U.S. patent application number 17/551232 was filed with the patent office on 2022-04-07 for reduction of tooth staining derived from cationic antibacterials.
The applicant listed for this patent is The Procter & Gamble Company. Invention is credited to Niranjan Ramji, Douglas Craig Scott.
Application Number | 20220105012 17/551232 |
Document ID | / |
Family ID | 1000006028810 |
Filed Date | 2022-04-07 |
United States Patent
Application |
20220105012 |
Kind Code |
A1 |
Ramji; Niranjan ; et
al. |
April 7, 2022 |
REDUCTION OF TOOTH STAINING DERIVED FROM CATIONIC
ANTIBACTERIALS
Abstract
Disclosed are oral care compositions having reduced tooth
staining propensity and comprising in a pharmaceutically acceptable
carrier, a cationic antimicrobial agent and an anti-stain agent
comprising one or more materials from each of at least two of the
following chemical groups: Group 1. anionic agents, Group 2.
aldehydes, ketones, and other reactive carbonyl compounds and Group
3. nonionic ethoxylated surfactants. Examples of cationic
antimicrobial agent include quaternary ammonium compounds such as
cetylpyridinium chloride, cetyl pyridinium fluoride,
tetradecylpyridinium chloride, N-tetradecyl-4-ethyl pyridinium
chloride and domiphen bromide; chlorhexidine; and metal ion sources
to supply metal ions such as stannous, zinc or copper.
Inventors: |
Ramji; Niranjan; (Mason,
OH) ; Scott; Douglas Craig; (Loveland, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Procter & Gamble Company |
Cincinnati |
OH |
US |
|
|
Family ID: |
1000006028810 |
Appl. No.: |
17/551232 |
Filed: |
December 15, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16781388 |
Feb 4, 2020 |
11253451 |
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17551232 |
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15630283 |
Jun 22, 2017 |
10596086 |
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16781388 |
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13529044 |
Jun 21, 2012 |
10123953 |
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15630283 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/19 20130101; A61K
8/55 20130101; A61K 8/86 20130101; A61K 8/4926 20130101; A61Q
17/005 20130101; A61K 8/43 20130101; A61K 8/35 20130101; A61K 8/27
20130101; A61Q 11/00 20130101; A61K 8/416 20130101; A61K 8/33
20130101; A61K 8/73 20130101 |
International
Class: |
A61K 8/27 20060101
A61K008/27; A61K 8/33 20060101 A61K008/33; A61K 8/35 20060101
A61K008/35; A61K 8/41 20060101 A61K008/41; A61K 8/43 20060101
A61K008/43; A61K 8/49 20060101 A61K008/49; A61Q 11/00 20060101
A61Q011/00; A61Q 17/00 20060101 A61Q017/00; A61K 8/19 20060101
A61K008/19; A61K 8/55 20060101 A61K008/55; A61K 8/73 20060101
A61K008/73; A61K 8/86 20060101 A61K008/86 |
Claims
1. A dentifrice composition, comprising: a. cationic antimicrobial
agent comprising stannous fluoride; b. anionic agent comprising
sodium lauryl sulfate; c. first agent comprising pyrophosphate,
tripolyphosphate, or mixtures thereof; and d. second agent
comprising flavoring agent, the flavoring agent comprising
aldehyde, ketone, or mixtures thereof.
2. The dentifrice composition of claim 1, wherein the composition
comprises cocamidopropyl betaine.
3. The dentifrice composition of claim 2, wherein the composition
comprises from about 2% to about 30% of the first agent, by weight
of the dentifrice composition.
4. The dentifrice composition of claim 3, wherein the composition
comprises from about 5% to about 25% of the first agent, by weight
of the dentifrice composition.
5. The dentifrice composition of claim 2, wherein the composition
is a single-phase composition.
6. The dentifrice composition of claim 5, wherein the flavoring
agent comprises 4-methoxybenzaldehyde (anisaldehyde);
1,3-benzodioxole-5-carbaldehyde (heliotropin);
3,4-dimethoxybenzaldehyde (veratraldehyde);
3-methyl-1,2-cyclopentadione; phenethyl formate; acetophenone;
phenylacetaldehyde; 4-methylacetophenone; .rho.-toluacetaldehyde;
3,5,5-trimethyl-2-cyclohexene-1-one (isophorone);
gamma-undecalactone; .rho.-methyl cinnamaldehyde;
4-phenyl-2-butanone (benzyl acetone); octanal;
6-isopropyl-3-methyl-1-cyclohex-2-enone (piperitone);
(S)-4-(1-methylethenyl)-1-cyclohexene-1-carboxaldehyde
(perillaldehyde); 4-(1-methylethyl) benzaldehyde (cuminaldehyde);
.alpha.-methyl cinnamaldehyde; isomenthone; menthone; carvone;
decanal; 3-hydroxy-2-methyl-4H-pyran-4-one (maltol);
.rho.-isopropyl phenylacetaldehyde; trans-citral;
3-methyl-2-pentylcyclopent-2-ene-1-one (dihydrojasmone);
.beta.-napthylmethyl ketone, tiglic aldehyde, ethyl vanillin,
isovaleraldehyde, or mixtures thereof.
7. The dentifrice composition of claim 5, wherein the composition
comprises saccharin.
8. The dentifrice composition of claim 7, wherein the composition
comprises titanium dioxide.
9. The dentifrice composition of claim 8, wherein the composition
comprises from about 0.25% to about 5% of the titanium dioxide, by
weight of the dentifrice composition.
10. The dentifrice composition of claim 9, wherein the flavoring
agent comprises 4-methoxybenzaldehyde (anisaldehyde);
1,3-benzodioxole-5-carbaldehyde (heliotropin);
3,4-dimethoxybenzaldehyde (veratraldehyde);
3-methyl-1,2-cyclopentadione; phenethyl formate; acetophenone;
phenylacetaldehyde; 4-methylacetophenone; .rho.-toluacetaldehyde;
3,5,5-trimethyl-2-cyclohexene-1-one (isophorone);
gamma-undecalactone; .rho.-methyl cinnamaldehyde;
4-phenyl-2-butanone (benzyl acetone); octanal;
6-isopropyl-3-methyl-1-cyclohex-2-enone (piperitone);
(S)-4-(1-methylethenyl)-1-cyclohexene-1-carboxaldehyde
(perillaldehyde); 4-(1-methylethyl) benzaldehyde (cuminaldehyde);
.alpha.-methyl cinnamaldehyde; isomenthone; menthone; carvone;
decanal; 3-hydroxy-2-methyl-4H-pyran-4-one (maltol);
.rho.-isopropyl phenylacetaldehyde; trans-citral;
3-methyl-2-pentylcyclopent-2-ene-1-one (dihydrojasmone);
.beta.-napthylmethyl ketone, tiglic aldehyde, ethyl vanillin,
isovaleraldehyde, or mixtures thereof.
11. The dentifrice composition of claim 10, wherein the flavoring
agent comprises 4-methoxybenzaldehyde (anisaldehyde);
1,3-benzodioxole-5-carbaldehyde (heliotropin);
3,4-dimethoxybenzaldehyde (veratraldehyde);
3-methyl-1,2-cyclopentadione; phenethyl formate; acetophenone;
phenylacetaldehyde; 4-methylacetophenone; .rho.-toluacetaldehyde;
3,5,5-trimethyl-2-cyclohexene-1-one (isophorone);
gamma-undecalactone; .rho.-methyl cinnamaldehyde, or mixtures
thereof.
12. The dentifrice composition of claim 1, wherein the composition
comprises from about 0.05% to about 5% of the sodium lauryl
sulfate, by weight of the dentifrice composition.
13. The dentifrice composition of claim 12, wherein the composition
comprises from about 2% to about 30% of the first agent, by weight
of the dentifrice composition.
14. The dentifrice composition of claim 13, wherein the composition
comprises from about 5% to about 25% of the first agent, by weight
of the dentifrice composition.
15. The dentifrice composition of claim 14, wherein the composition
comprises cocamidopropyl betaine.
16. The dentifrice composition of claim 15, wherein the composition
is a single-phase composition.
17. The dentifrice composition according to claim 15, wherein the
compositions comprises from about 10% to about 50% of silica
abrasive, by weight of the dentifrice composition.
18. The dentifrice composition of claim 15, wherein the flavoring
agent comprises 4-methoxybenzaldehyde (anisaldehyde);
1,3-benzodioxole-5-carbaldehyde (heliotropin);
3,4-dimethoxybenzaldehyde (veratraldehyde);
3-methyl-1,2-cyclopentadione; phenethyl formate; acetophenone;
phenylacetaldehyde; 4-methylacetophenone; .rho.-toluacetaldehyde;
3,5,5-trimethyl-2-cyclohexene-1-one (isophorone);
gamma-undecalactone; .rho.-methyl cinnamaldehyde;
4-phenyl-2-butanone (benzyl acetone); octanal;
6-isopropyl-3-methyl-1-cyclohex-2-enone (piperitone);
(S)-4-(1-methylethenyl)-1-cyclohexene-1-carboxaldehyde
(perillaldehyde); 4-(1-methylethyl) benzaldehyde (cuminaldehyde);
.alpha.-methyl cinnamaldehyde; isomenthone; menthone; carvone;
decanal; 3-hydroxy-2-methyl-4H-pyran-4-one (maltol);
.rho.-isopropyl phenylacetaldehyde; trans-citral;
3-methyl-2-pentylcyclopent-2-ene-1-one (dihydrojasmone);
.beta.-napthylmethyl ketone, tiglic aldehyde, ethyl vanillin,
isovaleraldehyde, or mixtures thereof.
19. The dentifrice composition according to claim 18, wherein the
flavoring agent comprises 4-methoxybenzaldehyde (anisaldehyde);
1,3-benzodioxole-5-carbaldehyde (heliotropin);
3,4-dimethoxybenzaldehyde (veratraldehyde);
3-methyl-1,2-cyclopentadione; phenethyl formate; acetophenone;
phenylacetaldehyde; 4-methylacetophenone; .rho.-toluacetaldehyde;
3,5,5-trimethyl-2-cyclohexene-1-one (isophorone);
gamma-undecalactone; .rho.-methyl cinnamaldehyde, or mixtures
thereof.
20. The dentifrice composition of claim 19, wherein the composition
comprises zinc.
Description
TECHNICAL FIELD
[0001] The present invention relates to oral care compositions
containing an agent to eliminate or reduce tooth staining,
specifically staining derived from cationic antimicrobial agents
used in oral care compositions to reduce oral bacteria and to
prevent and treat bacteria-mediated diseases or conditions of the
oral cavity including dental plaque, caries, calculus, gingivitis,
periodontal disease and breath malodor.
BACKGROUND OF THE INVENTION
[0002] Cationic materials which possess antimicrobial activity have
been used in oral compositions 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. Dental plaque is a mixed matrix of
bacteria, epithelial cells, leukocytes, macrophages and other oral
exudate. Bacteria comprise approximately three-quarters of the
plaque matrix. Any given sample of dental plaque could contain as
many as 400 different varieties of microorganisms. This mix
includes both aerobic and anaerobic bacteria, fungi, viruses and
protozoa. This matrix of organisms and oral exudate continues to
expand and coalesces with other plaque growths situated nearby. The
bacteria synthesize levans and glucans from sucrose found in the
oral cavity providing energy for the microorganisms. These glucans,
levans, and microorganisms form an adhesive skeleton for the
continued proliferation of plaque. Dental calculus, or tartar as it
is sometimes called, is a deposit which forms on the surfaces of
the teeth at the gingival margin. Mature calculus consists of an
inorganic portion which is largely calcium phosphate arranged in a
hydroxyapatite crystal lattice structure similar to bone, enamel
and dentine. An organic portion is also present and consists of
desquamated epithelial cells, leukocytes, salivary sediment, food
debris and various types of microorganisms. Developing plaque can
adhere most easily at relatively irregular surfaces, such as those
afforded by calculus. Calculus and plaque along with behavioral and
environmental factors lead to formation of dental stains,
significantly affecting the aesthetic appearance of teeth.
