
affinities. This results in under-stabilized stannous in the
composition and loss to formula components (e.g., silica) over
time. Thus, unexpectedly, an optimum mixture of mono- and
polydentate coordinating ligands is needed to properly stabilize
the metal ion without impeding its reactivity. As such, the present
invention is directed to oral care compositions that provide an
unexpectedly high soluble tin amount throughout the shelf life of
the oral care composition while providing an optimally reactive
stannous capable of providing tin-related oral care benefits
without interfering with the activity of other reacting
species.
[0019] In FIG. 1, we have illustrated the reduction in
hydroxyapatite solubility reflected by the change in pH (.DELTA.pH)
after 5 minutes of a citric acid solution following the
introduction of a slurry-supernatant-treated HAP powder. The
different metal ligand ratios are indicated at the bottom. We have
illustrated the region of optimum reactivity where the stabilizing
Sn:monodentate:polydentate complex is neither too strong (thus
preventing a solubility reduction benefit) nor too weak (thus
inhibiting fluoride uptake). The optimum reactivity zone is
indicated by the light gray band the cuts horizontally through the
Figure. The samples have been shaded according to: Experimental
Controls (white bar); Monodentate Ligands Only (black bar); Citrate
Polydentate (right diagonal hash); Tripolyphosphate Polydentate
(horizontal hash); Pyrophosphate Polydentate (left diagonal hash);
Oxalate Polydentate (dotted); Mixed Phosphate-Citrate Polydentate
(vertical hash); Mixed Oxalate-Citrate Polydentate (cross hash).
Abbreviations: CCP (Crest Cavity Protection, Procter & Gamble,
Cincinnati, Ohio); CPHAGP (Crest ProHealth Advanced Gum Protection,
Procter & Gamble, Cincinnati, Ohio); Sn (stannous); Gluc
(gluconate); Lac (lactate); Ortho (orthophosphate); Ox (oxalate);
Cit (citrate); Tripoly (tripolyphosphate); Pyro
(pyrophosphate).
Definitions
[0020] To define more clearly the terms used herein, the following
definitions are provided. Unless otherwise indicated, the following
definitions are applicable to this disclosure. If a term is used in
this disclosure but is not specifically defined herein, the
definition from the IUPAC Compendium of Chemical Terminology, 2nd
Ed (1997), can be applied, as long as that definition does not
conflict with any other disclosure or definition applied herein, or
render indefinite or non-enabled any claim to which that definition
is applied.
[0021] The term "oral care composition", as used herein, includes a
product, which in the ordinary course of usage, is not
intentionally swallowed for purposes of systemic administration of
particular therapeutic agents, but is rather retained in the oral
cavity for a time sufficient to contact dental surfaces or oral
tissues. Examples of oral care compositions include dentifrice,
tooth gel, subgingival gel, mouth rinse, mousse, foam, mouth spray,
lozenge, chewable tablet, chewing gum, tooth whitening strips,
floss and floss coatings, breath freshening dissolvable strips, or
denture care or adhesive product. The oral care composition may
also be incorporated onto strips or films for direct application or
attachment to oral surfaces.
[0022] The term "dentifrice composition", as used herein, includes
tooth or subgingival-paste, gel, or liquid formulations unless
otherwise specified. The dentifrice composition may be a
single-phase composition or may be a combination of two or more
separate dentifrice compositions. The dentifrice composition may be
in any desired form, such as deep striped, surface striped,
multilayered, having a gel surrounding a paste, or any combination
thereof. Each dentifrice composition in a dentifrice comprising two
or more separate dentifrice compositions may be contained in a
physically separated compartment of a dispenser and dispensed
side-by-side.
[0023] "Active and other ingredients" useful herein may be
categorized or described herein by their cosmetic and/or
therapeutic benefit or their postulated mode of action or function.
However, it is to be understood that the active and other
ingredients useful herein can, in some instances, provide more than
one cosmetic and/or therapeutic benefit or function or operate via
more than one mode of action. Therefore, classifications herein are
made for the sake of convenience and are not intended to limit an
ingredient to the particularly stated function(s) or activities
listed.
[0024] The term "orally acceptable carrier" comprises one or more
compatible solid or liquid excipients or diluents which are
suitable for topical oral administration. By "compatible," as used
herein, is meant that the components of the composition are capable
of being commingled without interaction in a manner which would
substantially reduce the composition's stability and/or efficacy.
The carriers or excipients of the present invention can include the
usual and conventional components of mouthwashes or mouth rinses,
as more fully described hereinafter: Mouthwash or mouth rinse
carrier materials typically include, but are not limited to one or
more of water, alcohol, humectants, surfactants, and acceptance
improving agents, such as flavoring, sweetening, coloring and/or
cooling agents.
[0025] The term "substantially free" as used herein refers to the
presence of no more than 0.05%, preferably no more than 0.01%, and
more preferably no more than 0.001%, of an indicated material in a
composition, by total weight of such composition.
[0026] The term "essentially free" as used herein means that the
indicated material is not deliberately added to the composition, or
preferably not present at analytically detectable levels. It is
meant to include compositions whereby the indicated material is
present only as an impurity of one of the other materials
deliberately added.
[0027] The term "oral hygiene regimen` or "regimen" can be for the
use of two or more separate and distinct treatment steps for oral
health. e.g. toothpaste, mouth rinse, floss, toothpicks, spray,
water irrigator, massager.
[0028] The term "total water content" as used herein means both
free water and water that is bound by other ingredients in the oral
care composition.
[0029] For the purpose of the present invention, the relevant
molecular weight (MW) to be used is that of the material added when
preparing the composition e.g., if the chelant is a citrate
species, which can be supplied as citric acid, sodium citrate or
indeed other salt forms, the MW used is that of the particular salt
or acid added to the composition but ignoring any water of
crystallization that may be present.
[0030] While compositions and methods are described herein in terms
of "comprising" various components or steps, the compositions and
methods can also "consist essentially of" or "consist of" the
various components or steps, unless stated otherwise.
[0031] As used herein, the word "or" when used as a connector of
two or more elements is meant to include the elements individually
and in combination; for example, X or Y, means X or Y or both.
[0032] As used herein, the articles "a" and "an" are understood to
mean one or more of the material that is claimed or described, for
example, "an oral care composition" or "a bleaching agent."
[0033] All measurements referred to herein are made at about
23.degree. C. (i.e. room temperature) unless otherwise
specified.
[0034] Generally, groups of elements are indicated using the
numbering scheme indicated in the version of the periodic table of
elements published in Chemical and Engineering News, 63(5), 27,
1985. In some instances, a group of elements can be indicated using
a common name assigned to the group; for example, alkali metals for
Group 1 elements, alkaline earth metals for Group 2 elements, and
so forth.
[0035] Several types of ranges are disclosed in the present
invention. When a range of any type is disclosed or claimed, the
intent is to disclose or claim individually each possible number
that such a range could reasonably encompass, including end points
of the range as well as any sub-ranges and combinations of
sub-ranges encompassed therein.
[0036] The term "about" means that amounts, sizes, formulations,
parameters, and other quantities and characteristics are not and
need not be exact, but can be approximate and/or larger or smaller,
as desired, reflecting tolerances, conversion factors, rounding
off, measurement errors, and the like, and other factors known to
those of skill in the art. In general, an amount, size,
formulation, parameter or other quantity or characteristic is
"about" or "approximate" whether or not expressly stated to be
such. The term "about" also encompasses amounts that differ due to
different equilibrium conditions for a composition resulting from a
particular initial mixture. Whether or not modified by the term
"about," the claims include equivalents to the quantities. The term
"about" can mean within 10% of the reported numerical value,
preferably within 5% of the reported numerical value.
[0037] The oral care composition can be in any suitable form, such
as a solid, liquid, powder, paste, or combinations thereof. The
oral care composition can be dentifrice, tooth gel, subgingival
gel, mouth rinse, mousse, foam, mouth spray, lozenge, chewable
tablet, chewing gum, tooth whitening strips, floss and floss
coatings, breath freshening dissolvable strips, or denture care or
adhesive product. The components of the oral care composition can
be incorporated into a film, a strip, a foam, or a fiber-based
dentifrice composition.
[0038] The oral care compositions, as described herein, comprise
tin, monodentate ligand, and polydentate ligand. Additionally, the
oral care compositions can comprise other optional ingredients, as
described below. The section headers below are provided for
convenience only. In some cases, a compound can fall within one or
more sections. For example, stannous fluoride can be a tin compound
and/or a fluoride compound. Additionally, for example, oxalic acid,
or salts thereof, can be a dicarboxylic acid, a polydentate ligand,
and/or a whitening agent.
Tin
[0039] The oral care composition of the present invention comprise
tin, which can be provided by a tin ion source. The tin ion source
can be any suitable compound that can provide tin ions in an oral
care composition and/or deliver tin ions to the oral cavity when
the oral care composition is applied to the oral cavity. The tin
ion source can comprise one or more tin containing compounds, such
as stannous fluoride, stannous chloride, stannous bromide, stannous
iodide, stannous oxide, stannous oxalate, stannous sulfate,
stannous sulfide, stannic fluoride, stannic chloride, stannic
bromide, stannic iodide, stannic sulfide, and/or mixtures thereof.
The tin ion source can comprise stannous fluoride, stannous
chloride, and/or mixture thereof. The tin ion source can also be a
fluoride-free tin ion source, such as stannous chloride.
[0040] The oral care composition can comprise from about 0.0025% to
about 5%, from about 0.01% to about 10%, from about 0.2% to about
1%, from about 0.4% to about 1%, or from about 0.3% to about 0.6%,
by weight of the oral care composition, of tin and/or a tin ion
source.
