U.S. patent application number 10/975963 was filed with the patent office on 2005-05-26 for stannous oral compositions.
This patent application is currently assigned to The Procter & Gamble Company. Invention is credited to Bacca, Lori Ann, Busscher, Henk J., Glandorf, William M., White, Donald J. JR..
Application Number | 20050112070 10/975963 |
Document ID | / |
Family ID | 22598539 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050112070 |
Kind Code |
A1 |
Glandorf, William M. ; et
al. |
May 26, 2005 |
Stannous oral compositions
Abstract
Disclosed are oral compositions comprising a stannous ion
source, a fluoride ion source, and a polymeric mineral surface
active agent that binds stannous, said compositions providing
adequate therapeutic efficacy with minimal side effects of tooth
staining and astringency. The composition simultaneously provides
reduction and control of supragingival calculus. The present oral
care compositions may be formulated as single phase or dual phase
compositions. The present invention also provides a method for
effective delivery of stannous-containing compositions with minimal
side effects of tooth staining or astringency and with effective
tartar control by administering to a subject a stable dentifrice
composition comprising a clinically effective amount of stannous
fluoride and/or other stannous salts in combination with a fluoride
ion source and a polymeric mineral surface active agent, preferably
a phosphate- or phosphonate-containing polymer.
Inventors: |
Glandorf, William M.;
(Mason, OH) ; Bacca, Lori Ann; (Lebanon, OH)
; White, Donald J. JR.; (Fairfield, OH) ;
Busscher, Henk J.; (Thesinge, NL) |
Correspondence
Address: |
THE PROCTER & GAMBLE COMPANY
INTELLECTUAL PROPERTY DIVISION
WINTON HILL TECHNICAL CENTER - BOX 161
6110 CENTER HILL AVENUE
CINCINNATI
OH
45224
US
|
Assignee: |
The Procter & Gamble
Company
Cincinnati
OH
|
Family ID: |
22598539 |
Appl. No.: |
10/975963 |
Filed: |
October 28, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10975963 |
Oct 28, 2004 |
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10351205 |
Jan 24, 2003 |
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6821507 |
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10351205 |
Jan 24, 2003 |
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09710440 |
Nov 10, 2000 |
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6555094 |
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60165350 |
Nov 12, 1999 |
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Current U.S.
Class: |
424/52 |
Current CPC
Class: |
A61K 8/81 20130101; A61K
8/73 20130101; A61K 8/19 20130101; A61K 8/731 20130101; A61P 1/02
20180101; A61K 2800/88 20130101; A61Q 11/00 20130101; A61K 8/21
20130101; A61K 8/24 20130101; A61K 8/90 20130101; A61K 8/8147
20130101; A61K 8/365 20130101 |
Class at
Publication: |
424/052 |
International
Class: |
A61K 007/18 |
Claims
What is claimed is:
1. An oral composition having antimicrobial activity effective for
reducing plaque and gingivitis, said composition comprising: a. a
stannous ion source that comprises a stannous salt and delivers
from about 3,000 ppm to about 15,000 ppm stannous ions, b. a
fluoride ion source, and c. a condensed phosphorylated polymer,
wherein said condensed phosphorylated polymer agent binds stannous
ions and is substantive to mineral surfaces.
2. The oral composition according to claim 1 wherein the fluoride
ion source is capable of providing from about 50 ppm to about 3500
ppm of fluoride ions.
3. The oral composition according to claim 1 comprising from about
1% to about 35% of the condensed phosphorylated polymer.
4. The oral composition according to claim 3 wherein the
phosphorylated polymer is a condensed linear polyphosphate having
an average chain length of about 4 or more, wherein said
polyphosphate is water-soluble and susceptible to hydrolysis.
5. The oral composition according to claim 1 wherein the fluoride
ion source comprises stannous fluoride.
6. The oral composition according to claim 5 wherein the stannous
ion source comprises stannous chloride dihydrate.
7. The oral composition according to claim 6 additionally
comprising a gluconate salt.
8. The oral composition according to claim 4 wherein the molar
ratio of polyphosphate anion to stannous ion is from about 0.2:1 to
about 5:1.
9. The oral composition according to claim 4 wherein the condensed
polyphosphate has an average chain length of about 21.
10. The oral composition according to claim 1 wherein the stannous
ion source and fluoride ion source are physically separated from
the condensed phosphorylated polymer.