Behavioral and environmental factors that contribute to teeth
staining propensity include regular use of products that contain
staining chemicals or color bodies such as coffee, tea, cola or
tobacco and use of stain promoting oral products, such as those
containing cationic antimicrobial agents.
[0003] Among the most common of cationic antimicrobial agents known
to cause tooth staining are quaternary ammonium compounds such as
cetylpyridinium chloride and metal ion sources such as stannous
fluoride and stannous chloride. The tooth staining potential of
these cationic materials has long been documented. Among the many
approaches that have been suggested to reduce and control tooth
staining and to whiten teeth is by the use of bleaches or oxidants
such as peroxide. Essentially, bleaches act by oxidizing color
bodies and existing stains. However, bleaches added to oral care
products are typically present in low concentrations due to
stability and safety limits. At these low concentrations, bleaches
such as peroxide, are generally ineffective to control stain and
whiten teeth. Furthermore, bleaches do not functionally act to
prevent acquisition of stains.
[0004] There continues to be a need for oral care products that
provide enhanced overall cleaning and hygiene while also
controlling tooth staining. Chemical technologies have now been
identified that can effectively reduce tooth staining derived from
cationic antimicrobials such as CPC. These chemical agents do not
involve the use of bleaches or oxidants and significantly do not
compromise the bioavailability of the cationic antimicrobials and
therefore, their antimicrobial potency.
SUMMARY OF THE INVENTION
[0005] The present invention is directed to oral care compositions
comprising in a pharmaceutically acceptable carrier, a combination
of a cationic antimicrobial agent that causes tooth staining and an
anti-stain agent comprising at least two different materials from
the following chemical groups:
[0006] Group 1. anionic agents,
[0007] Group2. aldehydes, ketones, and other reactive carbonyl
compounds and
[0008] Group 3. nonionic ethoxylated surfactants.
[0009] Examples of Group 1 anionic agents are compounds and
polymers containing phosphate, carboxy or sulfate groups such as
carboxymethyl dextran (degree of substitution=0.1, MW=10,000) and
tetrapotasium pyrophosphate.
[0010] Examples of Group 2 aldehydes, ketones and other reactive
carbonyl compounds are 4-methoxybenzaldehyde (anisaldehyde);
1,3-benzodioxole-5-carbaldehyde (heliotropin);
3,4-Dimethoxybenzaldehyde (veratraldehyde);
3-methyl-1,2-cyclopentadione; phenethyl formate, acetophenone;
phenylacetaldehyde; 4-methylacetophenone; .rho.-toluacetaldehyde;
3,5,5-trimethyl-2-cyclohexene-1-one (isophorone);
gamma-undecalactone; or .rho.-methylcinnamaldehyde.
[0011] Examples of Group 3 nonionic ethoxylated surfactants are
ethoxylated linear alcohols such as those wherein the number of
carbons in the alcohol chain is between about 18 to55, the ethoxy
units by weight is at least 80% and the average molecular weight of
the polymer is about 2000 to about 5000.
[0012] Examples of cationic antimicrobial agent include quaternary
ammonium compounds such as cetylpyridinium chloride,
tetradecylpyridinium chloride, N-tetradecyl-4-ethyl pyridinium
chloride and domiphen bromide; metal ion sources to supply metal
ions such as stannous, zinc and copper; and chlorhexidine.
[0013] These and other features, aspects, and advantages of the
present invention will become evident to those skilled in the art
from the detailed description which follows.
BRIEF DESCRIPTION OF DRAWINGS
[0014] FIG. 1 illustrates the reaction between an aldehyde and a
salivary protein by thioacetal formation.
[0015] FIG. 2 is a summary of the protocols used in the
HAP-Pellicle and Bovine Tooth in vitro staining models.
DETAILED DESCRIPTION OF THE INVENTION
[0016] While the specification concludes with claims particularly
pointing out and distinctly claiming the invention, it is believed
that the present invention will be better understood from the
following description.
[0017] All percentages and ratios used hereinafter are by weight of
total composition, unless otherwise indicated. All percentages,
ratios, and levels of ingredients referred to herein are based on
the actual amount of the ingredient, and do not include solvents,
fillers, or other materials with which the ingredient may be
combined as a commercially available product, unless otherwise
indicated. All measurements referred to herein are made at about
25.degree. C. unless otherwise specified.
[0018] Herein, "comprising" means that other steps and other
components which do not affect the end result can be added. This
term encompasses the terms "consisting of" and "consisting
essentially of."
[0019] As used herein, the word "include," and its variants, are
intended to be non-limiting, such that recitation of items in a
list is not to the exclusion of other like items that may also be
useful in the materials, compositions, devices, and methods of this
invention.
[0020] As used herein, the words "preferred", "preferably" and
variants refer to embodiments of the invention that afford certain
benefits, under certain circumstances. However, other embodiments
may also be preferred, under the same or other circumstances.
Furthermore, the recitation of one or more preferred embodiments
does not imply that other embodiments are not useful, and is not
intended to exclude other embodiments from the scope of the
invention.
[0021] By "oral care composition" is meant 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 substantially all of the dental surfaces
and/or oral tissues for purposes of oral activity. The oral care
composition may be in various forms including toothpaste,
dentifrice, tooth gel, subgingival gel, mouth rinse, mousse, foam,
denture product, mouthspray, lozenge, chewable tablet or chewing
gum. The oral care composition may also be incorporated onto strips
or films for direct application or attachment to oral surfaces.
[0022] The term "dentifrice", as used herein, means 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 the gel surrounding
the 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] The term "dispenser", as used herein, means any pump, tube,
or container suitable for dispensing compositions such as
dentifrices.
[0024] The term "mouth rinse", as used herein, includes liquid
formulations referred in the art as mouthwashes or dental rinses,
mouth sprays, dental solutions and irrigation fluids.
[0025] The term "teeth" refers to natural teeth as well as
artificial teeth or dental prosthesis.
[0026] The terms "pharmaceutically acceptable carrier", "orally
acceptable carrier" or "excipients" include safe and effective
materials and conventional additives such as those used in oral
care compositions including but not limited to fluoride ion
sources, antimicrobial agents, anti-inflammatory agents,
anti-calculus or anti-tartar agents, desensitizing agents, peroxide
sources, abrasives such as silica, buffering agents, alkali metal
bicarbonate salts, thickening materials, humectants, water,
surfactants, emulsifying agents, anti-stain agents, tooth
substantive agents, titanium dioxide, xylitol, essential oils, a
coolant, a sweetening agents or other sensates and coloring
agents.
[0027] The term "essential oils" as used herein refers to volatile
oils distilled or expressed from plants and constituents of these
volatile oils. Typical essential oils and their main constituents
are those obtained for example from thyme (thymol, carvacrol),
oregano (carvacrol, terpenes), lemon (limonene, terpinene,
phellandrene, pinene, citral), lemongrass (citral, methylheptenone,
citronellal, geraniol), orange flower (linalool, .beta.-pinene,
limonene), orange (limonene, citral), anise (anethole, safrol),
clove (eugenol, eugenyl acetate, caryophyllene), rose (geraniol,
citronellol), rosemary (borneol, bornyl esters, camphor), geranium
(geraniol, citronellol, linalool), lavender (linalyl acetate,
linalool), citronella (geraniol, citronellol, citronellal,
camphene), eucalyptus (eucalyptol); peppermint (menthol, menthyl
esters), spearmint (carvone, limonene, pinene); wintergreen (methyl
salicylate), camphor (safrole, acetaldehyde, camphor), bay
(eugenol, myrcene, chavicol), cinnamon (cinnamaldehyde, cinnamyl
acetate, eugenol), tea tree (terpinen-4-ol, cineole), and cedar
leaf (.alpha.-thujone, .beta.-thujone, fenchone). Essential oils
are widely used in perfumery and as flavorings, medicine and
solvents [See Kirk-Othmer Encyclopedia of Chemical Technology,
4.sup.th Edition and The Merck Index, 13.sup.th Edition].
[0028] Active and other ingredients useful herein may be
categorized or described by their cosmetic and/or therapeutic
benefit or their postulated mode of action or function. However,
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 application or applications listed.
[0029] In one embodiment of the present invention, oral care
compositions are provided comprising a cationic antimicrobial agent
comprising one or a mixture of a quaternary ammonium compound
selected from cetylpyridinium chloride, tetradecylpyridinium
chloride, N-tetradecyl-4-ethyl pyridinium chloride or domiphen
bromide; a stannous ion source; a zinc ion source or a copper ion
source in combination with an anti-staining agent. The
anti-staining agent will preferably comprise one or more materials
from each of at least two of the following chemical groups:
[0030] Group 1. anionic agents,
[0031] Group 2. aldehydes, ketones and reactive carbonyl compounds
and
[0032] Group 3. nonionic ethoxylated surfactants.
[0033] The cationic antimicrobial agents effectively promote oral
hygiene, particularly by controlling plaque and calculus
proliferation. However, their use has been observed to lead to
staining of tooth surfaces or discoloration. The exact mechanisms
for the formation of dental stain derived from the use of these
cationic antimicrobials have not been clearly established. One
explanation that has been offered is that as the cationic
antimicrobial agents remove plaque they also denature protein from
saliva in the oral environment and the denatured protein can then
act as a nucleating agent which is deposited onto and stains or
discolors teeth. Another theory is that in the absence of dental
plaque, additional Ca.sup.+2 and PO4.sup.-3, particularly from
saliva, can be deposited on the tooth surface and such deposits can
include color bodies which ultimately stain the tooth surface as a
calcified deposit thereon.
[0034] Studies were conducted at the Procter & Gamble
laboratories to further elucidate the staining problem. Using cetyl
pyridinium chloride (CPC) as the stain promoting antimicrobial, it
was observed that initial stain formation with CPC occurs on the
pellicle surface of the teeth. This stain is a result of the
interaction between salivary proteins such as mucin and dietary
chromogens or color bodies such as tea polyphenols. The observed
stain is exacerbated in the presence of CPC or other cationic
antimicrobials such as stannous salts. As has been reported in
literature, there are significant interactions between the basic
proline rich proteins in saliva and tea polyphenols [See e.g., J.
Dent. Res., 84(1), 73-781(2005); Biochem. J., 297, 249-260 (1994);
"Grape and Wine Tannins Precipitation by Proline Rich Proteins",
Poster at the 2.sup.nd International Electronic Conference of
Synthetic Organic Chemistry (ECSOC-2, Sep. 1-30, 1998)]. In fact it
has been reported that sodium dodecylsulfate (SDS) polyacrylamide
gel electrophoresis of a mixture of saliva and tea extract resulted
in the disappearance of the basic proline rich protein bands
indicating a precipitation of the basic proline rich proteins with
tea polyphenols. The proline rich proteins are inducible in the
stomach and saliva and is the body's natural defense mechanism to
complex the larger polyphenols to precipitate them, preventing
their absorption and hence reducing their toxicity. The interaction
of sodium dodecylsulfate (SDS) and nonionic surfactants with mucin
has also been reported [Langmuir, 18, 9383-9392(2002)]. Our studies
have demonstrated that there is a similar interaction between CPC
with other anionic proteins in saliva resulting in the
precipitation of the protein and CPC on the tooth surface. The
co-precipitate of CPC and protein subsequently interacts with
dietary chromogens such as tea polyphenols resulting in tooth
staining.