Monodentate Ligand
[0041] The oral care composition comprises a monodentate ligand
having a molecular weight (MW) of less than 1000 g/mol. A
monodentate ligand has a single functional group that can interact
with the central atom, such as a tin ion. The monodentate ligand
must be suitable for the use in oral care composition, which can be
include being listed in Generally Regarded as Safe (GRAS) list with
the United States Food and Drug Administration or other suitable
list in a jurisdiction of interest.
[0042] The monodentate ligand, as described herein, can include a
single functional group that can chelate to, associate with, and/or
bond to tin. Suitable functional groups that can chelate to,
associate with, and/or bond to tin include carbonyl, amine, among
other functional groups known to a person of ordinary skill in the
art. Suitable carbonyl functional groups can include carboxylic
acid, ester, amide, or ketones.
[0043] The monodentate ligand can comprise a single carboxylic acid
functional group. Suitable monodentate ligands comprising
carboxylic acid can include compounds with the formula R--COOH,
wherein R is any organic structure. Suitable monodentate ligands
comprising carboxylic acid can also include aliphatic carboxylic
acid, aromatic carboxylic acid, sugar acid, salts thereof, and/or
combinations thereof.
[0044] The aliphatic carboxylic acid can comprise a carboxylic acid
functional group attached to a linear hydrocarbon chain, a branched
hydrocarbon chain, and/or cyclic hydrocarbon molecule. The
aliphatic carboxylic acid can be fully saturated or unsaturated and
have one or more alkene and/or alkyne functional groups. Other
functional groups can be present and bonded to the hydrocarbon
chain, including halogenated variants of the hydrocarbon chain. The
aliphatic carboxylic acid can also include hydroxyl acids, which
are organic compounds with an alcohol functional group in the
alpha, beta, or gamma position relative to the carboxylic acid
functional group. A suitable alpha hydroxy acid includes lactic
acid and/or a salt thereof.
[0045] The aromatic carboxylic acid can comprise a carboxylic acid
functional group attached to at least one aromatic functional
group. Suitable aromatic carboxylic acid groups can include benzoic
acid, salicylic acid, and/or combinations thereof.
[0046] The carboxylic acid can include formic acid, acetic acid,
propionic acid, butyric acid, valeric acid, caproic acid, enanthic
acid, caprylic acid, ascorbic acid, benzoic acid, caprylic acid,
cholic acid, glycine, alanine, valine, isoleucine, leucine,
phenylalanine, linoleic acid, niacin, oleic acid, propanoic acid,
sorbic acid, stearic acid, gluconate, lactate, carbonate,
chloroacetic acid, dichloroacetic acid, trichloroacetic acid, salts
thereof, and/or combinations thereof.
[0047] The oral care composition can include from about 0.01% to
about 10%, from about 0.1% to about 15%, from about 1% to about 5%,
or from about 0.0001 to about 25%, by weight of the composition, of
the monodentate ligand.
Polydentate Ligand
[0048] The oral care composition comprises polydentate ligand
having a molecular weight (MW) of less than 1000 g/mol. A
polydentate ligand has at least two functional groups that can
interact with the central atom, such as a tin ion. Additionally,
the polydentate ligand must be suitable for the use in oral care
composition, which can be include being listed in Generally
Regarded as Safe (GRAS) list with the United States Food and Drug
Administration or another suitable list in a jurisdiction of
interest.
[0049] The polydentate ligand, as described herein, can include at
least two functional groups that can chelate to, associate with,
and/or bond to tin. The polydentate ligand can comprise a bidentate
ligand (i.e. with two functional groups), tridentate (i.e. with
three functional groups), tetradentate (i.e. with four functional
groups), etc.
[0050] Suitable functional groups that can chelate to, associate
with, and/or bond to tin include carbonyl, phosphate, nitrate,
amine, among other functional groups known to a person of ordinary
skill in the art. Suitable carbonyl functional groups can include
carboxylic acid, ester, amide, or ketones. Suitable compounds
comprising phosphate include orthophosphate, phosphate,
polyphosphate, salts thereof, and/or combinations thereof. Suitable
phosphate compounds include phosphate salts, organophosphates, or
combinations thereof. Suitable phosphate salts include salts of
orthophosphate, hydrogen phosphate, dihydrogen phosphate, alkylated
phosphates, polyphosphates, and/or combinations thereof.
[0051] The polydentate ligand can comprise two or more carboxylic
acid functional groups. Suitable polydentate ligands comprising
carboxylic acid can include compounds with the formula
HOOC--R--COOH, wherein R is any organic structure. Suitable
polydentate ligands comprising two or more carboxylic acid can also
include dicarboxylic acid, tricarboxylic acid, tetracarboxylic
acid, etc.
[0052] Other suitable polydentate ligands include compounds
comprising at least two phosphate functional groups. Thus, the
polydentate ligand can comprise polyphosphate, as described
herein.
[0053] Other suitable polydentate ligands include hops beta acids,
such as lupulone, colupulone, adlupulone, and/or combinations
thereof. The hops beta acid can be synthetically derived and/or
extracted from a natural source.
[0054] The polydentate ligand can comprise oxalic acid, oxalic
acid, malonic acid, succinic acid, glutaric acid, adipic acid,
pimelic acid, suberic acid, azerlaic acid, sebacic acid,
undecanedioic acid, dodecanedioic acid, bras sylic acid, thapsic
acid, japanic acid, phellogenic acid, equisetolic acid, malic acid,
tartaric acid, citric acid, phytic acid, pyrophosphate,
tripolyphosphate, tetrapolyphosphate, hexametaphoshate, salts
thereof, and/or combinations thereof.
[0055] The oral care composition can include from about 0.01% to
about 10%, from about 0.1% to about 15%, from about 1% to about 5%,
or from about 0.0001 to about 25%, by weight of the composition, of
the polydentate ligand.
Ratio of Tin to Monodentate Ligand to Polydentate Ligand
[0056] The oral care composition, as described herein, comprises a
ratio of tin to monodentate ligand to polydentate ligand that
provides an unexpectedly high amount of soluble tin and/or a
superior fluoride uptake. Suitable ratios of tin to monodentate
ligand to polydentate ligand can be from about 1:0.5:0.5 to about
1:5:5, from about 1:0.5:0.75 to about 1:5:5, from about 1:1:1 to
about 1:5:5, from about 1:1:0.5 to about 1:2.5:2.5, from about
1:1:1 to about 1:2:2, from about 1:0.5:0.5 to about 1:3:1, or from
about 1:0.5:0.5 to about 1:1:3.
[0057] Desired herein are oral care compositions with a soluble Sn
of at least about 1000 ppm, 2000 ppm, 4000 ppm, at least about 4500
ppm, at least about 5000 ppm, at least about 6000 ppm, and/or at
least about 8000 ppm. Also desired herein are oral care
compositions with a fluoride uptake of at least about 6.5
.mu.g/cm.sup.2, at least about 7.0 .mu.g/cm.sup.2, at least about
8.0 .mu.g/cm.sup.2, or at least about 9.0 .mu.g/cm.sup.2 after a
time period of at least about 9 days, 30 days, 65 days, 75 days,
100 days, 200 days, 365 days and/or 400 days.
[0058] In total, while not wishing to be bound by theory it is
believed that the soluble Sn amount is correlated to bioavailable
Sn as it is freely available to provide an oral health benefit.
Fully bound Sn (i.e. Sn that is overchelated) or precipitated Sn
(i.e. insoluble tin salts, such as Sn(OH).sub.2 and/or Sn-based
stains can form when Sn is underchelated) would not be included in
the measurement for soluble Sn. Additionally, while not wishing to
be bound by theory, it is believed that a carefully balanced ratio
of Sn to monodentate and polydentate ligands can provide a high
amount of bioavailable fluoride and Sn ions without some of the
negatives to the use of cationic antimicrobial agents, such as
surface staining. Thus, additional screening experiments were done
to quantify and qualify the ranges and identities of monodentate
and polydentate ligands.
Dicarboxylic Acid
[0059] The polydentate ligand can comprise dicarboxylic acid. The
dicarboxylic acid comprises a compound with two carboxylic acid
functional groups. The dicarboxylic acid can comprise a compound or
salt thereof defined by Formula I.
##STR00001##
[0060] R can be null, alkyl, alkenyl, allyl, phenyl, benzyl,
aliphatic, aromatic, polyethylene glycol, polymer, O, N, P, and/or
combinations thereof.
[0061] The dicarboxylic acid can comprise oxalic acid, malonic
acid, succinic acid, glutaric acid, adipic acid, pimelic acid,
suberic acid, azerlaic acid, sebacic acid, undecanedioic acid,
dodecanedioic acid, bras sylic acid, thap sic acid, japanic acid,
phellogenic acid, equisetolic acid, malic acid, tartaric acid,
salts thereof, or combinations thereof. The dicarboxylic acid can
comprise suitable salts of dicarboxylic acid, such as, for example,
monoalkali metal oxalate, dialkali metal oxalate, monopotassium
monohydrogen oxalate, dipotassium oxalate, monosodium monohydrogen
oxalate, disodium oxalate, titanium oxalate, and/or other metal
salts of oxalate. The dicarboxylic acid can also include hydrates
of the dicarboxylic acid and/or a hydrate of a salt of the
dicarboxylic acid.
[0062] The oral care composition can comprise from about 0.01% to
about 10%, from about 0.1% to about 15%, from about 1% to about 5%,
or from about 0.0001 to about 25%, by weight of the oral care
composition, of dicarboxylic acid.
Tricarboxylic Acid
[0063] The polydentate ligand can comprise tricarboxylic acid. The
tricarboxylic acid comprises a compound with three carboxylic acid
functional groups. The tricarboxylic acid can comprise a compound
or salt thereof defined by Formula II.
##STR00002##
[0064] R can be alkyl, alkenyl, allyl, phenyl, benzyl, aliphatic,
aromatic, polyethylene glycol, polymer, O, N, P, and/or
combinations thereof.