11. The oral composition according to claim 1 wherein the ratio of
the composition's in-vitro Plaque Glycolysis Regrowth Model score
to the composition's in-vitro Pellicle Tea Stain Model score is at
least about 1.2.
12. The oral composition according to claim 1 wherein the
composition's in-vitro Plaque Glycolysis Regrowth Model score is at
least about 60%.
13. The oral composition according to claim 1 wherein the
composition's in-vitro Pellicle Tea Stain Model score is less than
about 75%.
14. The oral composition according to claim 12 wherein the
composition's in-vitro Plaque Glycolysis Regrowth Model score is at
least about 70%.
15. The oral composition according to claim 12 wherein the
composition's in-vitro Plaque Glycolysis Regrowth Model score is at
least about 80%.
16. The oral composition according to claim 13 wherein the
composition's in-vitro Pellicle Tea Stain Model score is less than
about 60%.
17. The oral composition according to claim 13 wherein the
composition's in-vitro Pellicle Tea Stain Model score is less than
about 50%.
18. The oral composition according to claim 13 wherein the
composition's in-vitro Pellicle Tea Stain Model score is less than
about 25%.
19. The oral composition according to claim 1 wherein the oral
composition is substantially free of alkali metal pyrophosphate
salt.
20. The oral formulation according to claim 1 wherein the oral
composition additionally comprises a poloxamer.
Description
[0001] This application is a divisional of U.S. application Ser.
No. 10/351,205, filed Jan. 24, 2003, which is a divisional of U.S.
application Ser. No. 09/710,440, filed Nov. 10, 2000 now U.S. Pat.
No. 6,555,094 and which claims the benefit of U.S. Provisional
Application No. 60/165,350, filed Nov. 12, 1999.
TECHNICAL FIELD
[0002] The present invention relates to improved oral compositions
containing stannous salts, such as stannous fluoride. These
improved compositions provide a spectrum of intraoral benefits
derived from stannous fluoride and/or other stannous salt,
including antimicrobial effects, control of breath malodor, control
of dental plaque growth and metabolism, reduced gingivitis,
decreased progression to periodontal disease, reductions in
dentinal hypersensitivity and reduced coronal and root dental
caries. These improved compositions provide the aforementioned
benefits with significant improvements compared to conventional
stannous containing compositions, including: 1) reduced levels of
dental staining; 2) reduced astringency thereby improving aesthetic
characteristics of the compositions; and 3) reduction in dental
calculus formation. The improved stannous containing compositions
provide these benefits primarily through the combined effects of
stannous and polymeric mineral surface active agents, preferably
including anionic polymers, such as condensed polyphosphate or
polyposphonate. The invention also relates to methods of at least
maintaining therapeutic efficacy while decreasing staining and
improving the aesthetic desirability of oral compositions
containing stannous salts, such as stannous fluoride.
BACKGROUND OF THE INVENTION
[0003] Stannous fluoride is commonly known for its efficacy when
formulated into oral products. Stannous fluoride was the first
fluoride source incorporated into toothpastes for therapeutic
efficacy in the control of dental caries. Stannous fluoride gels,
rinses, and dentifrices have since been shown to provide clinical
efficacy for the reduction of dental caries, dentinal
hypersensitivity, dental plaque and gingivitis. In addition to
these clinical effects, formulations containing stannous fluoride
may also help to provide improved breath benefits through chemical
and antibacterial actions. Stannous fluoride formulations typically
include stabilization systems designed to maintain bioavailable
(i.e., soluble and reactive) levels of stannous during shelf
storage, accounting for loss of stannous to oxidation or
precipitation. Therefore, stannous fluoride formulations may
contain other additional stannous containing ingredients, which may
provide important stabilization benefits for efficacy. High
concentrations of stannous in dental formulations help to ensure
stability of stannous fluoride and therefore clinical efficacy of
formulations containing the latter. Unfortunately, although
stannous fluoride compositions are known to be highly effective,
successful commercial utilization is complicated by complexity in
the development of formulations providing adequate stannous
fluoride stability and in the side effects of stannous.
Formulations providing increased or improved efficacy typically
promote increased side effects. This limits clinical and commercial
applications.