[0035] We have found that by the use of certain anionic agents, we
are able to reduce aggregation of salivary proteins, either by
direct hydrophobic (insertion into non polar region of the protein)
or charged interaction of the anionic agent with the salivary
proteins or by the formation of a counter ion with the pyridinium
ring of the CPC. The anionic agent is more tightly bound to the
pyridinium ring than the chloride ion, which then reduces the
interaction of CPC with the salivary proteins.
[0036] Some aldehydes have been also been demonstrated to react
with salivary proteins by thioacetal formation as illustrated in
FIG. 1, thereby reducing the negative charge density on the surface
of the protein and thus, the protein interaction with the
positively charged pyridinium ring of CPC.
[0037] When combined, the anionic agent and aldehyde provide even
better anti-staining results compared to using these agents
separately. It is believed the combination enables stronger
interaction between the aldehyde and the protein compared to the
interaction between the protein and CPC, as CPC is now tightly
bound to a large anionic counter ion and thus less available to
interact with the protein. This would explain the observed synergy
when using the combination of a lightly charged anionic agent and
certain aldehydes or ketones in studies described below.
[0038] Similarly we have demonstrated that the use of ethoxylates
having the right balance of alkyl and ethoxy units can effectively
solubilize salivary proteins, thereby reducing staining.
Importantly, the use of the above agents do not significantly
impact the bioavailability of CPC, which is surprising and
unexpected, given previous findings that the bioavailability of
quaternary ammonium antimicrobials is affected by the presence of
anionic materials and even nonionic materials that have some
partial negative charge (due to hydroxyl, ester, aldehydes and
ketone functional groups) as in some ethoxylated surfactants
(US20050169852A1 to Roberge, et al.).
[0039] A similar approach can be used to control tooth staining
derived from other cationic antimicrobials such as stannous, zinc
or copper salts used in dentifrice, gel or rinse oral care
products.
Evaluation of Tooth Staining Potential of Cationic Antimicrobials
and Anti-Staining Activity of Agents:
[0040] A. In Vitro Models
[0041] Two models were used to evaluate tooth staining potential of
compositions containing cationic antimicrobials. CPC was used as
the model stain-promoting antimicrobial. The general protocols for
the models described below are summarized in FIG. 2.
HAP-Pellicle Model:
[0042] The protocol of the HAP-pellicle model involves the
development of a pellicle on hydroxyapatite (HAP) powder to
simulate pellicle covered teeth. The procedure starts by incubating
10 mg of HAP powder with pooled parotid saliva at 35 C for 1 hour.
The saliva is removed after centrifugation and the prepared HAP
powder is treated with CPC solution (positive control), water
(negative control) or CPC test rinse solution for 1 minute in the
presence of saliva. Each treatment solution (controls and test) is
removed after centrifugation. The HAP residue is washed with saliva
for 1 minute and removed after centrifugation. It is then treated
with tea solution for 1 minute. The tea solution is then removed
from the treated HAP after centrifugation. The treated HAP is
washed with saliva as described earlier. 2 additional cycles of
treatment are carried out. After 3 cycles of treatment, the HAP is
dissolved and absorbance read from 350-550 nm. The AUC (Area Under
the Curve) of absorbance between 350-550 nm is the measure of
stain. Each test set is run in triplicate.
Bovine Tooth Model
[0043] This model utilizes extracted bovine teeth which have been
mounted on polyacrylic material. Bovine tooth are first bleached
with dilute peroxide followed by washing with water. The bleached
teeth are incubated with saliva for 4 hours and then dried. The
teeth are then imaged to get baseline color values (L*a*b*), using
digital photography using the white light imaging system (Fuji 2000
Camera). The teeth are then incubated in saliva for 18 hours to
generate a mature pellicle coating. The saliva is then removed and
the teeth are treated with a dentifrice slurry (containing no
antimicrobials) for 2 minutes. The dentifrice slurry is removed and
the teeth are washed with water for 1 minute. The teeth specimens
are now ready for treatment. Teeth specimens are treated with CPC
solution (positive control), water (negative control) or CPC test
rinse solution for 1 minute in the presence of saliva. The teeth
are then incubated with saliva for 20 minutes at 35.degree. C. Each
specimen is subsequently treated with a freshly made tea solution
for 15 minutes, followed by another washing and incubation with
saliva for 20 minutes. A total of 6 treatment cycles are carried
out. After 6 cycles, the teeth are dried and L*a*b* values are
measured using photo imaging. L* represents lightness on the y
axis, a* represents chroma (red-green) on the x axis, and b*
represents chroma (yellow-blue) on the z axis. Changes in the
individual L*, a*, and b* components (.DELTA. values) are
calculated by subtracting the L*a*b* measurements of treated teeth
from the L*a*b* measurements of untreated and unstained teeth. The
total color change (.DELTA.E) is calculated as the square root of
the sum of the square of the .DELTA. values. All tests are carried
out with a replicate of four teeth.
[0044] B. Evaluation of Anti-Staining Activity of Aldehydes,
Ketones and Anionic Agents
[0045] Mouth rinse formulations were evaluated in the bovine tooth
model described above. The treatment composition contained 0.07%
CPC as antimicrobial and anisaldehyde, anionic chelant or
combinations as anti-staining agent. The base composition
containing 0.07% CPC without anti-staining agent was the positive
(staining) control and water was the negative (non-staining)
control. Results are shown below.
TABLE-US-00001 %Reduction in Treatment Group stain (normalized)
0.07% CPC Base 0.00 Base + 0.1% Anisaldehyde 24.20 Base + 0.15% TK
Pyrophosphate 30.08 Base + 0.1% CM Dextran 31.18 Base + 0.1%
Anisaldehyde/0.15% TK Pyro 95.62 Base + 0.1% Anisaldehyde/0.1% CM
Dextran 81.11 Water 100.00
[0046] These results demonstrate that each of the agents used alone
provide reduction of stain. Surprisingly, there was synergy on the
combination of anisaldehyde with either CM dextran or
tetrapotassium pyrophosphate (TKPP) in reducing or nearly
eliminating staining. Importantly, the bioavailability of the CPC
in the rinse formulations as measured using in vitro Disk Retention
Assay (DRA) was between 80-100%, indicating that the anti-stain
additives did not significantly affect CPC bioavailability. The DRA
method is described in commonly assigned application WO 05/072693
and in S. J. Hunter-Rinderle, et al., "Evaluation of
Cetylpyridinium Chloride-Containing Mouthwashes Using In Vitro Disk
Retention and Ex Vivo Plaque Glycolysis Methods," J. Clin. Den.,
1997, 8:107-113. These assays are recommended for use in the
proposed OTC monograph (Federal Register Vol. 68, No. 103 Part 356,
"Oral Health Care Drug Products For Over-The-Counter Human Use;
Antigingivitis/Antiplaque Drug Products; Establishment of a
Monograph: Proposed Rules"). This method is designed as a
performance assay to analyze mouth rinse formulations containing
from about 0.03% to about 0.1% CPC to quantitatively determine the
"free" ("unbound") or "bioavailable" level of CPC needed for
clinical efficacy. The DRA measures the amount of CPC "binding" to
standardized cellulose filter disks during filtration of an
undiluted mouth rinse sample. The "bioavailable" CPC binds to the
hydroxyl groups on the cellulose fiber during filtration while CPC,
which has been rendered "non-bioavailable" (or "bound")" through
interactions with mouth rinse components, simply passes through the
filter paper, i.e., the positive charge on the compound is no
longer available for binding to the negatively charged cellulose
disks. In this way, the DRA test provides an estimate of the amount
of CPC available for activity, i.e., binding to bacteria and
mucosal surfaces, during use of the mouth rinse. DRA measurements
of CPC availability have been positively correlated to results of
in vitro microbiological assays and in vivo germ kill tests.
Historically, cellulose fibers have been used in other applications
to similarly monitor biological activity of drug actives ("Dairy
Products" in Official Methods of Analysis of the Association of
Chemical Analytical Chemists. 13.sup.th ed., 1980, Chapter 16:256).
The method has been validated and shown to perform with acceptable
accuracy, precision, and selectivity.
[0047] Mouth rinse formulations comprising from about 0.035 to
about 0.1% CPC would pass the DRA test if assay results show the
level of bioavailable CPC to be .gtoreq.324 ppm. For example, a
formulation comprising 0.05% CPC at 72% bioavailability would
provide 360 ppm CPC. Testing of products containing bioavailable
levels of CPC of 324 ppm demonstrates positive clinical
(antigingivitis, antiplaque) outcomes. Determination of CPC
bioavailability in a finished product is important to product
performance as it readily defines the amount (concentration) of
active available for deposition at the site of action. Because the
positively charged (cationic) hydrophilic region is critical to
antimicrobial activity, any formulation component that diminishes
the activity of this cationic group or that competes with the group
may inactivate the product. Desirably, a formulation containing
0.05% CPC would have at least about 65% bioavailability to deliver
at least about 324 ppm bioavailable CPC. A formulation containing a
lower level of CPC such as 0.04% would need to have at least about
81% bioavailability to deliver the minimum required level of
bioavailable CPC for antigingivitis efficacy. Depending upon the
particular application and the concentration of CPC or other
quaternary ammonium agent, about 50% bioavailability may be
acceptable.
[0048] Chemical structure activity modeling of stain reduction data
(using the HAP saliva pellicle model to evaluate mouth rinses
containing 0.07% cetylpyridinium chloride) was carried out. Water
was used as the negative control and 0.07% solution of
cetylpyridinium chloride was the positive control.
[0049] The data set was used to develop a Structural Activity
Relationship (SAR) model to correlate the observed reduction of
stain to specific chemical structural features of test compounds.
The best regression equation was determined and further used to
predict % reduction of stain for other chemical ingredients. In
order to develop the QSAR (Quantitative Structural Activity
Relationship), the % reduction of stain as determined by the above
experiment at 0.1% anti-stain active concentration was used in the
CaChe 7.1 molecular modeling programme from Fujitsu Limited. The %
Reduction of Stain from a training set of 15 chemical samples was
used to calculate the Complete Quantum QSAR. The CAChe MOPAC
(Molecular Orbital Package) application determines both an optimum
geometry and the electronic properties of molecules by solving the
Schrodinger equation using the semi-empirical Hamiltonians AM1, PM3
and PM5, developed by M. J. S. Dewar and J. J. P. Stewart. [See J.
Am. Chem. Soc. (1985),107, 3902; J. Comput. Chem. (1989),10, 209;
MOPAC 2002, (1999).] The following regression equation, which is
the best from 50803424 possible triple combinations of 674
descriptors, gave the highest r{circumflex over ( )}2=0.8849.
% Reduction in stain from CPH=-0.2535*(Carbon
count).sup.2-15.9064*sqrt(donatable hydrogen
count)-956.4721*1.0/[cube root(bonded gravitational
index)]+130.7168
[0050] The cross-validated correlation coefficient
(cvr.sup.2=0.7998) suggests that the stability of the equation on
addition of similar training data is likely to be reasonable as it
is above 0.70. Eq. 1 below calculates the bonded gravitational
index (G.sub.I) over all bonded atoms i, j in the molecule, which
reflects the effective mass distribution in the molecule and
effectively describes the molecular dispersion forces in the bulk
liquid media.
G.sub.I=.SIGMA..sub.ij.sup.over all bonded
atoms(m.sub.im.sub.j/r.sub.ij.sup.2) Eq. 1
[0051] In the above equations, carbon count=total number of carbon
atoms in the molecule, donatable hydrogen count=number of hydrogen
atoms in a molecule that has labile H atoms (such as in OH, COOH
and NH.sub.2 groups), m.sub.i and m.sub.j=the atomic masses of the
bonded atoms, and r.sub.ij=respective bond lengths.