[0065] The tricarboxylic acid can comprise citric acid, isocitric
acid, aconitic acid, propane-1,2,3-tricarboxcylic acid, trimesic
acid, any tricarboxylic acid in the citric acid cycle or Krebs
Cycle, salts thereof, or combinations thereof. The tricarboxylic
acid can comprise suitable salts of tricarboxylic acid, such as for
example, sodium citrate.
[0066] The oral care composition can comprise from about 0.01% to
about 10%, from about 0.1% to about 15%, from about 1% to about 5%,
or from about 0.0001 to about 25%, by weight of the oral care
composition, of tricarboxylic acid.
Polyphosphate
[0067] The polydentate ligand can comprise polyphosphate, which can
be provided by a polyphosphate source. A polyphosphate source can
comprise one or more polyphosphate molecules. Polyphosphates are a
class of materials obtained by the dehydration and condensation of
orthophosphate to yield linear and cyclic polyphosphates, such as
phytic acid, of varying chain lengths. Thus, polyphosphate
molecules are generally identified with an average number (n) of
polyphosphate molecules, as described below. A polyphosphate is
generally understood to consist of two or more phosphate molecules
arranged primarily in a linear configuration, although some cyclic
derivatives may be present.
[0068] Preferred polyphosphates are those having an average of two
or more phosphate groups so that surface adsorption at effective
concentrations produces sufficient non-bound phosphate functions,
which enhance the anionic surface charge as well as hydrophilic
character of the surfaces. Preferred in this invention are the
linear polyphosphates having the formula: XO(XPO.sub.3).sub.nX,
wherein X is sodium, potassium, ammonium, or any other alkali metal
cations and n averages from about 2 to about 21, from about 2 to
about 14, or from about 2 to about 7. Alkali earth metal cations,
such as calcium, are not preferred because they tend to form
insoluble fluoride salts from aqueous solutions comprising a
fluoride ions and alkali earth metal cations. Thus, the oral care
compositions disclosed herein can be free of or substantially free
of calcium pyrophosphate.
[0069] Some examples of suitable polyphosphate molecules include,
for example, pyrophosphate (n=2), tripolyphosphate (n=3),
tetrapolyphosphate (n=4), sodaphos polyphosphate (n=6), hexaphos
polyphosphate (n=13), benephos polyphosphate (n=14),
hexametaphosphate (n=21), which is also known as Glass H.
Polyphosphates can include those polyphosphate compounds
manufactured by FMC Corporation, ICL Performance Products, and/or
Astaris.
[0070] The oral care composition can comprise from about 0.01% to
about 15%, from about 0.1% to about 10%, from about 0.5% to about
5%, from about 1 to about 20%, or about 10% or less, by weight of
the oral care composition, of the polyphosphate source.
Alternatively, the oral care composition can be essentially free
of, substantially free of, or free of polyphosphate. The oral care
composition can be essentially free of, substantially free of, ar
free of cyclic polyphosphate. The oral care composition can be
essentially free of, substantially free of, or free of phytic acid,
which can lead to insoluble tin and/or zinc compounds.
Fluoride
[0071] The oral care composition can comprise fluoride, which can
be provided by a fluoride ion source. The fluoride ion source can
comprise one or more fluoride containing compounds, such as
stannous fluoride, sodium fluoride, potassium fluoride, amine
fluoride, sodium monofluorophosphate, zinc fluoride, and/or
mixtures thereof.
[0072] The fluoride ion source and the tin ion source can be the
same compound, such as for example, stannous fluoride, which can
generate tin ions and fluoride ions. Additionally, the fluoride ion
source and the tin ion source can be separate compounds, such as
when the tin ion source is stannous chloride and the fluoride ion
source is sodium monofluorophosphate or sodium fluoride.
[0073] The fluoride ion source and the zinc ion source can be the
same compound, such as for example, zinc fluoride, which can
generate zinc ions and fluoride ions. Additionally, the fluoride
ion source and the zinc ion source can be separate compounds, such
as when the zinc ion source is zinc phosphate and the fluoride ion
source is stannous fluoride.
[0074] The fluoride ion source can be essentially free of or free
of stannous fluoride. Thus, the oral care composition can comprise
sodium fluoride, potassium fluoride, amine fluoride, sodium
monofluorophosphate, zinc fluoride, and/or mixtures thereof.
[0075] The oral care composition can comprise a fluoride ion source
capable of providing from about 50 ppm to about 5000 ppm, and
preferably from about 500 ppm to about 3000 ppm of free fluoride
ions. To deliver the desired amount of fluoride ions, the fluoride
ion source may be present in the oral care composition at an amount
of from about 0.0025% to about 5%, from about 0.01% to about 10%,
from about 0.2% to about 1%, from about 0.5% to about 1.5%, or from
about 0.3% to about 0.6%, by weight of the oral care composition.
Alternatively, the oral care composition can comprise less than
0.1%, less than 0.01%, be essentially free of, be substantially
free of, or free of a fluoride ion source.
Metal
[0076] The oral care composition, as described herein, can comprise
metal, which can be provided by a metal ion source comprising one
or more metal ions. The metal ion source can comprise or be in
addition to the tin ion source and/or the zinc ion source, as
described herein. Suitable metal ion sources include compounds with
metal ions, such as, but not limited to Sn, Zn, Cu, Mn, Mg, Sr, Ti,
Fe, Mo, B, Ba, Ce, Al, In and/or mixtures thereof. The metal ion
source can be any compound with a suitable metal and any
accompanying ligands and/or anions.
[0077] Suitable ligands and/or anions that can be paired with metal
ion sources include, but are not limited to acetate, ammonium
sulfate, benzoate, bromide, borate, carbonate, chloride, citrate,
gluconate, glycerophosphate, hydroxide, iodide, oxalate, oxide,
propionate, D-lactate, DL-lactate, orthophosphate, pyrophosphate,
sulfate, nitrate, tartrate, and/or mixtures thereof.
[0078] The oral care composition can comprise from about 0.01% to
about 10%, from about 1% to about 5%, or from about 0.5% to about
15% of metal and/or a metal ion source.
Zinc
[0079] The oral care composition can comprise zinc, which can be
provided by a zinc ion source. The zinc ion source can comprise one
or more zinc containing compounds, such as zinc fluoride, zinc
lactate, zinc oxide, zinc phosphate, zinc chloride, zinc acetate,
zinc hexafluorozirconate, zinc sulfate, zinc tartrate, zinc
gluconate, zinc citrate, zinc malate, zinc glycinate, zinc
pyrophosphate, zinc metaphosphate, zinc oxalate, and/or zinc
carbonate. The zinc ion source can be a fluoride-free zinc ion
source, such as zinc phosphate, zinc oxide, and/or zinc
citrate.
[0080] The zinc and/or zinc ion source may be present in the total
oral care composition at an amount of from about 0.01% to about
10%, from about 0.2% to about 1%, from about 0.5% to about 1.5%, or
from about 0.3% to about 0.6%, by weight of the dentifrice
composition. Alternatively, the oral care composition can be
essentially free of, substantially free of, or free of zinc.
pH
[0081] The pH of the oral care compositions as described herein can
be from about 4 to about 7, from about 4.5 to about 6.5, or from
about 4.5 to about 5.5. The pH of the oral care compositions, as
described herein, can also be at least about 6, at least about 6.5,
or at least about 7. The pH of a mouthrinse solution can be
determined as the pH of the neat solution. The pH of a dentifrice
composition can be determined as a slurry pH, which is the pH of a
mixture of the dentifrice composition and water, such as a 1:4,
1:3, or 1:2 mixture of the dentifrice composition and water. The pH
of the oral care compositions as described herein have a preferred
pH of from about 4 to about 10, from about 5 to about 9, from about
6 to 8, or about 7.
[0082] The oral care composition can comprise one or more buffering
agents. Buffering agents, as used herein, refer to agents that can
be used to adjust the slurry pH of the oral care compositions. The
buffering agents include alkali metal hydroxides, carbonates,
sesquicarbonates, borates, silicates, phosphates, imidazole, and
mixtures thereof. Specific buffering agents include monosodium
phosphate, trisodium phosphate, sodium hydroxide, potassium
hydroxide, alkali metal carbonate salts, sodium carbonate,
imidazole, pyrophosphate salts, citric acid, and sodium citrate.
The oral care composition can comprise one or more buffering agents
each at a level of from about 0.1% to about 30%, from about 1% to
about 10%, or from about 1.5% to about 3%, by weight of the present
composition.
Surfactants
[0083] The oral care composition can comprise one or more
surfactants. The surfactants can be used to make the compositions
more cosmetically acceptable. The surfactant is preferably a
detersive material which imparts to the composition detersive and
foaming properties. Suitable surfactants are safe and effective
amounts of anionic, cationic, nonionic, zwitterionic, amphoteric
and betaine surfactants, such as sodium lauryl sulfate, sodium
lauryl isethionate, sodium lauroyl methyl isethionate, sodium
cocoyl glutamate, sodium dodecyl benzene sulfonate, alkali metal or
ammonium salts of lauroyl sarcosinate, myristoyl sarcosinate,
palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl sarcosinate,
polyoxyethylene sorbitan monostearate, isostearate and laurate,
sodium lauryl sulfoacetate, N-lauroyl sarcosine, the sodium,
potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or
N-palmitoyl sarcosine, polyethylene oxide condensates of alkyl
phenols, cocoamidopropyl betaine, lauramidopropyl betaine, palmityl
betaine, sodium cocoyl glutamate, and the like. Sodium lauryl
sulfate is a preferred surfactant. The oral care composition can
comprise one or more surfactants each at a level from about 0.01%
to about 15%, from about 0.3% to about 10%, or from about 0.3% to
about 2.5%, by weight of the oral care composition.