[0004] One of the most notable side effects of regular use of
stannous fluoride is yellow-brown tooth staining. This stain is
derived from pellicle, plaque and dietary component reactions with
available stannous deposited on tooth surfaces during treatment
with effective stannous fluoride formulations.
[0005] A second side effect routinely encountered during use of
effective stannous fluoride formulations is unacceptable
formulation astringency. Astringents are locally applied protein
precipitants whose low cell permeability restricts actions to cell
surfaces and interstitial spaces. Strong astringents can induce
contraction and wrinkling of the tissues and mucous secretions can
be precipitated or reduced. Within oral products, these chemical
actions produce an unpleasant `drying` sensation in the oral
cavity, such as on the tongue, gingival tissues or buccal
epithelia. Stannous formulations containing sufficient stannous for
bioavailability are routinely described as astringent by patients
and consumers and this property is undesirable. The astringency is
most noticeable after use of the product.
[0006] A third side effect of the regular use of stannous fluoride
dentifrice compositions is the decreased efficacy in reducing
dental calculus with these compositions. The present inventors have
established that stannous fluoride dentifrices proven effective for
antimicrobial, antigingivitis and other expected benefits do not
always show reproducible clinical actions toward the prevention of
accumulation of undesirable supragingival dental calculus. The
control of supragingival calculus formation along with other
clinical benefits is desired by professionals, patients and
consumers. The multifunctional activity of oral compositions can
simplify hygiene and provide a holistic approach to maintenance
therapeutic oral health.
[0007] Previous attempts to develop effective and consumer
acceptable stannous fluoride oral compositions have attempted to
solve these cumulative detriments, however none have been fully
successful. U.S. Pat. No. 5,004,597, issued to Majeti et al.,
discloses oral compositions containing stannous fluoride and
gluconate salts. The inclusion of stannous gluconate results in
improved formulation efficacy and stability. While effective, this
formulation produces undesirable levels of tooth staining.
Moreover, the formulation had unacceptable aesthetics, derived
primarily from the astringency of stannous. Likewise, U.S. Pat. No.
5,578,293, issued to Prencipe et al., discloses the use of an
organic acid compound to stabilize the stannous ion concentration.
Coupled with the stannous fluoride and citrate as the organic acid,
the formulations also include soluble pyrophosphate salts. U.S.
Pat. No. 4,323,551 to Parran et al., discloses the use of
pyrophosphate salts to provide anticalculus benefits. Clinical
research has established the potential of anionic mineral surface
active inhibitors, such as pyrophosphates, in preventing the
development of natural and antimicrobial induced tooth staining.
(Grossman, Bollmer, Sturzenberger and Vick; Journal of Clinical
Dentistry 6(4): 185-187, 1995). In the Prencipe et al. patent, all
examples include sufficient amount of either citric acid and/or
sodium citrate dihydrate to stabilize the stannous ions and to
prevent precipitation. These levels also directly inhibit stannous
binding to pyrophosphate salts. If stannous did bind to the
pyrophosphate salts, studies support that this would decrease the
antimicrobial activity of the stannous fluoride. The level of
citrate needed to effectively stabilize the stannous ion against
precipitation and pyrophosphate binding also significantly detracts
from the aesthetics of the stannous composition. The composition
will be salty, sour, and the stannous bound to citrate will still
act as an astringent, which reduces the overall taste
acceptability. U.S. Pat. No. 5,213,790, issued to Lukacovic et al.,
also discloses the use of a citrate ion source in a stannous
composition. U.S. Pat. No. 5,780,015, issued to Fisher et al.,
discloses the use of dual phase dentifrice containing a potassium
salt and a stannous salt wherein hydrogenated castor oil is used to
help reduce astringency. The stannous salt is stabilized through
the use of an organic acid compound as described in Prencipe et al.
Another attempt to produce efficacious stannous composition is
described in U.S. Pat. No. 5,716,600, issued to Zhrandik et al.
This patent discloses low water formulations which help to prevent
the stannous fluoride from degradation over time. No attempts are
made to reduce the staining of the formulation.
[0008] U.S. Pat. No. 5,017,363, issued to Suhonen, discloses a
stannous ion chelating copolymer of an alkyl vinyl ether and maleic
anhydride or acid in an amount to effectively stabilize stannous
ions. Suhonen also discloses that the compositions are
substantially free from silica, soluble phosphates such as soluble
pyrophosphates (e.g., tetrasodium pyrophosphate and tetrapotassium
pyrophosphate), and aldehyde group containing compounds, since the
stabilizing function of the stannous ion chelating polymer is not
effective in the presence of these ingredients.