[0052] Based on the above model, the predicted Normalized % Stain
Reduction values of many other reactive carbonyl compounds are
listed below. These compounds have a predicted stain reduction that
is comparable to anisaldehyde. The stain reduction from 0.07% CPC
solution (positive control) was normalized with water having stain
reduction of 100%, i.e., produced no stain. Preferred among the
agents listed below are those having a % normalized stain reduction
value of at least about 10%, at least about 20%, at least about 30%
or at least about 40%. Agents having below about 10% stain
reduction in this model are predicted to have minimal
performance.
TABLE-US-00002 Active Normalized % Stain Reduction heliotropin
82.87 veratraldehyde 70.35 3-methyl-1,2-cyclopentadione 55.33
anisaldehyde 54.93 phenethyl formate 54.77 acetophenone 40.46
phenylacetaldehyde 40.03 4-methylacetophenone 37.07
.rho.-Toluacetaldehyde 36.65 Isophorone 33.95 gamma-undecalactone
31.87 .rho.-methyl cinnamaldehyde 30.58 benzylacetone 29.55 octanal
28.84 (--) piperitone 28.70 perillaldehyde 27.58 cuminaldehyde
26.80 .alpha.-methyl cinnamaldehyde 26.49 isomenthone 26.03
menthone 26.00 carvone 23.64 decanal 20.78 maltol 20.24
p-Isopropylphenylacetaldehyde 19.37 trans-citral 17.81
dihydrojasmone 17.56 beta-napthylmethyl ketone 13.15 tiglic
aldehyde 8.85 ethyl vanillin 7.03 isovaleraldehyde 6.39
[0053] Using chemical structure activity modeling described above
and the Bovine tooth Model, the following anionic compounds are
anticipated to have similar anti-staining activity as carboxymethyl
dextran and tetrapotassium pyrophosphosphate. These compounds
contain anionic phosphate, carboxy or sulfate groups, are at least
slightly water soluble or water-dispersible and are used in the
acid form or as alkali metal or ammonium salts thereof. Preferred
anionic agents are those having a % normalized stain reduction
value of at least about 10%, at least about 20%, at least about 30%
or at least about 40%.
TABLE-US-00003 Active Normalized % stain reduction tetra potassium
pyrophosphate 55.15 phytic acid 42.99 D-fructose-1-6-biphosphate
41.83 dihydroxyacetone phosphate 40.70 D-Erythrose-4-phosphate
34.40 Glycerol phosphate 33.43 creatine phosphate 30.70
D-ribose-5-phosphate 28.31 D-fructose-6-phosphate 28.16
D-xylose-5-phosphate 24.73 glyceraldehyde-3-phosphate 22.66
.alpha.-D-glucose-6-phosphate 15.65 .alpha.-D-glucose-1-phosphate
15.52 uridine-5-phosphate 11.37 ascorbyl phosphate 11.35
Xylitol-5-phosphate 8.01 DL malic acid 6.61
[0054] The following polymeric materials are anticipated to have
anti-staining activity: dextran sulfate; lower molecular weight
polymers (about 15,000 or less) such as carboxymethyl
hydroxypropylcellulose, carboxymethyl methylcellulose;
acrylic-maleic acid copolymers; and carboxymethyl starch. Polymers
having a low charge density are preferred. Examples include lightly
charged carboxylated, phosphated or sulfated water soluble polymers
such as celluloses, dextrans, starches and the like with a degree
of anionic group substitution (DS) of 0.2 or less. DS of 0.2 is
defined as 2 anionic group substituent units (e.g., carboxymethyl,
phosphate or sulfate) per 10 repeating units in the polymer, e.g.,
glucose units in cellulose). By "water soluble polymers" herein is
meant to include polymers that are solvatable or hydratable with
water forming transparent, translucent, or semi-opaque solutions or
gels, which are generally accepted as uniformly dispersed in water
or in a predominately water containing medium. It is known that
water soluble polymers do not necessarily form "true" solutions but
can exist as hydrated particles that are fully or partially
solvated and uncoiled.
[0055] A lower molecular weight of the polymer is preferred as
lower viscosity build in the formulation may be desired. For
example, for a mouth rinse formulation the desired viscosity is
about 1 to 5 cP. Furthermore, it is believed that the lower
molecular weight polymers can better interact with the salivary
proteins and partition into one another better. At higher molecular
weights (>15,000), the protein would interact with an entangled
polymer network rather than identifiable polymer strands or coils
and the protein partition coefficient would become independent of
molecular weight. The anionic polymers useful herein would have
average molecular weight (MW) of about 15,000 or less, about 10,
000 or less or about 5000 or less.
[0056] C. Evaluation of Anti-Staining Activity of Nonionic
Ethoxylated Surfactants (Ethoxylates)
[0057] The staining potential of an emulsion rinse containing 0.1%
CPC and 0.3% flavor oil was evaluated using 0.05% of a nonionic
ethoxylated linear alcohol surfactant (available under the
tradename Performathox 490 from Baker Hughes, MW=4522; HLB 18),
having the following general structure. Staining results as
evaluated by the bovine tooth model are as follows.
##STR00001##
TABLE-US-00004 Group Group delta E % Stain Reduction 0.07% CPC
19.02 0.0 0.07% CPC + 0.05% 15.92 43.7 Performathox 490 Water 11.94
100.0
[0058] The HAP-pellicle model was used to evaluate ethoxylates of
different carbon chain lengths, EO units, EO weight %, HLB and
molecular weights for stain reduction when incorporated at
different concentrations in an emulsion rinse containing 0.1% CPC
as described in co-filed patent application entitled MOUTH RINSE
EMULSIONS. Results are summarized in Table 1 below. A positive #
for Normalized Stain Reduction from base rinse indicates a
reduction in stain while a negative number indicates increased
staining. Modeling of the resultant data set indicates that
ethoxylated alcohols having 18 or more carbons in the alcohol
chain, about 35 or more EO (ethylene oxide) units and molecular
weight between about 2,000 to about 15,000 would provide a benefit
in stain reduction without compromising bioavailability of CPC.
Preferred for use herein are ethoxylates having about 25 to 55
carbons in the alcohol chain, from 50 to 100 EO units and MW
between about 2,000 to about 5,000.
TABLE-US-00005 TABLE 1 Evaluation of Anti-Stain Performance of
Ethoxylates # # % EO Normalized Carbons EO by Mol. % Stain Material
(tail) Units Wt. HLB Wt. Polymer Reduction DRA Sigma 458988 34 10
50 10 920 0.05 -64.61 95.09 Sigma 458988 34 10 50 10 920 0.1 -85.81
93.98 Sigma 458988 34 10 50 10 920 0.2 -95.58 91.71 Brij 30 (Brij
L4) 12 4 51 9.7 362 0.05 -42.95 90.99 Brij 30 (Brij L4) 12 4 51 9.7
362 0.1 -64.30 80.98 Brij 30 (Brij L4) 12 4 51 9.7 362 0.2 -88.15
71.78 Brij 98 (Brij O 20) 18 20 78 18 1150 0.05 -18.95 86.95 Brij
98 (Brij O 20) 18 20 78 18 1150 0.1 12.25 71.79 Brij 98 (Brij O 20)
18 20 78 18 1150 0.2 46.61 62.87 Perfornnathox 450 34 10 50 10 920
0.05 -23.37 91.5 Perfornnathox 450 34 10 50 10 920 0.1 -33.73 84.3
Perfornnathox 450 34 10 50 10 920 0.15 -37.57 81.4 Perfornnathox
450 34 10 50 10 920 0.2 -45.31 75.5 Perfornnathox 480 34 40 80 16
2300 0.05 6.39 90.1 Perfornnathox 480 34 40 80 16 2300 0.1 19.09
82.1 Perfornnathox 480 34 40 80 16 2300 0.15 33.96 74.8
Perfornnathox 480 34 40 80 16 2300 0.2 26.02 71.8 Perfornnathox 490
40 90 90 18 4522 0.05 13.68 86.2 Perfornnathox 490 40 90 90 18 4522
0.1 18.77 80.9 Perfornnathox 490 40 90 90 18 4522 0.15 43.37 75.9
Perfornnathox 490 40 90 90 18 4522 0.2 32.71 72.6 Perfornnathox 750
50 16 50 10 1400 0.05 -51.84 96.3 Perfornnathox 750 50 16 50 10
1400 0.1 -41.43 93.4 Perfornnathox 750 50 16 50 10 1400 0.15 -72.63
92.2 Perfornnathox 750 50 16 50 10 1400 0.2 -92.81 88.6 Brij S100
18 100 94 18.8 4654 0.05 19.82 85.5 Brij S100 18 100 94 18.8 4654
0.1 19.82 78.7 Brij S100 18 100 94 18.8 4654 0.15 26.57 74.4 Brij
S100 18 100 94 18.8 4654 0.2 34.76 71.7
[0059] The total amount of anti-stain agent included in the present
compositions will be from about 0.01% to about 5%, from about
0.025% to about 3% or from about 0.1% to about 2%. The anti-stain
agents will be at least slightly water-soluble (about 0.1%
solubility at 25.degree. C., preferably higher) or be
water-dispersible for optimum interaction with salivary proteins
and the cationic antimicrobial agent.
Cationic Antimicrobial Agents
[0060] Cationic antimicrobial agents that are known for their
propensity to induce tooth staining include quaternary ammonium
salts, bis-biquanide salts; and metal ion sources that provide
metal ions such as stannous, zinc and copper. These cationic agents
provide effectiveness in killing, and/or altering metabolism,
and/or suppressing the growth of, microorganisms which cause
topically-treatable infections and diseases of the oral cavity,
such as plaque, caries, gingivitis, and periodontal disease. The
level of antimicrobial agent is dependent on the type of
antimicrobial agent and other factors and typically will be from
about 0.01% to about 5.0%, by weight of the composition.
[0061] The quaternary ammonium compounds in the compositions of the
present invention include those in which one or two of the
substitutes on the quaternary nitrogen has a carbon chain length
(typically alkyl group) from about 8 to about 20, typically from
about 10 to about 18 carbon atoms while the remaining substitutes
(typically alkyl or benzyl group) have a lower number of carbon
atoms, such as from about 1 to about 7 carbon atoms, typically
methyl or ethyl groups. Cetylpyridinium chloride, cetyl pyridinium
fluoride, tetradecylpyridinium chloride, N-tetradecyl-4-ethyl
pyridinium chloride, domiphen bromide, benzalkonium chloride,
benzethonium chloride, methyl benzethonium chloride, dodecyl
trimethyl ammonium bromide, dodecyl dimethyl (2-phenoxyethyl)
ammonium bromide, benzyl dimethoxystearyl ammonium chloride,
quaternized 5-amino-1,3-bis(2-ethyl-hexyl)-5-methyl hexa
hydropyrimidine, lauryl trimethylammonium chloride, cocoalkyl
trimethylammonium chloride, cetyl trimethylammonium bromide,
di-isobutylphenoxyethyl-dimethylbenzylammonium chloride, dodecyl
trimethyl ammonium bromide, are exemplary of typical quaternary
ammonium antimicrobial agents. Other compounds are
bis[4-(R-amino)-1-pyridinium] alkanes as disclosed in U.S. Pat. No.
4,206,215 to Bailey. The pyridinium compounds are the preferred
quaternary ammonium compounds, particularly preferred being
cetylpyridinium, or tetradecylpyridinium halide salts (i.e.,
chloride, bromide, fluoride and iodide). Particularly preferred are
cetylpyridinium chloride and fluoride salts. The quaternary
ammonium antimicrobial agents are included in the present invention
at levels of at least about 0.025 or at least about 0.035% or at
least about 0.045% to about 1.0%, or from about 0.025% to about
0.1% by weight of the composition.