Thickening Agent
[0084] The oral care composition can comprise one or more
thickening agents. Thickening agents can be useful in the oral care
compositions to provide a gelatinous structure that stabilizes the
toothpaste against phase separation. Suitable thickening agents
include polysaccharides, polymers, and/or silica thickeners. Some
non-limiting examples of polysaccharides include starch; glycerite
of starch; gums such as gum karaya (sterculia gum), gum tragacanth,
gum arabic, gum ghatti, gum acacia, xanthan gum, guar gum and
cellulose gum; magnesium aluminum silicate (Veegum); carrageenan;
sodium alginate; agar-agar; pectin; gelatin; cellulose compounds
such as cellulose, carboxymethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxymethyl
carboxypropyl cellulose, methyl cellulose, ethyl cellulose, and
sulfated cellulose; natural and synthetic clays such as hectorite
clays; and mixtures thereof.
[0085] The thickening agent can comprise polysaccharides.
Polysaccharides that are suitable for use herein include
carageenans, gellan gum, locust bean gum, xanthan gum, carbomers,
poloxamers, modified cellulose, and mixtures thereof. Carageenan is
a polysaccharide derived from seaweed. There are several types of
carageenan that may be distinguished by their seaweed source and/or
by their degree of and position of sulfation. The thickening agent
can comprise kappa carageenans, modified kappa carageenans, iota
carageenans, modified iota carageenans, lambda carrageenan, and
mixtures thereof. Carageenans suitable for use herein include those
commercially available from the FMC Company under the series
designation "Viscarin," including but not limited to Viscarin TP
329, Viscarin TP 388, and Viscarin TP 389.
[0086] The thickening agent can comprise one or more polymers. The
polymer can be a polyethylene glycol (PEG), a polyvinylpyrrolidone
(PVP), polyacrylic acid, a polymer derived from at least one
acrylic acid monomer, a copolymer of maleic anhydride and methyl
vinyl ether, a crosslinked polyacrylic acid polymer, of various
weight percentages of the oral care composition as well as various
ranges of average molecular ranges. The polymer can comprise
polyacrylate crosspolymer, such as polyacrylate crosspolymer-6.
Suitable sources of polyacrylate crosspolymer-6 can include Sepimax
Zen.TM. commercially available from Seppic.
[0087] The thickening agent can comprise inorganic thickening
agents. Some non-limiting examples of suitable inorganic thickening
agents include colloidal magnesium aluminum silicate, silica
thickeners. Useful silica thickeners include, for example, include,
as a non-limiting example, an amorphous precipitated silica such as
ZEODENT.RTM. 165 silica. Other non-limiting silica thickeners
include ZEODENT.RTM. 153, 163, and 167, and ZEOFREE.RTM. 177 and
265 silica products, all available from Evonik Corporation, and
AEROSIL.RTM. fumed silicas.
[0088] The oral care composition can comprise from 0.01% to about
15%, from 0.1% to about 10%, from about 0.2% to about 5%, or from
about 0.5% to about 2% of one or more thickening agents.
Abrasive
[0089] The oral care composition of the present invention can
comprise an abrasive. Abrasives can be added to oral care
formulations to help remove surface stains from teeth. Preferably,
the abrasive is a calcium abrasive or a silica abrasive.
[0090] The calcium abrasive can be any suitable abrasive compound
that can provide calcium ions in an oral care composition and/or
deliver calcium ions to the oral cavity when the oral care
composition is applied to the oral cavity. The oral care
composition can comprise from about 5% to about 70%, from about 10%
to about 60%, from about 20% to about 50%, from about 25% to about
40%, or from about 1% to about 50% of a calcium abrasive. The
calcium abrasive can comprise one or more calcium abrasive
compounds, such as calcium carbonate, precipitated calcium
carbonate (PCC), ground calcium carbonate (GCC), chalk, dicalcium
phosphate, calcium pyrophosphate, and/or mixtures thereof.
[0091] The oral care composition can also comprise a silica
abrasive, such as silica gel (by itself, and of any structure),
precipitated silica, amorphous precipitated silica (by itself, and
of any structure as well), hydrated silica, and/or combinations
thereof. The oral care composition can comprise from about 5% to
about 70%, from about 10% to about 60%, from about 10% to about
50%, from about 20% to about 50%, from about 25% to about 40%, or
from about 1% to about 50% of a silica abrasive.
[0092] The oral care composition can also comprise another
abrasive, such as bentonite, perlite, titanium dioxide, alumina,
hydrated alumina, calcined alumina, aluminum silicate, insoluble
sodium metaphosphate, insoluble potassium metaphosphate, insoluble
magnesium carbonate, zirconium silicate, particulate thermosetting
resins and other suitable abrasive materials. The oral care
composition can comprise from about 5% to about 70%, from about 10%
to about 60%, from about 10% to about 50%, from about 20% to about
50%, from about 25% to about 40%, or from about 1% to about 50% of
another abrasive.
Amino Acid
[0093] The oral care composition can comprise amino acid. The amino
acid can comprise one or more amino acids, peptide, and/or
polypeptide, as described herein.
[0094] Amino acids, as in Formula II, are organic compounds that
contain an amine functional group, a carboxyl functional group, and
a side chain (R in Formula III) specific to each amino acid.
Suitable amino acids include, for example, amino acids with a
positive or negative side chain, amino acids with an acidic or
basic side chain, amino acids with polar uncharged side chains,
amino acids with hydrophobic side chains, and/or combinations
thereof. Suitable amino acids also include, for example, arginine,
histidine, lysine, aspartic acid, glutamic acid, serine, threonine,
asparagine, glutamine, cysteine, selenocysteine, glycine, proline,
alanine, valine, isoleucine, leucine, methionine, phenylalanine,
tyrosine, tryptophan, citrulline, ornithine, creatine,
diaminobutanoic acid, diaminoproprionic acid, salts thereof, and/or
combinations thereof.
[0095] Suitable amino acids include the compounds described by
Formula III, either naturally occurring or synthetically derived.
The amino acid can be zwitterionic, neutral, positively charged, or
negatively charged based on the R group and the environment. The
charge of the amino acid, and whether particular functional groups,
can interact with tin at particular pH conditions, would be well
known to one of ordinary skill in the art.
##STR00003##
[0096] Suitable amino acids include one or more basic amino acids,
one or more acidic amino acids, one or more neutral amino acids, or
combinations thereof.
[0097] The oral care composition can comprise from about 0.01% to
about 20%, from about 0.1% to about 10%, from about 0.5% to about
6%, or from about 1% to about 10% of amino acid, by weight of the
oral care composition.
[0098] The term "neutral amino acids" as used herein include not
only naturally occurring neutral amino acids, such as alanine,
asparagine, cysteine, glutamine, glycine, isoleucine, leucine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine, valine, but also biologically acceptable amino acid which
has an isoelectric point in range of pH 5.0 to 7.0. The
biologically preferred acceptable neutral amino acid has a single
amino group and carboxyl group in the molecule or a functional
derivative hereof, such as functional derivatives having an altered
side chain albeit similar or substantially similar physio chemical
properties. In a further embodiment the amino acid would be at
minimum partially water soluble and provide a pH of less than 7 in
an aqueous solution of 1 g/1000 ml at 25.degree. C.
[0099] Accordingly, neutral amino acids suitable for use in the
invention include, but are not limited to, alanine, aminobutyrate,
asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline,
isoleucine, leucine, methionine, phenylalanine, proline, serine,
taurine, threonine, tryptophan, tyrosine, valine, salts thereof, or
mixtures thereof. Preferably, neutral amino acids used in the
composition of the present invention may include asparagine,
glutamine, glycine, salts thereof, or mixtures thereof. The neutral
amino acids may have an isoelectric point of 5.0, or 5.1, or 5.2,
or 5.3, or 5.4, or 5.5, or 5.6, or 5.7, or 5.8, or 5.9, or 6.0, or
6.1, or 6.2, or 6.3, or 6.4, or 6.5, or 6.6, or 6.7, or 6.8, or
6.9, or 7.0, in an aqueous solution at 25.degree. C. Preferably,
the neutral amino acid is selected from proline, glutamine, or
glycine, more preferably in its free form (i.e. uncomplexed). If
the neutral amino acid is in its salt form, suitable salts include
salts known in the art to be pharmaceutically acceptable salts
considered to be physiologically acceptable in the amounts and
concentrations provided.
Whitening Agent
[0100] The oral care composition may comprise from about 0.1% to
about 10%, from about 0.2% to about 5%, from about 1% to about 5%,
or from about 1% to about 15%, by weight of the oral care
composition, of a whitening agent. The whitening agent can be a
compound suitable for whitening at least one tooth in the oral
cavity. The whitening agent may include peroxides, metal chlorites,
perborates, percarbonates, peroxyacids, persulfates, dicarboxylic
acids, and combinations thereof. Suitable peroxides include solid
peroxides, hydrogen peroxide, urea peroxide, calcium peroxide,
benzoyl peroxide, sodium peroxide, barium peroxide, inorganic
peroxides, hydroperoxides, organic peroxides, and mixtures thereof.
Suitable metal chlorites include calcium chlorite, barium chlorite,
magnesium chlorite, lithium chlorite, sodium chlorite, and
potassium chlorite. Other suitable whitening agents include sodium
persulfate, potassium persulfate, peroxydone, 6-phthalimido peroxy
hexanoic acid, Pthalamidoperoxycaproic acid, or mixtures
thereof.
Humectant
[0101] The oral care composition can comprise one or more
humectants, have low levels of a humectant, or be free of a
humectant. Humectants serve to add body or "mouth texture" to an
oral care composition or dentifrice as well as preventing the
dentifrice from drying out. Suitable humectants include
polyethylene glycol (at a variety of different molecular weights),
propylene glycol, glycerin (glycerol), erythritol, xylitol,
sorbitol, mannitol, butylene glycol, lactitol, hydrogenated starch
hydrolysates, and/or mixtures thereof. The oral care composition
can comprise one or more humectants each at a level of from 0 to
about 70%, from about 5% to about 50%, from about 10% to about 60%,
or from about 20% to about 80%, by weight of the oral care
composition.