[0009] U.S. Pat. No. 5,338,537, issued to White, Jr. et al.,
discloses the use of a low molecular weight diphosphonic acid,
which is used as a binding agent for stannous to help reduce the
tendency of staining from the composition. While effective in
reducing staining potential, laboratory studies have demonstrated
that the antibacterial activity of formulations containing stannous
complexed with the low molecular weight diphosphonic acid is very
low. Similar results are obtained on formulation with soluble
pyrophosphate salts, in the absence of strong citrate chelation, as
described above.
[0010] Based on the foregoing, it appears that the same chemical
and biochemical binding sites may be involved for both
antibacterial/antiplaque activity and for stabilization and
reducing the tooth staining potential of stannous fluoride. Thus,
to achieve stabilization and/or reduction of tooth staining,
antibacterial/antiplaqu- e activity may be compromised. This makes
the development of optimal stannous fluoride oral compositions
difficult and explains the limited number of stannous fluoride
compositions in the marketplace today. To improve consumer
acceptance and compliance with the use of oral compositions
containing stannous, a stannous composition is needed which has
high efficacy but with low level of staining and other negative
aesthetics, such as astringency. Moreover, it is desirable that
these formulations provide simultaneous efficacy toward the
reduction and control of dental calculus formation.
SUMMARY OF THE INVENTION
[0011] The present invention relates to oral compositions
comprising a stannous ion source, a fluoride ion source, and a
polymeric mineral surface active agent that binds stannous, said
compositions providing adequate therapeutic efficacy with minimal
side effects of tooth staining and astringency. The compositions
simultaneously provide reduction and control of supragingival
calculus. The present oral care compositions may be formulated as
single phase or dual phase compositions. The present invention also
provides a method for effective delivery of stannous-containing
compositions with minimal side effects of tooth staining or
astringency and with effective tartar control by administering to a
subject a stable dentifrice composition comprising a clinically
effective amount of stannous fluoride and/or other stannous salts
in combination with a polymeric mineral surface active agent,
preferably a phosphate- or phosphonate-containing polymer.
[0012] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0013] While the specification concludes with claims, which
particularly point out and distinctly claim the invention, it is
believed the present invention will be better understood from the
following description.
[0014] All percentages used herein are by weight of the dentifrice
composition, unless otherwise specified. The ratios used herein are
molar ratios of the overall composition, unless otherwise
specified. All measurements are made at 25.degree. C., unless
otherwise specified.
[0015] Herein, "comprising" means that other steps and other
ingredients which do not affect the end result can be added. This
term encompasses the terms "consisting of" and "consisting
essentially of".
[0016] The oral composition of the present invention may be in the
form of a toothpaste, dentifrice, tooth powder, topical oral gel,
mouthrinse, denture product, mouthspray, lozenge, oral tablet, or
chewing gum.
[0017] The term "dentifrice", as used herein, means paste, gel, or
liquid formulations unless otherwise specified. The dentifrice
composition may be in any desired form, such as deep striped,
surface striped, multi-layered, having the gel surrounding the
paste, or any combination thereof.
[0018] If a dual phase oral composition is desired, each oral
composition will be contained in a physically separated compartment
of a dispenser and dispensed side-by-side. The term "dispenser", as
used herein, means any pump, tube, or container suitable for
dispensing toothpaste.
[0019] The oral composition may be a single phase oral composition
or may be a combination of the two or more oral compositions. The
oral composition is a product, which in the ordinary course of
administration, 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 tooth surfaces and/or oral tissues for
purposes of oral activity. The term "total composition" as used
herein means the total composition delivered to the oral cavity,
regardless of whether it contains a single phase or multiple
phases.
[0020] The term "aqueous carrier" as used herein means any safe and
effective materials for use in the compositions of the present
invention. Such materials include tartar control agents,
antibacterial agents, abrasive polishing materials, peroxide
sources, alkali metal bicarbonate salts, thickening materials,
humectants, water, buffering agents, surfactants, titanium dioxide,
flavor system, sweetening agents, coloring agents, and mixtures
thereof.
[0021] Herein, the terms "tartar" and "calculus" are used
interchangeably and refer to mineralized dental plaque
biofilms.