[0062] The present compositions may comprise a metal ion source
that provides stannous ions, zinc ions, copper ions, or mixtures
thereof as antimicrobial agent. The metal ion source can be a
soluble or a sparingly soluble compound of stannous, zinc, or
copper with inorganic or organic counter ions. Examples include the
fluoride, chloride, chlorofluoride, acetate, hexafluorozirconate,
sulfate, tartrate, gluconate, citrate, malate, glycinate,
pyrophosphate, metaphosphate, oxalate, phosphate, carbonate salts
and oxides of stannous, zinc, and copper.
[0063] Stannous, zinc and copper ions have been found to help in
the reduction of gingivitis, plaque, sensitivity, and improved
breath benefits. The composition may comprise from about 50 ppm to
about 20,000 ppm metal ion of the total composition, from about 500
ppm to about 15,000 ppm or from about 3,000 ppm to about 10,000
ppm. This is the total amount of metal ions (stannous, zinc, copper
and mixtures thereof) for delivery to the tooth surface.
[0064] Dentifrices containing stannous salts, such as stannous
fluoride and stannous chloride, are described in U.S. Pat. No.
5,004,597 to Majeti et al. Other descriptions of stannous salts and
ingredients needed to stabilize the stannous are found in U.S. Pat.
No. 5,578,293 issued to Prencipe et al. and in U.S. Pat. No.
5,281,410 issued to Lukacovic et al.
[0065] Stannous salts useful herein include stannous fluoride and
stannous chloride dihydrate, stannous acetate, stannous tartrate
and sodium stannous citrate. Examples of suitable zinc ion sources
are zinc oxide, zinc sulfate, zinc chloride, zinc citrate, zinc
lactate, zinc gluconate, zinc malate, zinc tartrate, zinc
carbonate, zinc phosphate, and other salts listed in U.S. Pat. No
4,022,880. Examples of suitable copper ion sources are listed in
U.S. Pat. No. 5,534,243 and include the chloride, sulfate
gluconate, and glycinate salts. The combined metal ion sources will
typically be present in an amount of from about 0.05% to about 11%,
by weight of the final composition, from about 0.5 to about 7%, or
from about 1% to about 5%. The stannous salts will typically be
present in an amount of from about 0.1 to about 7%, from about 1%
to about 5%, or from about 1.5% to about 3% by weight of the total
composition. The amount of zinc or copper salts will typically
range from about 0.01 to about 5%, from about 0.05 to about 4%, or
from about 0.1 to about 3.0%. Preferred metal ion sources include
stannous fluoride, stannous chloride, stannous chloride dihydrate,
zinc citrate, zinc lactate, zinc sulfate, zinc chloride, zinc
acetate, zinc oxide, copper sulfate, and copper gluconate.
Additional Antimicrobial Agents
[0066] The present compositions may additionally comprise other
orally-effective antimicrobial agents including non-cationic agents
such as halogenated diphenyl ethers, phenolic compounds including
phenol and its homologs, mono and poly-alkyl and aromatic
halophenols, resorcinol and its derivatives, bisphenolic compounds
and halogenated salicylanilides, benzoic esters, and halogenated
carbanilides, essential oils; enzymes such as endoglycosidase,
papain, dextranase, mutanase, and mixtures thereof. The level of
other antimicrobial agent will also depend on the type of
antimicrobial agent and other factors and typically will be from
about 0.01% to about 5.0%, by weight of the composition.
[0067] Antimicrobially-effective essential oils include one or more
of flavor/fragrance chemicals such as citral, neral, geranial,
geraniol, nerol, eucalyptol, eugenol, eugenyl acetate, carvacrol,
thymol, o-cymen-5-ol (isopropylmethylphenol, IPMP), farnesol,
benzyl alcohol, benzaldehyde, hinokitiol (isopropyltropolone),
terpinene-4-ol, zingerone, allyl isothiocyanate, dipentene,
.alpha.-pinene, .beta.-pinene, menthol, methyl salicylate,
anethole, carvone, limonene, ocimene, n-decyl alcohol, citronellal,
citronellol, methyl acetate, citronellyl acetate, methyl eugenol,
linalool, ethyl linalool, camphor, safrole, chlorothymol, guaiacol,
phenol, phenyl salicylate, cinnamic acid, guaiacol, isoeugenol,
dihydroeugenol, vanillyl butyl ether, 5-propenylguaethol,
4-ethyl-2-methoxyphenol, 4-allyl-2-methoxyphenol acetate, and
4-methyl guaiacol. Natural sources of these chemicals may be used.
The selection of the essential oils to is based on demonstration of
their activity against microorganisms known to be involved in
undesirable oral cavity conditions such as gingivitis, periodontal
disease and oral malodor. For example, useful herein is a blend of
essential oils comprising at least two components, a first
component selected from acyclic or non-ring structures such as
citral, neral, geranial, geraniol, nerol or derivatives thereof and
a second component selected from ring-containing structures such as
eucalyptol, eugenol, carvacrol or derivatives thereof. These
essential oil blends are described in commonly-assigned patent
application published as US20080253976A1. The essential oil blend
is used at a level of at least about 0.02% by weight of the
composition to provide effective antimicrobial activity.
[0068] A number of the above antimicrobially effective essential
oil chemicals are aldehydes and ketones which are useful as
anti-stain agents.
[0069] In addition to the components described above, the present
compositions may comprise additional optional components
collectively referred to as orally acceptable carrier materials,
which are described in the following paragraphs.
Orally Acceptable Carrier Materials
[0070] The orally acceptable carrier materials comprise 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.
In particular, the carrier materials should not have a negative
effect on the bioavailability of the cationic antimicrobials or on
the anti-staining activity of the anti-stain agents used
herein.
[0071] The carriers or excipients of the present invention can
include the usual and conventional components of dentifrices,
non-abrasive gels, subgingival gels, mouthwashes or rinses, mouth
sprays, chewing gums, lozenges and breath mints as more fully
described hereinafter.
[0072] The choice of a carrier to be used is basically determined
by the way the composition is to be introduced into the oral
cavity. Carrier materials for toothpaste, tooth gel or the like
include abrasive materials, sudsing agents, binders, humectants,
flavoring and sweetening agents, etc. as disclosed in e.g., U.S.
Pat. No. 3,988,433 to Benedict. Carrier materials for biphasic
dentifrice formulations are disclosed in U.S. Pat. No. 5,213,790,
issued May 23, 1993, U.S. Pat. Nos. 5,145,666, and 5,281,410 all to
Lukacovic et al. and in U.S. Pat. Nos. 4,849,213 and 4,528,180 to
Schaeffer. Mouthwash, rinse or mouth spray carrier materials
typically include water, flavoring and sweetening agents, etc., as
disclosed in, e.g., U.S. Pat. No. 3,988,433 to Benedict. Lozenge
carrier materials typically include a candy base; chewing gum
carrier materials include a gum base, flavoring and sweetening
agents, as in, e.g., U.S. Pat. No. 4,083,955 to Grabenstetter et
al. Sachet carrier materials typically include a sachet bag,
flavoring and sweetening agents. For subgingival gels used for
delivery of actives into the periodontal pockets or around the
periodontal pockets, a "subgingival gel carrier" is chosen as
disclosed in, e.g. U.S. Pat. Nos. 5,198,220 and 5,242,910 both to
Damani. Carriers suitable for the preparation of compositions of
the present invention are well known in the art. Their selection
will depend on secondary considerations like taste, cost, and shelf
stability, etc.
[0073] The compositions of the present invention may also be in the
form of non-abrasive gels and subgingival gels, which may be
aqueous or non-aqueous. In still another aspect, the invention
provides a dental implement impregnated with the present
composition. The dental implement comprises an implement for
contact with teeth and other tissues in the oral cavity, said
implement being impregnated with the present composition. The
dental implement can be impregnated fibers including dental floss
or tape, chips, strips, films and polymer fibers.
[0074] In one embodiment, the compositions of the subject invention
are in the form of dentifrices, such as toothpastes, tooth gels and
tooth powders. Components of such toothpaste and tooth gels
generally include one or more of a dental abrasive (from about 6%
to about 50%), a surfactant (from about 0.5% to about 10%), a
thickening agent (from about 0.1% to about 5%), a humectant (from
about 10% to about 55%), a flavoring agent (from about 0.04% to
about 2%), a sweetening agent (from about 0.1% to about 3%), a
coloring agent (from about 0.01% to about 0.5%) and water (from
about 2% to about 45%). Such toothpaste or tooth gel may also
include one or more of an anticaries agent (from about 0.05% to
about 0.3% as fluoride ion) and an anticalculus agent (from about
0.1% to about 13%). Tooth powders, of course, contain substantially
all non-liquid components.
[0075] Other embodiments of the subject invention are liquid
products, including mouthwashes or mouth rinses, mouth sprays,
dental solutions and irrigation fluids. Components of such
mouthwashes and mouth sprays typically include one or more of water
(from about 45% to about 95%), ethanol (from about 0% to about
25%), a humectant (from about 0% to about 50%), a surfactant (from
about 0.01% to about 7%), a flavoring agent (from about 0.04% to
about 2%), a sweetening agent (from about 0.1% to about 3%), and a
coloring agent (from about 0.001% to about 0.5%). Such mouthwashes
and mouth sprays may also include one or more of an anticaries
agent (from about 0.05% to about 0.3% as fluoride ion) and an
anticalculus agent (from about 0.1% to about 3%). Components of
dental solutions generally include one or more of water (from about
90% to about 99%), preservative (from about 0.01% to about 0.5%),
thickening agent (from 0% to about 5%), flavoring agent (from about
0.04% to about 2%), sweetening agent (from about 0.1% to about 3%),
and surfactant (from 0% to about 5%).
[0076] Types of orally acceptable carrier materials or excipients,
which may optionally be included in compositions of the present
invention, along with specific non-limiting examples, are described
in the following paragraphs.
Desensitizing Agent
[0077] The present compositions may optionally contain a dentinal
desensitizing agent such as salts of potassium, calcium, strontium
and tin including nitrate, chloride, fluoride, phosphates,
pyrophosphate, polyphosphate, citrate, oxalate and sulfate.
Anticalculus Agent
[0078] The present compositions may optionally include an
anticalculus agent, such as a pyrophosphate salt as a source of
pyrophosphate ion. The pyrophosphate salts useful in the present
compositions include the dialkali metal pyrophosphate salts,
tetraalkali metal pyrophosphate salts, and mixtures thereof.
Disodium dihydrogen pyrophosphate (Na.sub.2H.sub.2P.sub.2O.sub.7),
tetrasodium pyrophosphate (Na.sub.4P.sub.2O.sub.7), and
tetrapotassium pyrophosphate (K.sub.4P.sub.2O.sub.7) in their
unhydrated as well as hydrated forms are the preferred species. In
compositions of the present invention, the pyrophosphate salt may
be present in one of three ways: predominately dissolved,
predominately undissolved, or a mixture of dissolved and
undissolved pyrophosphate.
[0079] Compositions comprising predominately dissolved
pyrophosphate refer to compositions where at least one
pyrophosphate ion source is in an amount sufficient to provide at
least about 1.0% free pyrophosphate ions. The amount of free
pyrophosphate ions may be from about 1% to about 15%, from about
1.5% to about 10% in one embodiment, and from about 2% to about 6%
in another embodiment. Free pyrophosphate ions may be present in a
variety of protonated states depending on the pH of the
composition.