Water
[0102] The oral care composition of the present invention can be a
dentifrice composition that is anhydrous, a low water formulation,
or a high water formulation. In total, the oral care composition
can comprise from 0% to about 99%, about 20% or greater, about 30%
or greater, about 50% or greater, up to about 45%, or up to about
75%, by weight of the composition, of water. Preferably, the water
is USP water.
[0103] In a high water dentifrice formulation, the dentifrice
composition comprises from about 45% to about 75%, by weight of the
composition, of water. The high water dentifrice composition can
comprise from about 45% to about 65%, from about 45% to about 55%,
or from about 46% to about 54%, by weight of the composition, of
water. The water may be added to the high water dentifrice
formulation and/or may come into the composition from the inclusion
of other ingredients.
[0104] In a low water dentifrice formulation, the dentifrice
composition comprises from about 10% to about 45%, by weight of the
composition, of water. The low water dentifrice composition can
comprise from about 10% to about 35%, from about 15% to about 25%,
or from about 20% to about 25%, by weight of the composition, of
water. The water may be added to the low water dentifrice
formulation and/or may come into the composition from the inclusion
of other ingredients.
[0105] In an anhydrous dentifrice formulation, the dentifrice
composition comprises less than about 10%, by weight of the
composition, of water. The anhydrous dentifrice composition
comprises less than about 5%, less than about 1%, or 0%, by weight
of the composition, of water. The water may be added to the
anhydrous formulation and/or may come into the dentifrice
composition from the inclusion of other ingredients.
[0106] The dentifrice composition can also comprise other orally
acceptable carrier materials, such as alcohol, humectants,
polymers, surfactants, and acceptance improving agents, such as
flavoring, sweetening, coloring and/or cooling agents.
[0107] The oral care composition can also be a mouth rinse
formulation. A mouth rinse formulation can comprise from about 75%
to about 99%, from about 75% to about 95%, or from about 80% to
about 95% of water.
Other Ingredients
[0108] The oral care composition can comprise a variety of other
ingredients, such as flavoring agents, sweeteners, colorants,
preservatives, buffering agents, or other ingredients suitable for
use in oral care compositions, as described below.
[0109] Flavoring agents also can be added to the oral care
composition. Suitable flavoring agents include oil of wintergreen,
oil of peppermint, oil of spearmint, clove bud oil, menthol,
anethole, methyl salicylate, eucalyptol, cassia, 1-menthyl acetate,
sage, eugenol, parsley oil, oxanone, alpha-irisone, marjoram,
lemon, orange, propenyl guaethol, cinnamon, vanillin, ethyl
vanillin, heliotropine, 4-cis-heptenal, diacetyl,
methyl-para-tert-butyl phenyl acetate, and mixtures thereof.
Coolants may also be part of the flavor system. Preferred coolants
in the present compositions are the paramenthan carboxyamide agents
such as N-ethyl-p-menthan-3-carboxamide (known commercially as
"WS-3") or N-(Ethoxycarbonylmethyl)-3-p-menthanecarboxamide (known
commercially as "WS-5"), and mixtures thereof. A flavor system is
generally used in the compositions at levels of from about 0.001%
to about 5%, by weight of the oral care composition. These
flavoring agents generally comprise mixtures of aldehydes, ketones,
esters, phenols, acids, and aliphatic, aromatic and other
alcohols.
[0110] Sweeteners can be added to the oral care composition to
impart a pleasing taste to the product. Suitable sweeteners include
saccharin (as sodium, potassium or calcium saccharin), cyclamate
(as a sodium, potassium or calcium salt), acesulfame-K, thaumatin,
neohesperidin dihydrochalcone, ammoniated glycyrrhizin, dextrose,
levulose, sucrose, mannose, sucralose, stevia, and glucose.
[0111] Colorants can be added to improve the aesthetic appearance
of the product. Suitable colorants include without limitation those
colorants approved by appropriate regulatory bodies such as the FDA
and those listed in the European Food and Pharmaceutical Directives
and include pigments, such as TiO.sub.2, and colors such as
FD&C and D&C dyes.
[0112] Preservatives also can be added to the oral care
compositions to prevent bacterial growth. Suitable preservatives
approved for use in oral compositions such as methylparaben,
propylparaben, benzoic acid, and sodium benzoate can be added in
safe and effective amounts.
[0113] Titanium dioxide may also be added to the present
composition. Titanium dioxide is a white powder which adds opacity
to the compositions. Titanium dioxide generally comprises from
about 0.25% to about 5%, by weight of the oral care
composition.
[0114] Other ingredients can be used in the oral care composition,
such as desensitizing agents, healing agents, other caries
preventative agents, chelating/sequestering agents, vitamins, amino
acids, proteins, other anti-plaque/anti-calculus agents,
opacifiers, antibiotics, anti-enzymes, enzymes, pH control agents,
oxidizing agents, antioxidants, and the like.
Oral Care Composition Forms
[0115] Suitable compositions for the delivery of the tin,
monodentate ligand, and/or polydentate ligand include emulsion
compositions, such as the emulsions compositions of U.S. Patent
Application Publication No. 2018/0133121, which is herein
incorporated by reference in its entirety, unit-dose compositions,
such as the unit-dose compositions of U.S. Patent Application
Publication No. 2019/0343732, which is herein incorporated by
reference in its entirety, leave-on oral care compositions, jammed
emulsions, dentifrice compositions, mouth rinse compositions,
mouthwash compositions, tooth gel, subgingival gel, mouth rinse,
mousse, foam, mouth spray, lozenge, chewable tablet, chewing gum,
tooth whitening strips, floss and floss coatings, breath freshening
dissolvable strips, denture care products, denture adhesive
products, or combinations thereof.
Examples
[0116] The invention is further illustrated by the following
examples, which are not to be construed in any way as imposing
limitations to the scope of this invention. Various other aspects,
modifications, and equivalents thereof which, after reading the
description herein, may suggest themselves to one of ordinary skill
in the art without departing from the spirit of the present
invention or the scope of the appended claims.
Fluoride Uptake
[0117] The Enamel Fluoride Uptake by FDA Method 40 is a method used
to determine the amount of fluoride delivered to demineralized
enamel specimens from a single 30-minute treatment of 1:3
dentifrice slurry supernatant.
[0118] A core of sound human enamel with a diameter of 3-4 mm was
extracted from whole human teeth. The cores were mounted on an
acrylic rod and the surfaces were ground using 600 grit. The cores
were then polished with 0.05.mu. polish (Alumina Suspension Gamma
B, MetLab Corp, catalog #M303-128). Specimens were stored in an
airtight container above a small amount of deionized water
(.about.1-5 mL) in a standard laboratory refrigerator
(.about.2-4.degree. C.).
[0119] Each enamel specimen was inspected and samples with large
cracks or uneven calcification were discarded. Specimens were
polished again for 10 minutes using 0.05.mu. polish. Samples were
sonicated with a sonicator in deionized water for 15-30 min. Enamel
specimens were then rinsed with standard deionized water and wiped
to remove any residual polish.
[0120] Enamel specimens were then demineralized. 25 mL of MHDP
(N-2-hydroxyethyl, methane hydroxy diphosphonate) demineralization
solution (0.025M lactic acid, 2.times.10.sup.-4M MHDP) was placed
in a 30 mL plastic vial for each specimen. An enamel specimen was
placed on the cap of each vial. Each cap was placed on the top of
the vial to submerge the enamel specimen in the MHDP
demineralization solution. The enamel specimen was not allowed to
touch the bottom of the vial. Specimens were left in the
demineralization solution for 48 hours at ambient conditions to
form artificial caries lesions. The rods were tapped twice daily to
remove any bubbles. After 48 hours, specimens were removed from the
demineralization solution and rinsed thoroughly with deionized
water.
[0121] If the sample was a paste dentifrice, 10 g of dentifrice was
placed in a 50 mL tri-pour plastic beaker. 30 mL of deionized water
was added to the beaker. An x-shaped stir bar was placed on top of
the dentifrice in each beaker and the beaker was placed on a
magnetic stir plate. The dentifrice was broken up with a wooden
stick until the stir bar is capable of spinning freely at 300-400
rpm. The dentifrice slurry was stirred for 20 minutes. The slurry
was transferred to a centrifuge tube and centrifuged for 30 minutes
at 11,000 rpm.
[0122] Slurry supernatants were decanted into a 50 mL tri-pour
plastic beaker. An x-shaped stir bar was placed in the beaker and
the beaker was placed on a magnetic stir plate. The stir plate was
turned to 300-400 rpm. Lesioned enamel specimens were suspended
into each treatment. Each sample was treated for 30 minutes. After
30 minutes, each sample was rinsed with deionized water. Samples
were stored in an airtight container above a small amount of
deionized water (.about.1-5 mL) in a standard laboratory
refrigerator (.about.2-4.degree. C.).
[0123] The samples were analyzed for fluoride content analysis by
collecting a portion of milled enamel powder following drilling to
a depth of 50 micro-meters, dissolving that enamel in acid, then
neutralizing and buffering it. Upon drilling a sample from the
enamel specimen, the area of the enamel drilled was recorded.
[0124] Fluoride uptake was directly measured using a Fluoride Ion
Specific Electrode (Thermo Scientific, Orion, 96-09-00, Waltham,
Mass.). Each specimen sample was placed on the end of the
electrode. A value of mV was recorded. This value was converted to
ppm fluoride by using a standard curve of prepared fluoride
standards. Fluoride uptake was calculated by dividing the mass of
fluoride in .mu.g by the total area sampled with the microdrill
biopsy.
[0125] The Enamel Fluoride Uptake method is based upon FDA Test
Method #40. The results for enamel fluoride uptake are provided
herein.