[0022] The term "stannous" as used herein, is defined to mean the
stannous that is in a dentifrice or other oral product, and
supplied by a source such as stannous salts including stannous
fluoride. It may refer to the stannous ions that are provided by a
stannous salt other than stannous fluoride, added for stabilization
purposes.
[0023] The present invention relates to oral compositions
comprising a stannous ion source, a fluoride ion source, and a
polymeric mineral surface active agent that binds stannous, said
compositions providing adequate therapeutic efficacy with minimal
side effects of tooth staining and astringency. The compositions
simultaneously provide reduction and control of supragingival
calculus. Aesthetic and astringency benefits of the combination of
stannous and polymeric mineral surface active agents are enhanced
by concurrent appropriate formulation, including utilization of
suitable poloxamer ingredients.
[0024] The polymeric mineral surface active agent is preferably a
polyphosphate having an average chain length of about 4 or more, a
polyphosphonate, or other phosphate- or phosphonate-containing
anionic polymers. One having ordinary skill in the art would assume
that a polymeric binding agent, such as a polyphosphate having an
average chain length of about 4 or more, would behave similarly to
the pyrophosphate or tripolyphosphate in stannous containing
dentifrice systems. The present inventors have found that chemical
binding of stannous using pyrophosphate, diphosphonate, or
tripolyphosphate to prevent stain formation, also produces
unacceptable losses in therapeutic potential. However, an
unexpected result occurs with the present polyphosphate and other
phosphate- or phosphonate-containing polymers as they are capable
of reducing the side effects of dental staining and formulation
astringency without significantly reducing the efficacy of the
stannous. The present inventors have in fact found that including
these polymeric mineral surface active agents in oral compositions
containing stannous salts such as stannous fluoride, provides
significant therapeutic efficacy with decreased levels of staining
and astringency, while simultaneously providing reductions in
supragingival calculus as compared to prior-art compositions
containing stannous fluoride alone or stannous fluoride with
stabilizing agents such as citrate.
[0025] The present oral care compositions may be formulated as
single phase or dual phase compositions. One embodiment of the
present invention provides a dual phase oral composition comprising
a first composition comprising a fluoride ion source and a stannous
ion source and a second composition comprising a linear
polyphosphate having an average chain length of about 4 or more,
wherein the second composition has a total water content of up to
about 20%.
[0026] A further embodiment of the present invention relates to a
single phase oral composition comprising a fluoride ion source, a
stannous ion source and a linear polyphosphate having an average
chain length of about 4 or more, wherein the linear polyphosphate
is stabilized against hydrolytic degradation.
[0027] The present invention also relates to single phase or dual
phase compositions comprising a fluoride ion source, a stannous ion
source and an anionic polymer of MW 500 or more containing
phosphonic acid or diphosphonic acid functionalities, alone or in
combination with carboxylate functionalities, wherein the oral
composition provides adequate therapeutic efficacy with minimal
side effects of tooth staining and astringency while simultaneously
providing cosmetic supragingival calculus reductions.
[0028] The invention also provides a method for effective delivery
of stannous-containing compositions with minimal side effects of
tooth staining or astringency and with effective tartar control by
administering to a subject a stable dentifrice composition
comprising a clinically effective amount of stannous fluoride
and/or other stannous salts in combination with a polymeric mineral
surface active agent, such as a phosphate- or
phosphonate-containing polymer. One method for delivery of this
improved stannous oral composition involves application of a
dentifrice comprising two dentifrice compositions which are
contained in physically separated compartments. Another method
involves administering to a subject a stable single-phase
dentifrice composition. One embodiment of a stable single phase
composition comprises a polyphosphate, or other phosphate- or
phosphonate-containing anionic polymer; a stannous source delivered
from a source other than stannous fluoride; and a fluoride source,
wherein the composition may have a limited total water content,
depending upon stability requirements.
[0029] A preferred method for delivery of the present improved
stannous-containing compositions involves application of a
dentifrice comprising two dentifrice compositions which are
contained in physically separated compartments. The physical
separation allows for adequate stabilization of each dentifrice
phase and ingredients therein. When combined in use, the chemical
interactions of stannous (from stannous fluoride and/or other
stannous salt) in one dentifrice phase with the polymeric binding
agent in a separate dentifrice phase allow appropriate delivery of
both ingredients, thus, producing full therapeutic activity along
with the provision of significant efficacy for the reduction of
dental calculus and with marked reductions in undesirable side
effects of tooth staining and astringency. The first dentifrice
composition comprises a polyphosphate, or other phosphate or
phosphonate containing anionic polymers and may have a limited
total water content, while the second phase composition comprises
stannous ions.