[0080] Compositions comprising predominately undissolved
pyrophosphate refer to compositions containing no more than about
20% of the total pyrophosphate salt dissolved in the composition,
or less than about 10% of the total pyrophosphate dissolved in the
composition. Tetrasodium pyrophosphate salt is a preferred
pyrophosphate salt in these compositions. Tetrasodium pyrophosphate
may be the anhydrous salt form or the decahydrate form, or any
other species stable in solid form in the dentifrice compositions.
The salt is in its solid particle form, which may be its
crystalline and/or amorphous state, with the particle size of the
salt preferably being small enough to be aesthetically acceptable
and readily soluble during use. The amount of pyrophosphate salt
useful in making these compositions is any tartar control effective
amount, generally from about 1.5% to about 15%, from about 2% to
about 10%, or from about 3% to about 8%, by weight of the
dentifrice composition.
[0081] Compositions may also comprise a mixture of dissolved and
undissolved pyrophosphate salts. Any of the above mentioned
pyrophosphate salts may be used.
[0082] The pyrophosphate salts are described in more detail in
Kirk-Othmer Encyclopedia of Chemical Technology, Third Edition,
Volume 17, Wiley-Interscience Publishers (1982).
[0083] Optional agents to be used in place of or in combination
with the pyrophosphate salt include such known materials as
synthetic anionic polymers, including polyacrylates and copolymers
of maleic anhydride or acid and methyl vinyl ether (e.g., Gantrez),
as described, for example, in U.S. Pat. No. 4,627,977, to Gaffar et
al., as well as, e.g., polyamino propane sulfonic acid (AMPS),
diphosphonates (e.g., EHDP; AHP), polypeptides (such as
polyaspartic and polyglutamic acids), and mixtures thereof.
Fluoride Ion Source
[0084] It is common to have a water-soluble fluoride compound
present in dentifrices and other oral compositions in an amount
sufficient to give a fluoride ion concentration in the composition,
and/or when it is used of from about 0.0025% to about 5.0% by
weight or from about 0.005% to about 2.0% by weight, to provide
anticaries effectiveness. A wide variety of fluoride ion-yielding
materials can be employed as sources of soluble fluoride in the
present compositions. Examples of suitable fluoride ion-yielding
materials are found in U.S. Pat. No. 3,535,421, Oct. 20, 1970 to
Briner et al. and U.S. Pat. No. 3,678,154, Jul. 18, 1972 to Widder
et al. Representative fluoride ion sources include: stannous
fluoride, sodium fluoride, potassium fluoride, sodium
monofluorophosphate, indium fluoride, amine fluoride and many
others. Stannous fluoride and sodium fluoride are among preferred
sources, as well as mixtures thereof.
Abrasives
[0085] Dental abrasives useful in the compositions of the subject
invention include many different materials. The material selected
must be one which is compatible within the composition of interest
and does not excessively abrade dentin. Suitable abrasives include,
for example, silicas including gels and precipitates, insoluble
sodium polymetaphosphate, hydrated alumina, calcium carbonate,
dicalcium orthophosphate dihydrate, calcium pyrophosphate,
tricalcium phosphate, calcium polymetaphosphate, and resinous
abrasive materials such as particulate condensation products of
urea and formaldehyde.
[0086] Another class of abrasives for use in the present
compositions is the particulate thermo-setting polymerized resins
as described in U.S. Pat. No. 3,070,510 issued to Cooley and
Grabenstetter. Suitable resins include, for example, melamines,
phenolics, ureas, melamine-ureas, melamine-formaldehydes,
urea-formaldehyde, melamine-urea-formaldehydes, cross-linked
epoxides, and cross-linked polyesters.
[0087] Silica dental abrasives of various types are preferred
because of their unique benefits of exceptional dental cleaning and
polishing performance without unduly abrading tooth enamel or
dentine. The silica abrasive polishing materials herein, as well as
other abrasives, generally have an average particle size ranging
between about 0.1 to about 30 microns, and preferably from about 5
to about 15 microns. The abrasive can be precipitated silica or
silica gels such as the silica xerogels described in Pader et al.,
U.S. Pat. No. 3,538,230 and DiGiulio, U.S. Pat. No. 3,862,307.
Examples include the silica xerogels marketed under the trade name
"Syloid" by the W.R. Grace & Company, Davison Chemical Division
and precipitated silica materials such as those marketed by the J.
M. Huber Corporation under the trade name, Zeodent.RTM.,
particularly the silicas carrying the designation Zeodent.RTM. 119,
Zeodent.RTM. 118, Zeodent.RTM. 109 and Zeodent.RTM. 129. The types
of silica dental abrasives useful in the toothpastes of the present
invention are described in more detail in Wason, U.S. Pat. No.
4,340,583; and in commonly-assigned U.S. Pat. Nos. 5,603,920;
5,589,160; 5,658,553; 5,651,958; and 6,740,311.
[0088] Mixtures of abrasives can be used such as mixtures of the
various grades of Zeodent.RTM. silica abrasives listed above. The
total amount of abrasive in dentifrice compositions of the subject
invention typically range from about 6% to about 70% by weight;
toothpastes generally contain from about 10% to about 50% of
abrasives, by weight of the composition. Dental solution, mouth
spray, mouthwash and non-abrasive gel compositions of the subject
invention typically contain little or no abrasive.
Tooth Substantive Agent
[0089] The present invention may include a tooth substantive agent
such as polymeric surface active agents (PMSA's), which are
polyelectrolytes, more specifically anionic polymers. The PMSA's
contain anionic groups, e.g., phosphate, phosphonate, carboxy, or
mixtures thereof, and thus, have the capability to interact with
cationic or positively charged entities. The "mineral" descriptor
is intended to convey that the surface activity or substantivity of
the polymer is toward mineral surfaces such as calcium phosphate
minerals or teeth.
[0090] PMSA's are useful in the present compositions because of
their stain prevention benefit. The PMSA's may provide a stain
prevention benefit because of their reactivity or substantivity to
mineral surfaces, resulting in desorption of portions of
undesirable adsorbed pellicle proteins, in particular those
associated with binding color bodies that stain teeth, calculus
development and attraction of undesirable microbial species. The
retention of these PMSA's on teeth can also prevent stains from
accruing due to disruption of binding sites of color bodies on
tooth surfaces.
[0091] The ability of PMSA's to bind stain promoting ingredients of
oral care products, for example, stannous ions and cationic
antimicrobials, is also believed to be helpful. The PMSA will also
provide tooth surface conditioning effects which produce desirable
effects on surface thermodynamic properties and surface film
properties, which impart improved clean feel aesthetics both during
and most importantly, following rinsing or brushing. Many of these
polymeric agents are also known or expected to provide tartar
control benefits when applied in oral compositions, hence providing
improvement in both the appearance of teeth and their tactile
impression to consumers.
[0092] The polymeric mineral surface active agents include an agent
which will have a strong affinity for the tooth surface, deposit a
polymer layer or coating on the tooth surface and produce the
desired surface modification effects. Suitable examples of such
polymers are polyelectrolytes such as condensed phosphorylated
polymers; polyphosphonates; copolymers of phosphate- or
phosphonate-containing monomers or polymers with other monomers
such as ethylenically unsaturated monomers and amino acids or with
other polymers such as proteins, polypeptides, polysaccharides,
poly(acrylate), poly(acrylamide), poly(methacrylate),
poly(ethacrylate), poly(hydroxyalkylmethacrylate), poly(vinyl
alcohol), poly(maleic anhydride), poly(maleate) poly(amide),
poly(ethylene amine), poly(ethylene glycol), poly(propylene
glycol), poly(vinyl acetate) and poly(vinyl benzyl chloride);
polycarboxylates and carboxy-substituted polymers; and mixtures
thereof. Suitable polymeric mineral surface active agents include
the carboxy-substituted alcohol polymers described in U.S. Pat.
Nos. 5,292,501; 5,213,789, 5,093,170; 5,009,882; and 4,939,284; all
to Degenhardt et al. and the diphosphonate-derivatized polymers in
U.S. Pat. No. 5,011,913 to Benedict et al; the synthetic anionic
polymers including polyacrylates and copolymers of maleic anhydride
or acid and methyl vinyl ether (e.g., Gantrez), as described, for
example, in U.S. Pat. No. 4,627,977, to Gaffar et al. Diphosphonate
modified polyacrylic acid is another example. Polymers with
activity must have sufficient surface binding propensity to desorb
pellicle proteins and remain affixed to enamel surfaces. For tooth
surfaces, polymers with end or side chain phosphate or phosphonate
functions are preferred although other polymers with mineral
binding activity may prove effective depending upon adsorption
affinity.
[0093] Additional examples of suitable phosphonate containing
polymeric mineral surface active agents include the geminal
diphosphonate polymers disclosed as anticalculus agents in U.S.
Pat. No. 4,877,603 to Degenhardt et al; phosphonate group
containing copolymers disclosed in U.S. Pat. No. 4,749,758 to
Dursch et al. and in GB 1,290,724 (both assigned to Hoechst)
suitable for use in detergent and cleaning compositions; and the
copolymers and cotelomers disclosed as useful for applications
including scale and corrosion inhibition, coatings, cements and
ion-exchange resins in U.S. Pat. No. 5,980,776 to Zakikhani et al.
and U.S. Pat. No. 6,071,434 to Davis et al. Additional polymers
include the water-soluble copolymers of vinylphosphonic acid and
acrylic acid and salts thereof disclosed in GB 1,290,724 wherein
the copolymers contain from about 10% to about 90% by weight
vinylphosphonic acid and from about 90% to about 10% by weight
acrylic acid, more particularly wherein the copolymers have a
weight ratio of vinylphosphonic acid to acrylic acid of 70%
vinylphosphonic acid to 30% acrylic acid; 50% vinylphosphonic acid
to 50% acrylic acid; or 30% vinylphosphonic acid to 70% acrylic
acid. Other suitable polymers include the water soluble polymers
disclosed by Zakikhani and Davis prepared by copolymerizing
diphosphonate or polyphosphonate monomers having one or more
unsaturated C.dbd.C bonds (e.g., vinylidene-1,1-diphosphonic acid
and 2-(hydroxyphosphinyl)ethylidene-1,1-diphosphonic acid), with at
least one further compound having unsaturated C.dbd.C bonds (e.g.,
acrylate and methacrylate monomers). Suitable polymers include the
diphosphonate/acrylate polymers supplied by Rhodia under the
designation ITC 1087 (Average MW 3000-60,000) and Polymer 1154
(Average MW 6000-55,000).
[0094] Suitable PMSA's will be stable and compatible with other
components of the oral care composition such as ionic fluoride,
cationic antimicrobials and metal ions, and are stable to
hydrolysis in high water content formulations, thus permitting a
simple single phase dentifrice or mouth rinse formulation. If the
PMSA does not have these stability and compatibility properties,
one option is a dual phase formulation with the PMSA separated from
the fluoride or other incompatible component. Another option is to
formulate non-aqueous, essentially non-aqueous or limited water
compositions to minimize reaction between the PMSA and other
components.
[0095] A preferred PMSA is a polyphosphate. 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. Preferred polyphosphates are those
having around three 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. The
polyphosphate salts desired include tripolyphosphate,
tetrapolyphosphate and hexametaphosphate, among others.
Polyphosphates larger than tetrapolyphosphate usually occur as
amorphous glassy materials. Preferred in this invention are the
linear polyphosphates having the formula: XO(XPO.sub.3).sub.nX,
wherein X is sodium, potassium or ammonium and n averages from
about 3 to about 125. Preferred polyphosphates are those having n
averaging from about 6 to about 21, such as those commercially
known as Sodaphos (n.apprxeq.6), Hexaphos (n.apprxeq.13), and Glass
H (n.apprxeq.21) and manufactured by FMC Corporation and Astaris.