Soluble Sn
[0126] This method is suitable for determination of soluble tin in
oral care toothpaste or dentifrice compositions from about 5 to
about 5,000 ppm Sn in the aqueous slurry supernatant. The slurry
was prepared by mixing 1 part toothpaste with 3 parts water. An
aliquot of slurry was acid digested, diluted, and analyzed by
inductively coupled plasma optical emission spectrometry (ICP-OES)
for each toothpaste measured. Results are reported here as ppm in
the neat aqueous phase of the toothpaste and/or dentifrice.
[0127] Several standards and reagents were prepared prior to the
beginning of the analysis. A 5% hydrochloric acid/5% Nitric acid
rinse solution was prepared by transferring 100 mL each of
concentrated HCl and concentrated HNO.sub.3 using a graduated
cylinder to a 2 L volumetric flask containing about 1 L of
ultrapure, 18 M.OMEGA. (DI) water. The solution was swirled to mix
and diluted to the mark of the graduated flask then mixed well by
repeated flask inversion.
[0128] A 1000 mg/L tin and 1000 mg/L gallium standard solution were
purchased (Sigma Aldrich, Merck KG.alpha.A, Darmstadt, Germany) for
preparation of the standard solutions according to TABLE 1. A pipet
was used to transfer accurate quantities of the standards to a 50
mL volumetric flask while a graduated cylinder was used for the
concentrated acids. After transfer, the volumetric flask was filled
to the line with DI water and mixed well.
TABLE-US-00001 TABLE 1 Soluble Sn Standard Solution Compositions
Conc HNO.sub.3 Conc HCL 1000 mg/L 1000 mg/L Solution (mL) (mL) Sn
Std (mL) Ga Std (mL) Cal Blank 2.5 2.5 0 0.2 Cal 10 mg/L Sn 2.5 2.5
0.5 0.2 LLOQ 0.5 mg/L Sn 2.5 2.5 0.025 0.2 QC 5 mg/L Sn 2.5 2.5
0.25 0.2
[0129] Slurries were prepared by weighing 2.00 grams of sample into
a tared round bottom 38 mL centrifuge tube containing 10 glass
beads. The weight was recorded to a minimum of 0.001 g. Immediately
before slurrying, 6.0 mL of DI water was transferred to the tubes.
Tubes were capped and placed on a vortexer, mixing the samples for
60 minutes at 1200 rpm. The tubes were removed from the vortexer
immediately following completion of the mixing cycle and placed in
a centrifuge. They were centrifuged at 21,000 relative centrifugal
force (RCF) for 10 minutes. Immediately following completion of
centrifugation, the tubes were removed, and the supernatant was
gently mixed by inverting slowly three times making sure the solid
plug at the bottom of the centrifuge tube was not disturbed before
the sample was decanted. The supernatant was then decanted into a15
mL screw cap sample tube, making sure most of the supernatant was
transferred.
[0130] The supernatant samples were then digested by accurately
weighing (to 0.001 g) a 0.5 mL aliquot of supernatant into a 50 mL
Falcon tube. Then 2.5 mL of concentrated HCl and HNO.sub.3 were
added. The tubes were covered with a polypropylene watch glass and
placed in a preheated block digester at 90.degree. C. for 30
minutes. The samples were removed the from the heat, the watch
class was rinsed three times with DI water (with about 1 mL each
time), and that rinsate was added to the digested supernatant. The
gallium standard (0.2 mL) was pipetted into the digested
supernatant and then the supernatant samples were diluted to 50 mL
with DI water. The tubes were capped and mixed. A digestion method
blank was prepared in the same manner using 0.5 mL of DI water
instead of supernatant. A method blank was prepared and analyzed
for each set of hot block digestions if more samples were prepared
than could fit into the hot block at once.
[0131] The ICP-OES (Perkin-Elmer 8300, Waltham, Mass., USA) was
operated by a trained and qualified operator with demonstrated
capability of running the instrument and accurately determining the
quantity of tin in oral care compositions. The ICP-OES operation
parameters were selected based on the model and configuration
according to the manufacturer's instructions. Samples were analyzed
according to the following protocol: [0132] 1. The ICP-OES was
preheated and optimized according to the manufacturer's guidelines.
Recommended system checks were performed. The system was
conditioned for 30 minutes prior to analysis by running the
HCl/HNO.sub.3 rinse solution through the sample introduction
system. [0133] 2. The method for determining tin using a gallium
internal standard at the manufacturer recommended wavelengths,
integration times, and observation modes was loaded into the
operating computer. [0134] 3. The 5% HCl/5% HNO.sub.3 rinse
solution was used to rinse the sample introduction system between
the analysis of each blank, standard, or test solution. [0135] 4.
Three to five readings were recorded for all solutions during
analysis. [0136] 5. The calibration blank was analyzed. [0137] 6.
The 10 ppm Sn standard was measured. [0138] 7. The 5 ppm Sn
standard was measured. [0139] 8. The 0.5 ppm LLOQ tin standard was
measured. [0140] 9. The method blank was measured. [0141] 10. The
test solutions were measured. [0142] 11. The 5 ppm Sn standard was
re-measured after every sixth test solution and after the last
sample. Enough standard was made to complete the analysis. [0143]
12. The 0.5 ppm LLOQ tin standard was measured at the end of the
sample analysis. The analysis was considered successful if the %
relative standard deviation of the replicate readings for the 10
ppm and the 5 ppm tin standards was less than about 3%. The 5-ppm
check standard was within 96-104% of its value. The LLOQ was within
75-125% of its value. The method blank showed less tin signal
intensity than the LLOQ sample. The recovery of the internal
standard in each analyzed solution was within 90-130% of its
value.
[0144] The soluble tin was determined according to the following
formula:
Soluble .times. .times. Tin .times. .times. in .times. .times.
Composition = Sn .times. .times. from .times. .times. ICP .times.
.times. ( .mu.g mL ) .times. Final .times. .times. volume .times.
.times. of .times. .times. test .times. .times. solution .times.
.times. ( mL ) Supernatant .times. .times. Weight .times. .times. (
g ) .times. Soluble .times. .times. Mass .times. .times. of .times.
.times. Composition .times. .times. ( g ) + Slurry .times. .times.
Water .times. .times. ( g ) Total .times. .times. Composition
.times. .times. Mass .times. .times. ( g ) . FORMULA .times.
.times. IV ##EQU00001##
HAP Dissolution
[0145] The HAP dissolution method was designed to test the acid
protection of a chosen test dentifrice. After treating
hydroxyapatite powder (HAP) with test dentifrice slurries, the HAP
was added to an acidic media and the change in pH was an indicator
of the degree of surface adsorption and/or protection from
acid.
[0146] Dentifrice slurries (1:3 paste:water) were prepared for all
treatment compositions. Specifically, 10 g of dentifrice paste was
combined with 30 g of deionized water in a 50 mL container with a
stir bar. The dentifrice was broken up with a spatula until the
stir bar moved freely at 300-400 rpm. The slurry was mixed on the
stir plate for 10-20 minutes and/or until a uniform slurry was
formed. The paste slurries were centrifuged at 15,000 rpm for 15
min to separate the solid components from the supernatant.
[0147] For each treatment, including for the water control, 0.300 g
of hydroxyapatite powder (HAP) was placed into a 50 mL round bottom
centrifuge tube with 4, 4 mm glass beads. For treatment with a
dentifrice paste, 24 mL of the prepared dentifrice supernatant was
added to the HAP. Each treated HAP sample was immediately vortex
mixed at 2500 rpm for 2 minutes. All samples were then centrifuged
at 15,000 rpm for 15 minutes. The liquid phase was decanted out of
the centrifuge tube, which left a HAP pellet. The remaining HAP
pellet was rinsed by adding deionized water, vortex mixing at 2500
rpm for 1 minute to completely disperse the pellet, centrifuging at
15,000 rpm for 15 minutes, and the liquid phase was decanted out of
the centrifuge tube then discarded. This rinsing step was repeated
two more times. The treated HAP pellet was dried in a 55.degree. C.
oven overnight.
[0148] Samples of HAP were analyzed for ApH. 25 mL of 10 mM citric
acid (1.9212 g of citric acid in 1 L of deionized water) was added
to a 50 mL beaker with a stir bar. The beaker was placed on a stir
plate (Metrohm, Herisau, Switerland, Model No. 728) and turned on.
The Titrano pH electrode (Metrohm, Herisau, Switzerland, Model No.
719S) was placed in the stirring beaker with citric acid. After
equilibration of the citric acid solution (until pH reads of
2.5.+-.0.001 pH for 30 seconds), 50 mg of the dried HAP powder was
added to the citric acid solution. The pH was recorded at 5 min.
The .DELTA.pH is determined by subtracting the pH reading at 5
minutes from the stable pH reading obtained immediately prior to
adding the treated HAP powder.
TABLE-US-00002 TABLE 2 Compositions Ex. 1 Ex. 2 Ex. 3 Ex. 4
1:1:0.33 1:1:0.67 1:1:1 1:2:1 Component (wt %) (wt %) (wt %) (wt %)
Sorbitol 48.0000 48.0000 48.0000 47.0000 Treated Water 21.1311
20.6161 20.0811 20.3791 SnF.sub.2 0.4540 0.4540 0.4540 0.4540
SnCl.sub.2 10% 0.5619 0.5619 0.5619 0.5619 silica blend Sodium
Gluconate 1.3000 1.3000 1.3000 1.3000 NaOH (50%) 0.8700 0.8700
0.8700 0.8700 Saccharin 0.4000 0.4000 0.4000 0.4000 Sucralose (25%)
0.2000 0.2000 0.2000 0.2000 Xanthan Gum 0.8750 0.8750 0.8750 0.8750
Carrageenan 1.5000 1.5000 1.5000 1.5000 Zinc Lactate -- -- -- 0.735
Zinc Citrate 0.5330 0.5330 0.5330 -- Na Citrate -- 0.5150 1.0500
1.5500 TiO.sub.2 0.5000 0.5000 0.5000 0.5000 Silica 17.5000 17.5000
17.5000 17.5000 SLSS (29%) 5.0000 5.0000 5.0000 5.0000 Flavor
1.1750 1.1750 1.1750 1.1750
[0149] TABLE 2 describes the compositions tested for fluoride
uptake and soluble Sn. Ex. 1 was a dentifrice composition with
stannous fluoride and stannous chloride. Ex. 1 included at least
two ligands for Sn:polydentate ligand (citrate) and monodentate
ligand (gluconate). Citrate ions were provided by zinc citrate.