[0030] The present compositions comprise essential components, as
well as optional components. The essential and optional components
of the compositions of the present invention are described in the
following paragraphs.
[0031] Stannous Ion Sources
[0032] The present invention includes a stannous ion source as one
essential component. The stannous ions are provided from stannous
fluoride and/or other stannous salt that are added to the oral
composition. Stannous fluoride has been found to help in the
reduction caries, gingivitis, plaque, sensitivity, and improved
breath benefits. The stannous provided in the oral composition will
provide efficacy to a subject using the composition. Other stannous
salts include stannous chloride dihydrate, stannous acetate,
stannous gluconate, stannous oxalate, stannous sulfate, stannous
lactate, and stannous tartrate. The preferred stannous ion sources
are stannous fluoride and stannous chloride dihydrate. The combined
stannous salts will be present in an amount of from about 0.1% to
about 11%, by weight of the total composition. Preferably, the
stannous salts are present in an amount of from about 0.5 to about
7%, more preferably from about 1% to about 5%, and most preferably
from about 1.5% to about 3% by weight of the total composition.
Formulations providing efficacy typically include stannous levels,
provided by stannous fluoride and stannous stabilizing salts,
ranging from about 3,000 ppm to about 15,000 ppm stannous ions in
the total composition. Below 3,000 ppm stannous the efficacy of the
stannous is not sufficient. Preferably, the stannous ion is present
in an amount of about 4,000 ppm to about 12,000 ppm, more
preferably 5,000 ppm to about 10,000 ppm.
[0033] Dentifrices containing stannous salts, particularly stannous
fluoride and stannous chloride, are described in U.S. Pat. No.
5,004,597 to Majeti et al., incorporated herein in its entirety.
Other descriptions of stannous salts 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., incorporated herein in its entirety. In
addition to the stannous ion source, other ingredients needed to
stabilize the stannous may also be included, such as the
ingredients described in Majeti et al. and Prencipe et al.
[0034] Fluoride Ion Sources
[0035] The oral compositions of the present invention will include
as a second essential component a soluble fluoride source capable
of providing bioavailable and efficacious fluoride ions. Soluble
fluoride ion sources include sodium fluoride, stannous fluoride,
indium fluoride, and sodium monofluorophosphate. Stannous fluoride
is the most preferred soluble fluoride source. This ingredient may
serve as both a/the stannous source and fluoride source. Norris et
al., U.S. Pat. No. 2,946,725, issued Jul. 26, 1960, and Widder et
al., U.S. Pat. No. 3,678,154 issued Jul. 18, 1972, disclose such
fluoride sources as well as others. Both patents are incorporated
herein by reference in their entirety.
[0036] The present compositions may contain a soluble fluoride ion
source capable of providing from about 50 ppm to about 3500 ppm,
and preferably from about 500 ppm to about 3000 ppm of free
fluoride ions. To deliver the desired amount of fluoride ions,
fluoride ion sources may be present in the total oral composition
at an amount of from about 0.1% to about 5%, preferably from about
0.2% to about 1%, and more preferably from about 0.3% to about
0.6%, by weight of the total composition delivered to the oral
cavity.
[0037] Polymeric Mineral Surface Active Agent
[0038] The present invention includes a polymeric surface active
agent (MSA). These agents show affinity for binding stannous, in
particular by stannous ion chelation, as evidenced by ionic
fluoride release from stannous fluoride (SnF.sub.2) and provision
of increased ionic form of fluoride upon binding of the stannous.
Effective agents also show surface reactivity toward calcium
phosphate minerals, and are thus expected to retard calculus or
tartar formation. The agents may also provide stain control and
surface conditioning. These agents will bind the stannous but will
still enable the combined mixture to provide the desired tartar
control, stain control, and surface conditioning, without having a
negative effect on the efficacy of stannous fluoride for the
control of dental caries, oral malodor and periodontal diseases
including gingivitis.