These polyphosphates may be used alone or in combination. Some
polyphosphates are susceptible to hydrolysis in high water
formulations at acid pH, particularly below pH 5. Thus it is
preferred to use longer-chain polyphosphates, such as Glass H
having an average chain length of about 21. Such longer-chain
polyphosphates when undergoing hydrolysis, produce shorter-chain
polyphosphates which are still effective to deposit onto teeth and
provide a stain preventive benefit.
[0096] Other polyphosphorylated compounds may be used in addition
to or instead of the polyphosphate, in particular
polyphosphorylated inositol compounds such as phytic acid,
myo-inositol pentakis(dihydrogen phosphate); myo-inositol
tetrakis(dihydrogen phosphate), myo-inositol trikis(dihydrogen
phosphate), and an alkali metal, alkaline earth metal or ammonium
salt thereof. Preferred herein is phytic acid, also known as
myo-inositol 1,2,3,4,5,6-hexakis (dihydrogen phosphate) or inositol
hexaphosphoric acid, and its alkali metal, alkaline earth metal or
ammonium salts. Herein, the term "phytate" includes phytic acid and
its salts as well as the other polyphosphorylated inositol
compounds.
[0097] The amount of tooth substantive agent may be from about 0.1%
to about 35% by weight of the total oral composition. In dentifrice
formulations, the amount is typically from about 2% to about 30%,
from about 5% to about 25%, or from about 6% to about 20%. In mouth
rinse compositions, the amount of tooth substantive agent is
typically from about 0.1% to 5% or from about 0.5% to about 3%.
[0098] In addition to creating surface modifying effects, the tooth
substantive agent may also function to solubilize insoluble salts.
For example, Glass H has been found to solubilize insoluble
stannous salts. Thus, in compositions containing stannous fluoride
for example, Glass H contributes to decreasing the stain promoting
effect of stannous.
Chelating Agents
[0099] Another optional agent is a chelating agent, also called
sequestrants, such as gluconic acid, tartaric acid, citric acid and
pharmaceutically-acceptable salts thereof. Chelating agents are
able to complex calcium found in the cell walls of the bacteria.
Chelating agents can also disrupt plaque by removing calcium from
the calcium bridges which help hold this biomass intact. However,
it is not desired to use a chelating agent which has an affinity
for calcium that is too high, as this may result in tooth
demineralization, which is contrary to the objects and intentions
of the present invention. Suitable chelating agents will generally
have a calcium binding constant of about 10.sup.1 to 10.sup.5 to
provide improved cleaning with reduced plaque and calculus
formation. Chelating agents also have the ability to complex with
metallic ions and thus aid in preventing their adverse effects on
the stability or appearance of products. Chelation of ions, such as
iron or copper, helps retard oxidative deterioration of finished
products.
[0100] Examples of suitable chelating agents are sodium or
potassium gluconate and citrate; citric acid/alkali metal citrate
combination; disodium tartrate; dipotassium tartrate; sodium
potassium tartrate; sodium hydrogen tartrate; potassium hydrogen
tartrate; sodium, potassium or ammonium polyphosphates and mixtures
thereof. The amounts of chelating agent suitable for use in the
present invention will typically be from about 0.1% to about 2.5%,
from about 0.5% to about 2.5%, or from about 1.0% to about
2.5%.
[0101] Still other chelating agents suitable for use in the present
invention are the anionic polymeric polycarboxylates. Such
materials are well known in the art, being employed in the form of
their free acids or partially or preferably fully neutralized water
soluble alkali metal (e.g. potassium and preferably sodium) or
ammonium salts. Examples are 1:4 to 4:1 copolymers of maleic
anhydride or acid with another polymerizable ethylenically
unsaturated monomer, preferably methyl vinyl ether
(methoxyethylene) having a molecular weight (M.W.) of about 30,000
to about 1,000,000. These copolymers are available for example as
Gantrez AN 139 (M.W. 500,000), AN 119 (M.W. 250,000) and S-97
Pharmaceutical Grade (M.W. 70,000), of GAF Chemicals
Corporation.
[0102] Other operative polymeric polycarboxylates include the 1:1
copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl
methacrylate, N-vinyl-2-pyrrolidone, or ethylene, the latter being
available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA
Grade 61, and 1:1 copolymers of acrylic acid with methyl or
hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl
ether or N-vinyl-2-pyrrolidone.
[0103] Additional operative polymeric polycarboxylates are
disclosed in U.S. Pat. Nos. 4,138,477 and 4,183,914 to Gaffar et
al. and include copolymers of maleic anhydride with styrene,
isobutylene or ethyl vinyl ether; polyacrylic, polyitaconic and
polymaleic acids; and sulfoacrylic oligomers of M.W. as low as
1,000 available as Uniroyal ND-2.
Surfactants
[0104] The present compositions may also comprise surfactants, also
commonly referred to as sudsing agents. Suitable surfactants are
those which are reasonably stable and foam throughout a wide pH
range. The surfactant may be anionic, nonionic, amphoteric,
zwitterionic, cationic, or mixtures thereof.
[0105] Anionic surfactants useful herein include the water-soluble
salts of alkyl sulfates having from 8 to 20 carbon atoms in the
alkyl radical (e.g., sodium alkyl sulfate) and the water-soluble
salts of sulfonated monoglycerides of fatty acids having from 8 to
20 carbon atoms. Sodium lauryl sulfate (SLS) and sodium coconut
monoglyceride sulfonates are examples of anionic surfactants of
this type. Other suitable anionic surfactants are sarcosinates,
such as sodium lauroyl sarcosinate, taurates, sodium lauryl
sulfoacetate, sodium lauroyl isethionate, sodium laureth
carboxylate, and sodium dodecyl benzenesulfonate. Mixtures of
anionic surfactants can also be employed. Many suitable anionic
surfactants are disclosed by Agricola et al., U.S. Pat. No.
3,959,458, issued May 25, 1976. The present composition typically
comprises an anionic surfactant at a level of from about 0.025% to
about 9%, from about 0.05% to about 5% in some embodiments, and
from about 0.1% to about 1% in other embodiments.
[0106] Another suitable surfactant is one selected from the group
consisting of sarcosinate surfactants, isethionate surfactants and
taurate surfactants. Preferred for use herein are alkali metal or
ammonium salts of these surfactants, such as the sodium and
potassium salts of the following: lauroyl sarcosinate, myristoyl
sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl
sarcosinate. The sarcosinate surfactant may be present in the
compositions of the present invention from about 0.1% to about 2.5%
or from about 0.5% to about 2.0% by weight of the total
composition.
[0107] Cationic surfactants useful in the present invention include
derivatives of aliphatic quaternary ammonium compounds having one
long alkyl chain containing from about 8 to 18 carbon atoms such as
lauryl trimethylammonium chloride; cetyl pyridinium chloride; cetyl
trimethylammonium bromide;
di-isobutylphenoxyethyl-dimethylbenzylammonium chloride; cocoalkyl
trimethylammonium chloride; cetyl pyridinium fluoride; etc. The
quaternary ammonium fluorides having detergent properties are
described in U.S. Pat. No. 3,535,421 to Briner et al. Certain
cationic surfactants can also act as germicides in the compositions
disclosed herein.
[0108] Nonionic surfactants that can be used in the compositions of
the present invention include compounds produced by the
condensation of alkylene oxide groups (hydrophilic in nature) with
an organic hydrophobic compound which may be aliphatic or
alkylaromatic in nature. Examples of suitable nonionic surfactants
include the Pluronics, polyethylene oxide condensates of alkyl
phenols, products derived from the condensation of ethylene oxide
with the reaction product of propylene oxide and ethylene diamine,
ethylene oxide condensates of aliphatic alcohols, long chain
tertiary amine oxides, long chain tertiary phosphine oxides, long
chain dialkyl sulfoxides and mixtures of such materials.
[0109] Zwitterionic synthetic surfactants useful in the present
invention include derivatives of aliphatic quaternary ammonium,
phosphonium, and sulfonium compounds, in which the aliphatic
radicals can be straight chain or branched, and wherein one of the
aliphatic substituents contains from about 8 to 18 carbon atoms and
one contains an anionic water-solubilizing group, e.g., carboxy,
sulfonate, sulfate, phosphate or phosphonate.
[0110] Suitable betaine surfactants are disclosed in U.S. Pat. No.
5,180,577 to Polefka et al. Typical alkyl dimethyl betaines include
decyl betaine or 2-(N-decyl-N,N-dimethylammonio) acetate, coco
betaine, myristyl betaine, palmityl betaine, lauryl betaine, cetyl
betaine, cetyl betaine, stearyl betaine, etc. The amidobetaines are
exemplified by cocoamidoethyl betaine, cocoamidopropyl betaine,
lauramidopropyl betaine and the like. The betaines of choice
include cocoamidopropyl betaines such as lauramidopropyl
betaine.
Thickening Agents
[0111] In preparing toothpaste or gels, thickening agents are added
to provide a desirable consistency to the composition, to provide
desirable active release characteristics upon use, to provide shelf
stability, and to provide stability of the composition, etc.
Suitable thickening agents include one or a combination of
carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose (HEC),
natural and synthetic clays (e.g., Veegum and laponite) and water
soluble salts of cellulose ethers such as sodium
carboxymethylcellulose (CMC) and sodium carboxymethyl hydroxyethyl
cellulose. Natural gums such as gum karaya, xanthan gum, gum
arabic, and gum tragacanth can also be used. Colloidal magnesium
aluminum silicate or finely divided silica can be used as part of
the thickening agent to further improve texture.
[0112] Suitable carboxyvinyl polymers useful as thickening or
gelling agents include carbomers which are homopolymers of acrylic
acid crosslinked with an alkyl ether of pentaerythritol or an alkyl
ether of sucrose. Carbomers are commercially available from B.F.
Goodrich as the Carbopol.RTM. series, including Carbopol 934, 940,
941, 956, and mixtures thereof.
[0113] Thickening agents are typically present in an amount from
about 0.1% to about 15%, from about 2% to about 10%, or from about
4% to about 8%, by weight of the total toothpaste or gel
composition, can be used. Higher concentrations may be used for
chewing gums, lozenges and breath mints, sachets, non-abrasive gels
and subgingival gels.
Humectants
[0114] Another optional carrier material of the present
compositions is a humectant. The humectant serves to keep
toothpaste compositions from hardening upon exposure to air, to
give compositions a moist feel to the mouth, and, for particular
humectants, to impart desirable sweetness of flavor to toothpaste
compositions. The humectant, on a pure humectant basis, generally
comprises from about 0% to about 70% or from about 5% to about 25%,
by weight of the compositions herein. Suitable humectants for use
in compositions of the subject invention include edible polyhydric
alcohols such as glycerin, sorbitol, xylitol, butylene glycol,
polyethylene glycol, propylene glycol and trimethyl glycine.