Gluconate ions were provided by sodium gluconate. The molar ratio
of Sn:mondentate:polydentate was 1 to 1 to 0.33 in Ex. 1.
[0150] Ex. 2 included monodentate ligand (gluconate) and
polydentate ligand (citrate). Ex. 2 included additional amounts of
polydentate ligand through the addition of sodium citrate. The
molar ratio of Sn:monodentate:polydentate was 1 to 1 to 0.67. Ex. 3
included monodentate ligand (gluconate) and polydentate ligand
(citrate). Ex. 3 included additional amounts of polydentate ligand
through the addition of sodium citrate. The molar ratio of
Sn:monodentate:polydentate was 1 to 1 to 1. Ex. 4 included
monodentate ligand (gluconate and lactate) and polydentate ligand
(citrate). The molar ratio of Sn:monodentate:polydentate was 1 to 2
to 1 with an additional amount of monodentate ligand. The
additional monodentate ligand was provided by zinc lactate.
[0151] TABLE 3 showed the fluoride uptake of Ex. 1-4 under a
variety of ligand ratios. The fluoride uptake increased with
additional amounts of ligand. For example, as the Sn to monodentate
to polydentate ligand ratio increased from 1 to 1 to 0.33 (Ex. 1)
to 1 to 1 to 1 (Ex. 3), the fluoride uptake increased from 6.31
.mu.g/cm.sup.2 at 9 days to 7.61 .mu.g/cm.sup.2. This result was
even more apparent at 230 days with a fluoride uptake of 5.86
.mu.g/cm.sup.2 for 1 to 1 to 0.33 (Ex. 1), but a fluoride uptake of
11.82 .mu.g/cm.sup.2 for 1 to 1 to 1 (Ex. 3). The fluoride uptake
increased to 9.08 .mu.g/cm.sup.2 upon the addition of zinc lactate
(Ex. 4). In total, the increased fluoride uptake trend is
consistent for at least a year. These increases in fluoride uptake
were unexpected because the amount of fluoride was held constant.
Instead, the only formulation change was the balancing of
ligands.
TABLE-US-00003 TABLE 3 Fluoride Uptake (in .mu.g/cm.sup.2) Example
Sn:Mono:Poly.sup.a ~9 d ~30 d ~65 d ~85 d ~230 d ~400 d 1 1:1:0.33
6.31 5.82 6.91 6.75 5.86 5.29 2 1:1:0.67 6.69 7.6 8.08 7.36 7.74
6.22 3 1:1:1 7.61 9.44 8.93 7.51 11.82 5.95 4 1:2:1 9.08 9.15 9.81
8.11 9.51 5.83 .sup.aSn:Monodentate Ligand:Polydentate Ligand Molar
Ratio
[0152] While not wishing to be bound by theory, we believe that the
under-stabilized Sn in Ex. 1 results in Sn being hyper reactive
with the surface of enamel and depositing a layer on the surface
that interferes with fluoride uptake. Sn is known to deposit onto
the enamel surface as a means of providing resistance to plaque and
dietary acids. Such a layer, if formed too thickly or too quickly,
can interfere with the penetration of fluoride into caries lesions.
It is believed that a carefully balanced ratio of Sn to monodentate
and polydentate ligands can provide a high amount of bioavailable
fluoride and Sn ions without some of the negatives to the use of
cationic antimicrobial agents.
TABLE-US-00004 TABLE 4 Soluble Sn (ppm) Example Sn:Mono:Poly.sup.a
~15 d ~45 d ~75 d ~100 d ~200 d ~365 d 1 1:1:0.33 3871 3314 2970
2863 2657 2653 2 1:1:0.67 4368 3894 3722 3203 3020 3268 3 1:1:1
4715 4276 4085 3856 3474 3299 4 1:2:1 5349 4200 4352 3856 3604 3429
.sup.aSn:Monodentate Ligand:Polydentate Ligand Molar Ratio
[0153] TABLE 4 unexpectedly shows that providing additional amounts
of polydentate ligand will lead to increased soluble Sn despite the
amount of Sn being held constant. While not wishing to be bound by
theory it is believed that the soluble Sn amount is correlated to
bioavailable Sn as it is freely available to provide an oral health
benefit. Fully bound Sn (i.e. Sn that is overchelated) or
precipitated Sn (i.e. insoluble tin salts, such as Sn(OH).sub.2
and/or Sn-based stains can form when Sn is underchelated) would not
be included in the measurement for soluble Sn. For example, as the
Sn to monodentate to polydentate ligand ratio increased from 1 to 1
to 0.33 (Ex. 1) to 1 to 1 to 1 (Ex. 3), the soluble Sn amount
increased from 3871 ppm to 4715 ppm at 15 days. This increase in
soluble Sn was still apparent at 365 days with an increased soluble
Sn amount from 2653 ppm (Ex. 1) to 3299 ppm (Ex. 4). There was also
an increased amount of soluble Sn when an additional monodentate
ligand was added to the 1 to 1 to 1 ratio (Ex. 4). The soluble Sn
amount of Ex. 4 was at 5349 ppm at 15 days and 3429 ppm at 365
days.
[0154] While not wishing to be bound by theory, it is believed that
a carefully balanced ratio of Sn to monodentate and polydentate
ligands can provide a high amount of bioavailable fluoride and Sn
ions without some of the negatives to the use of cationic
antimicrobial agents, such as surface staining or interference with
the uptake of fluoride. Thus, additional screening experiments were
done to quantify and qualify the ranges and identities of
monodentate and polydentate ligands.
[0155] The HAP dissolution method allows for the ability to screen
far larger number of conditions in just a few days as opposed to
fluoride uptake and/or soluble Sn measurements, which can take
months. The HAP dissolution method measures the amount of material
deposited on the surface of a hydroxyapatite (HAP) powder. The
.DELTA.pH is monitored as pre-treated hydroxyapatite powder is
treated with an acid challenge. A lower .DELTA.pH indicated more
material deposited on the surface of the HAP powder particles
because the acid was not able to dissolve the HAP coated with F
and/or Sn. In contrast, a higher .DELTA.pH is correlated with less
material depositing on the surface of the HAP powder because the
acid was able to dissolve the uncoated HAP.
[0156] A suitable composition should at least outperform (i.e.
deposit more material) the positive control of Crest.RTM. Cavity
Protection (1100 ppm NaF, no Sn ions) with a .DELTA.pH less than
about 0.9. Such performance would indicate that the Sn is not
over-stabilized. However, an under-stabilized composition may be
hyper reactive with the HAP powder resulting in thick, expansive,
acid-resistant coatings on the HAP powder surface indicative of
future interference with fluoride uptake into enamel. Consequently,
the .DELTA.pH should not be less than ca. 0.4. Such performance
(i.e., .DELTA.pH<ca. 0.4) would indicate that the Sn is
under-stabilized. Thus, in total, the optimized, or Goldilocks
range, for Sn stabilization is indicated by a .DELTA.pH in HAP
dissolution greater than about 0.4 but less than about 0.9 for a
composition that has been formulated with approximately 1100 ppm
fluoride. The range may shift depending on fluoride content;
however, .DELTA.pH of the Sn-containing composition should be less
than its Sn placebo and more than about 0.4. The preferred zone
relative to control formulas is illustrated in FIG. 1.
TABLE-US-00005 TABLE 5 Gluconate and Citrate Chelation Treatment
Sn:Mono:Poly Average .DELTA.pH % RSD Water N/A 1.42 1.69 Crest
.RTM. Cavity Protection N/A 0.95 0.72 Sn:Gluconate 1:1:0 0.31 4.95
1:1 Sn Gluconate 1:2:0 0.29 3.00 1:2 Sn:Gluconate:Citrate 1:1:1
0.64 1.32 1:1:1
[0157] TABLE 5 shows the HAP dissolution results for aqueous
solutions comprising Sn and gluconate-citrate chelation system.
Crest.RTM. Cavity Protection (CCP), the positive control, which
included 1100 ppm of NaF without any chelation system, had a
.DELTA.pH of about 0.95. The other comparative compositions
included SnF.sub.2 and one or more ligands, such monodentate and/or
polydentate ligand. In the Sn:Gluconate 1:1 molar ratio, the
.DELTA.pH was determined to be about 0.29 while increasing the
amount of the monodentate ligand to a 1:2 ratio resulted in a
relatively unchanged .DELTA.pH of about 0.31. As discussed herein,
a very low .DELTA.pH is indicative of under-stabilized Sn that is
hyper reactive with the HAP surface and that will interfere with
fluoride efficacy as observed by a reduced fluoride uptake.
Unexpectedly, when a monodentate ligand was combined with a
polydentate ligand, such as in the Sn:Gluconate:Citrate, the
.DELTA.pH was less than the .DELTA.pH of Crest Cavity Protection
indicating surface protection but not so low as the
monodentate-only complex. This suggests that the Sn is properly
stabilized to maintain high soluble Sn without being hyper reactive
with the enamel surface. The Sn:Gluconate:Citrate molar ratio of
1:1:1 had a .DELTA.pH of about 0.64. While not wishing to be bound
by theory, it is believed that when the monodentate/polydentate
ligand system is properly balanced with the amount of Sn, there is
a maximum amount of bioavailable Sn without causing stain or
interfering with fluoride uptake.
TABLE-US-00006 TABLE 6 Lactate Chelation System Treatment
Sn:Mono:Poly Average .DELTA.pH % RSD Water N/A 1.42 1.69 Crest
.RTM. Cavity N/A 0.95 0.72 Protection Sn:Gluconate 1:1:0 0.31 4.95
1:1 Sn Gluconate 1:2:0 0.29 3.00 1:2 Sn:Lactate 1:1:0 0.16 6.77 1:1
Sn:Lactate 1:2:0 0.12 3.62 1:2 Sn:Gluconate:Lactate 1:2:0 0.32 4.90
1:1:1 Sn:Lactate:Citrate 1:1:1 0.64 0.72 1:1:1
Sn:Gluc:Lactate:Citrate 1:2:1 0.62 1.46 1:1:1:1
[0158] TABLE 6 shows the impact of the addition of another
monodentate ligand, lactate. As observed with gluconate, the use of
a monodentate ligand, such as lactate in a Sn:monodentate molar
ratio has an extremely low .DELTA.pH, which likely indicated
Sn-staining and/or a decrease in fluoride uptake. Importantly,
adding more monodentate ligand, such as a Sn:monodentate molar
ratio of 1:2 did not result in a .DELTA.pH value within the
necessary range. Additionally, having two different monodentate
ligands did not result in a suitable value as Sn:Gluconate:Lactate
at 1:1:1 resulted in a .DELTA.pH of about 0.32. However,
unexpectedly, the combination of a monodentate and polydentate
ligand resulted in suitable .DELTA.pH values. For example,
Sn:Lactate:Citrate at 1:1:1 resulted in a .DELTA.pH value of about
0.64 while a Sn:Gluconate:Lactate:Citrate at 1:1:1:1 (i.e.a
Sn:monodentate:polydentate of 1:2:1) had a .DELTA.pH value of about
0.62. Thus, both a monodentate and polydentate ligand are needed to
carefully balance the amount of bioavailable Sn.
TABLE-US-00007 TABLE 7 Polyphosphates as Polydentate Ligands
Treatment Sn:Mono:Poly Average .DELTA.pH % RSD Water N/A 1.42 1.69
Crest .RTM. Cavity Protection N/A 0.95 0.72 Sn:Gluc:Tripoly 1:2:1
0.82 0.81 1:2:1 Sn:Gluc:Ortho:Pyro:Cit 1:1:5.84 0.69 1.72
1:1:1.67:2.5:1.67 Sn:Lac:Ortho:Pyro:Cit 1:1:1.67:2.5:1.67 1:1:5.84
0.70 1.84 Sn:Gluc:Pyro 1:1:2.5 0.80 1.58 1:1:2.5 Sn:Lac:Pyro
1:1:2.5 0.79 0.83 1:1:2.5
[0159] TABLE 7 shows that other suitable monodentate ligands
include phosphate-based compounds and that other suitable
polydentate ligands include polyphosphates. As observed with
citrate, the use of a polydentate ligand, such as phosphate
polydentate ligands (Ortho, Pyro, Tripoly) in a
Sn:monodentate:polydentate molar ratio has, unexpectedly, resulted
in suitable .DELTA.pH values. For example, Sn:Gluc:Tripoly 1:2:1
had a .DELTA.pH of about 0.82, which was within the desired range.
More complicated systems of multiple monodentate ligands and
multiple polydentate ligands were also beneficial if properly
balanced.
TABLE-US-00008 TABLE 8 Oxalate Chelation System Treatment
Sn:Mono:Poly Average .DELTA.pH % RSD Water N/A 1.42 1.69 Crest
.RTM. Cavity N/A 0.95 0.72 Protection Sn:Gluc:Oxalate 1:1:1 0.50
3.24 1:1:1 Sn:Gluc:Oxalate:Cit 1:1:2 0.68 1.05 1:1:2
[0160] TABLE 8 shows that oxalate and other dicarboxylic acids can
also act as suitable polydentate ligands. For example,
Sn:Gluc:Oxalate 1:1:1 had a .DELTA.pH of about 0.50, which was
within the preferred range.
[0161] TABLE 9 shows additional solution compositions with a
variety of Sn:Mono:Poly ratios. Ex. A is a SnF.sub.2/SnCl.sub.2
dentifrice with gluconate and citrate at a Sn:Mono:Poly ratio of
1:1:0.33. Ex. B adds additional citrate ions (polydentate ligand)
compared with Ex. A and has a Sn:Mono:Poly ratio of 1:1:0.67. Ex. C
adds even more citrate ions (polydentate ligand) and has a
Sn:Mono:Poly ratio of 1:1:1. Ex. D differs from Ex. A by adding
phosphate ions (polydentate ligand) and has a Sn:Mono:Poly ratio of
1:1.5:0.73. Ex. E differs from Ex. D by adding even more phosphate
ions (polydentate ligand) and has a Sn:Mono:Poly ratio of
1:1:1.63.
[0162] TABLE 10 shows the impact of the Sn:Mono:Poly ratios on the
amount of soluble Sn and fluoride uptake. Unexpectedly, the
fluoride uptake increases upon the addition of polydentate ligand,
but not increasing amount of monodentate ligands. For example, when
the Sn:Mono:Poly ratio increases from 1:1:0.33 to 1:1:0.67 to
1:1:1, the fluoride uptake increases from 6.72 .mu.g/cm.sup.2 to
7.18 .mu.g/cm.sup.2 to 8.00 .mu.g/cm.sup.2. At the same time, the
amount of soluble Sn remains high (at least about 8000 ppm Sn). In
contrast, when the Sn:Mono:poly ratio increases from 1:1:0.33 to
1:1:0.73 to 1:1:1.63, the fluoride uptake still increases from 6.72
.mu.g/cm.sup.2 to 6.99 .mu.g/cm.sup.2 to 10.83 .mu.g/cm.sup.2, but
the soluble Sn drops dramatically from at least about 8000 ppm to
3700 ppm at 1:1:0.73 to 1600 ppm at 1:2:0.33. This indicated that
while fluoride remained bioavailable, Sn ions were overchelated
with too much phosphate polydentate present.
TABLE-US-00009 TABLE 9 Solution Compositions Ex. A Ex. B Ex. C Ex.
D Ex. E Sorbitol 66.0179 65.6252 65.2694 65.7145 65.8512 Water
29.0759 28.8945 28.7450 28.9588 29.0093 SnF.sub.2 0.6240 0.6200
0.6169 0.6213 0.6225 SnCl.sub.2.sup.a 0.7725 0.7675 0.7633 0.7691
0.7705 Sodium 1.7857 1.7759 1.7653 1.7795 1.7819 Gluconate
NaOH.sup.b 0.9914 0.8918 0.7574 1.0165 -- Zinc Citrate 0.7326
0.7287 0.7240 0.7294 0.7307 SnCl.sub.2.sup.c -- -- -- -- -- NaF --
-- -- -- -- Sodium -- 0.6963 1.3587 -- -- Citrate NaH.sub.2PO.sub.4
-- -- -- 0.4109 1.2339 Sn:Mono:Poly 1:1:0.33 1:1:0.67 1:1:1
1:1:0.73 1:1.163 a10% Silica Blend .sup.b50 % solution in water
.sup.cPure Solid
TABLE-US-00010 TABLE 10 Fluoride Uptake and Soluble Sn Fluoride
Uptake Soluble Sn Sn Added Example Sn:Mono:Polya (.mu.g F/cm.sup.2)
(ppm) (ppm) Ex. A 1:1:0.33 6.72 8078 8384 Ex. B 1:1:0.67 7.18 8158
8330 Ex. C 1:1:1 8 8278 8288 Ex. D 1:1:073 6.99 3715 8348 Ex. E
1:1:1.63 10.83 1640 8364 .sup.aSn:Monodentate Ligand:Polydentate
Ligand Molar Ratio
[0163] In total, as described herein, stannous fluoride-based
compositions can be extremely complex to formulate. At a neutral
pH, a chelant system comprising monodentate and polydentate ligands
can carefully balance the chelation of SnF.sub.2 without causing Sn
surface staining or sacrificing fluoride uptake values.
[0164] As shown in TABLEs 2-10, compositions desired herein include
compositions comprising tin, monodentate ligand, and polydentate
ligand, wherein the ratio of tin to monodentate ligand to
polydentate ligand (tin:monodentate:polydentate) is from about
1:0.5:0.5 to about 1:5:5, from about 1:1:0.5: about 1:2.5:2.5, from
about 1:1:1 to about 1:2:2, from about 1:0.5:0.5 to about 1:3:1, or
from about 1:0.5:0.5 to about 1:1:3.
[0165] The dimensions and values disclosed herein are not to be
understood as being strictly limited to the exact numerical values
recited. Instead, unless otherwise specified, each such dimension
is intended to mean both the recited value and a functionally
equivalent range surrounding that value. For example, a dimension
disclosed as "40 mm" is intended to mean "about 40 mm."
[0166] Every document cited herein, including any cross referenced
or related patent or application and any patent application or
patent to which this application claims priority or benefit
thereof, is hereby incorporated herein by reference in its entirety
unless expressly excluded or otherwise limited. The citation of any
document is not an admission that it is prior art with respect to
any invention disclosed or claimed herein or that it alone, or in
any combination with any other reference or references, teaches,
suggests or discloses any such invention. Further, to the extent
that any meaning or definition of a term in this document conflicts
with any meaning or definition of the same term in a document
incorporated by reference, the meaning or definition assigned to
that term in this document shall govern.
[0167] While particular embodiments of the present invention have
been illustrated and described, it would be obvious to those
skilled in the art that various other changes and modifications can
be made without departing from the spirit and scope of the
invention. It is therefore intended to cover in the appended claims
all such changes and modifications that are within the scope of
this invention.
* * * * *