Flavor System
[0115] A flavor system is typically added to oral care
compositions, to provide a pleasant tasting composition and to
effectively mask any unpleasant taste and sensations due to certain
components of the composition such as antimicrobial actives or
peroxide. Pleasant tasting compositions improve user compliance to
prescribed or recommended use of oral care products. The present
flavor system will comprise flavor components, such as those that
have been found to be relatively stable in the presence of usual
oral care product actives, carrier materials or excipients. The
flavor system may comprise flavor ingredients including but not
limited to peppermint oil, corn mint oil, spearmint oil, oil of
wintergreen, clove bud oil, cassia, sage, parsley oil, marjoram,
lemon, lime, orange, cis-jasmone,
2,5-dimethyl-4-hydroxy-3(2H)-furanone,
5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone, vanillin, ethyl
vanillin, 2-methoxybenzaldehyde, benzaldehyde; cinnamaldehyde,
hexyl cinnamaldehyde, .alpha.-methyl cinnamaldehyde, ortho-methoxy
cinnamaldehyde, .alpha.-amyl cinnamaldehydepropenyl guaethol,
heliotropine, 4-cis-heptenal, diacetyl, methyl-.rho.-tert-butyl
phenyl acetate, menthol, methyl salicylate, ethyl salicylate,
1-menthyl acetate, oxanone, .alpha.-irisone, methyl cinnamate,
ethyl cinnamate, butyl cinnamate, ethyl butyrate, ethyl acetate,
methyl anthranilate, iso-amyl acetate, iso-amyl butyrate, allyl
caproate, eugenol, eucalyptol, thymol, cinnamic alcohol, octanol,
octanal, decanol, decanal, phenylethyl alcohol, benzyl alcohol,
.alpha.-terpineol, linalool, limonene, citral, maltol, ethyl
maltol, anethole, dihydroanethole, carvone, menthone,
.beta.-damascenone, ionone, gamma-decalactone, gamma-nonalactone,
gamma-undecalactone and mixtures thereof. Generally suitable
flavoring ingredients are those containing structural features and
functional groups that are less prone to redox reactions. These
include derivatives of flavor chemicals that are saturated or
contain stable aromatic rings or ester groups. Also suitable are
flavor chemicals that may undergo some oxidation or degradation
without resulting in a significant change in the flavor character
or profile. The flavor ingredients may be supplied in the
composition as single or purified chemicals or by addition of
natural oils or extracts that have preferably undergone a refining
treatment to remove components that are relatively unstable and may
degrade and alter the desired flavor profile, resulting in a less
acceptable product from an organoleptic standpoint. Flavoring
agents are generally used in the compositions at levels of from
about 0.001% to about 5%, by weight of the composition.
[0116] The flavor system will typically include a sweetening agent.
Suitable sweeteners include those well known in the art, including
both natural and artificial sweeteners. Some suitable water-soluble
sweeteners include monosaccharides, disaccharides and
polysaccharides such as xylose, ribose, glucose (dextrose),
mannose, galactose, fructose (levulose), sucrose (sugar), maltose,
invert sugar (a mixture of fructose and glucose derived from
sucrose), partially hydrolyzed starch, corn syrup solids,
dihydrochalcones, monellin, steviosides, and glycyrrhizin. Suitable
water-soluble artificial sweeteners include soluble saccharin
salts, i.e., sodium or calcium saccharin salts, cyclamate salts,
the sodium, ammonium or calcium salt of
3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide, the
potassium salt of
3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide
(acesulfame-K), the free acid form of saccharin, and the like.
Other suitable sweeteners include dipeptide based sweeteners, such
as L-aspartic acid derived sweeteners, such as
L-aspartyl-L-phenylalanine methyl ester (aspartame) and materials
described in U.S. Pat. No. 3,492,131,
L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide
hydrate, methyl esters of L-aspartyl-L-phenylglycerin and
L-aspartyl-L-2,5,dihydrophenyl-glycine,
L-aspartyl-2,5-dihydro-L-phenylalanine,
L-aspartyl-L-(1-cyclohexylen)-alanine, and the like. Water-soluble
sweeteners derived from naturally occurring water-soluble
sweeteners, such as a chlorinated derivative of ordinary sugar
(sucrose), known, for example, under as sucralose as well as
protein based sweeteners such as thaumatoccous danielli (Thaumatin
I and II) can be used. A composition typically contains from about
0.1% to about 10% of sweetener, by weight.
[0117] Suitable cooling agents or coolants include a wide variety
of materials such as menthol and derivatives thereof. Among
synthetic coolants, many are derivatives of or are structurally
related to menthol, i.e., containing the cyclohexane moiety, and
derivatized with functional groups including carboxamide, ketal,
ester, ether and alcohol. Examples include the
.rho.-menthanecarboxamide compounds such as
N-ethyl-p-menthan-3-carboxamide, known commercially as "WS-3", and
others in the series such as WS-5, WS-11, WS-14 and WS-30. An
example of a synthetic carboxamide coolant that is structurally
unrelated to menthol is N,2,3-trimethyl-2-isopropylbutanamide,
known as "WS-23". Additional suitable coolants include
3-1-menthoxypropane-1,2-diol known as TK-10, isopulegol (under the
tradename Coolact P) and .rho.-menthane-3,8-diol (under the
tradename Coolact 38D) all available from Takasago; menthone
glycerol acetal known as MGA; menthyl esthers such as menthyl
acetate, menthyl acetoacetate, menthyl lactate known as
Frescolat.RTM. supplied by Haarmann and Reimer, and monomenthyl
succinate under the tradename Physcool from V. Mane. The terms
menthol and menthyl as used herein include dextro- and levorotatory
isomers of these compounds and racemic mixtures thereof. TK-10 is
described in U.S. Pat. No. 4,459,425, Amano et al. WS-3 and other
carboxamide cooling agents are described for example in U.S. Pat.
Nos. 4,136,163; 4,150,052; 4,153,679; 4,157,384; 4,178,459 and
4,230,688. Additional N-substituted .rho.-menthane carboxamides are
described in WO 2005/049553A1 including
N-(4-cyanomethylphenyl)-.rho.-menthanecarboxamide,
N-(4-sulfamoylphenyl)-.rho.-menthanecarboxamide,
N-(4-cyanophenyl)-.rho.-menthanecarboxamide,
N-(4-acetylphenyl)-.rho.-menthanecarboxamide,
N-(4-hydroxymethylphenyl)-.rho.-menthanecarboxamide and
N-(3-hydroxy-4-methoxyphenyl)-.rho.-menthanecarboxamide.
[0118] In addition the flavor system may include sensates such as
salivating agents, hydration and moisturization agents, warming
agents, and numbing agents. These agents are present in the
compositions at a level of from about 0.001% to about 10% or from
about 0.1% to about 1%, by weight of the composition. Suitable
salivating agents include Jambu.RTM. manufactured by Takasago and
Optaflow.RTM. from Symrise. Examples of hydration agents include
polyols such as erythritol. Suitable numbing agents include
benzocaine, lidocaine, clove bud oil, and ethanol. Examples of
warming agents include ethanol, capsicum and nicotinate esters,
such as benzyl nicotinate.
Miscellaneous Carrier Materials
[0119] Water employed in the preparation of commercially suitable
oral compositions desirably would be of low ion content and free of
organic impurities. Water may comprise up to about 99% by weight of
the aqueous compositions herein. These amounts of water include the
free water which is added plus that which is introduced with other
materials, such as with sorbitol.
[0120] The present invention may also include an alkali metal
bicarbonate salt, which may serve a number of functions including
effervescent, abrasive, deodorant, buffering and adjusting pH. The
present composition may contain from about 0.5% to about 30%, from
about 0.5% to about 15% or from about 0.5% to about 5% of an alkali
metal bicarbonate such as sodium bicarbonate.
[0121] The pH of the present compositions may be adjusted through
the use of buffering agents. Buffering agents, as used herein,
refer to agents that can be used to adjust the pH of aqueous
compositions such as mouth rinses and dental solutions typically to
a range of about 3 to about 8, preferably from about 3 to about 6.
Buffering agents include sodium bicarbonate, monosodium phosphate,
trisodium phosphate, sodium hydroxide, sodium carbonate, sodium
acid pyrophosphate, citric acid, and sodium citrate. Buffering
agents are typically included at a level of from about 0.5% to
about 10%, by weight of the present compositions.
[0122] Emulsifying agents may be employed in the present
compositions. Examples of emulsifying agents include poloxamers
described above as a nonionic surfactant, which may also function
as binder, stabilizer, and other related functions. Poloxamers are
difunctional block-polymers terminating in primary hydroxyl groups
with molecular weights ranging from 1,000 to above 15,000.
Poloxamers are sold under the tradename of Pluronics and Pluraflo
by BASF, such as Poloxamer 407 and Pluraflo L4370. Other suitable
emulsifying agents include the polyacrylic acid Pemulen.RTM. series
available from B.F. Goodrich; Vitamin E acetate; Vitamin E
succinate and pegylated Vitamin E.
[0123] Titanium dioxide may also be added to the present
composition to add opacity to the compositions, typically at from
about 0.25% to about 5% by weight of dentifrice compositions.
[0124] Other optional agents that may be used in the present
compositions include dimethicone copolyols selected from alkyl- and
alkoxy-dimethicone copolyols, such as C12 to C20 alkyl dimethicone
copolyols and mixtures thereof. An example is cetyl dimethicone
copolyol marketed under the trade name Abil EM90. The dimethicone
copolyols aid in providing positive tooth feel benefits and may be
present at a level of from about 0.01% to about 25%.
Method of Use
[0125] The present invention also relates to the use of the
compositions for control of staining and for controlling bacterial
activity in the oral cavity which cause undesirable conditions
including plaque, caries, calculus, gingivitis, and periodontal
disease. The benefits of these compositions may increase over time
when the composition is used repeatedly.
[0126] The method of use or treatment herein comprises contacting a
subject's dental enamel surfaces and mucosa in the mouth with the
oral compositions according to the present invention. The method
may comprise brushing with a dentifrice or rinsing with a
dentifrice slurry or mouth rinse. Other methods include contacting
the topical oral gel, denture product, mouthspray, or other form
with the subject's teeth and oral mucosa. The subject may be any
person or animal in need of oral care. By animal is meant to
include household pets or other domestic animals, or animals kept
in captivity.
[0127] For example, a method of treatment may include a person
brushing a dog's teeth with one of the dentifrice compositions.
Another example would include rinsing a cat's mouth with an oral
composition for a sufficient amount of time to see a benefit. Pet
care products such as chews and toys may be formulated to contain
the present oral compositions. The composition may be incorporated
into a relatively supple but strong and durable material such as
rawhide, ropes made from natural or synthetic fibers, and polymeric
articles made from nylon, polyester or thermoplastic polyurethane.
As the animal chews, licks or gnaws the product, the incorporated
active elements are released into the animal's oral cavity into a
salivary medium, comparable to an effective brushing or
rinsing.
EXAMPLES
[0128] The following examples further describe and demonstrate
embodiments within the scope of the present invention. These
examples are given solely for the purpose of illustration and are
not to be construed as limitations of the present invention.
Example I Mouth Rinse Compositions
[0129] Mouth rinse compositions A-F according to the present
invention made using conventional methods are shown below with
amounts of components in weight %.
TABLE-US-00006 Components A B C D E F Water QS QS QS QS QS QS
Glycerin 5 5 5 5 7.5 10 Propylene glycol -- -- -- 3 -- -- Ethanol
-- -- -- -- 3 10 Methyl Paraben -- 0.02 0.02 -- -- -- Propyl
Paraben -- 0.005 0.005 -- -- -- CPC 0.074 0.074 0.074 0.05 0.07 0.1
Sucralose 0.03 0.03 0.03 0.05 0.05 0.07 Anisaldehyde 0.1 0.1 0.1 --
-- CM Dextran 0.1 0.1 0.1 -- 0.05 0.1 Flavor/sensate oils 0.1 0.05
0.05 0.3 0.3 0.4 Performathox 490 0.075 -- 0.05 0.1 0.05 0.05
[0130] 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".
[0131] All documents cited in the Detailed Description of the
Invention are, in relevant part, incorporated herein by reference;
the citation of any document is not to be construed as an admission
that it is prior art with respect to the present invention. To the
extent that any meaning or definition of a term in this written
document conflicts with any meaning or definition of the term in a
document incorporated by reference, the meaning or definition
assigned to the term in this written document shall govern.
[0132] 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 scope of the invention. The
scope of the claims should not be limited by the embodiments set
forth in the examples, but should be given the broadest
interpretation consistent with the description as a whole.
* * * * *