[0039] The present polymeric mineral surface active agents will
strongly bind stannous and retain biological reactivity while
inhibiting undesirable staining. Research has demonstrated that the
binding generally occurs on the end functions of the condensed
phosphate polymers. Binding may differ for other effective
phosphate or phosphonate containing polymers or co-polymers.
Therefore, a mineral surface active agent with phosphate end groups
providing the predominant binding are preferred. Even more
preferred are mineral surface active agents that have more than one
internal phosphate group in addition to the phosphate end
groups.
[0040] The polymeric mineral surface active agents that are useful
in the present invention include 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);
carboxy-substituted polymers; and mixtures thereof. Suitable
polymeric 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. Suitable structures include copolymers of
acrylic acid or methacrylic acid with phosphonates. A preferred
polymer is diphosphonate modified polyacrylic acid.
[0041] Suitable phosphonate-containing polymers such as shown below
are described in U.S. Pat. No. 5,980,776 to Zakikhani, et al.,
incorporated herein in its entirety.
[0042] 1. Co-Polymer of Acrylic Acid and Diphosphonic Acid with
Structure: 1
[0043] 2. Co-Polymer of Acrylic Acid and Vinylphosphonic Acid with
Structure: 2
[0044] 3. Co-Polymer of Methacrylic Acid and Vinylphosphonic Acid
with Structure: 3
[0045] 4. Co-Polymer of Acrylic Acid and Vinlydiphosphonic Acid
with Structure: 4
[0046] A preferred polymeric mineral surface active agent will be
stable with ionic fluoride and will not hydrolyze in high water
content formulations, thus permitting a simple single phase
dentifrice or mouthrinse formulation. If the polymeric mineral
surface active agent does not have these stability properties, it
is likely that a dual phase formulation with the polymeric mineral
surface active agent separated from the fluoride source will be
required.
[0047] A preferred polymeric mineral surface active agent 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.
Although pyrophosphates and tripolyphosphate are technically
polyphosphates, the polyphosphates desired are those having around
four or more phosphate molecules 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 pyrophosphates are
discussed separately under additional anticalculus agents. The
inorganic polyphosphate salts desired include tetrapolyphosphate
and hexametaphosphate, among others. Polyphosphates larger than
tetrapolyphosphate usually occur as amorphous glassy materials.
Preferred in this invention are the linear "glassy" polyphosphates
having the formula:
XO(XPO.sub.3).sub.nX
[0048] wherein X is sodium or potassium and n averages from about 6
to about 125. Preferred are polyphosphates manufactured by FMC
Corporation which are commercially known as Sodaphos (n=6),
Hexaphos (n=13), and Glass H (n=21). The most preferred
polyphosphate is Glass H. These polyphosphates may be used alone or
in a combination thereof.
[0049] It is also known that polyphosphates with an average chain
length greater than about 4 will react with ionic fluoride in oral
compositions at ambient temperature and produce monofluorophosphate
ions, in addition to altering the pH of the composition. This
reaction compromises the efficacy of the oral composition and its
ability to provide stable ionic fluoride and polyphosphate to the
oral surfaces. It is also known that to have stable polyphosphate,
the total water content of the dentifrice composition must be
controlled to reduce the hydrolysis of the polyphosphate. U.S. Pat.
No. 5,939,052 issued to White, Jr. et al., incorporated herein by
reference in its entirety, further describes the polyphosphates.
The phosphate sources are also described in more detail in
Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition,
Volume 18, Wiley-Interscience Publishers (1996), incorporated
herein by reference in its entirety, including all references
incorporated into Kirk-Othmer.
[0050] The amount of mineral surface agent required is an effective
amount which will bind the stannous, permit adequate antimicrobial
activity, reduce dental stain and formulation astringency, and be
capable of reducing dental calculus. An effective amount of a
mineral surface active agent will typically be from about 1% to
about 35%, preferably from about 2% to about 30%, more preferably
from about 5% to about 25%, and most preferably from about 6% to
about 20%, by weight of the total oral composition.
[0051] A sufficient amount of mineral surface active agent,
fluoride ions, and stannous ions must be present for the
composition to be effective. In formulating compositions containing
phosphate, the ratio total moles of phosphate anion to total moles
of stannous ion should also be controlled. For condensed
polyphosphate having an average of 21 phosphate repeating units,
the ideal molar ratio has been found to be a molar ratio of
phosphate anion to stannous ion of from about 0.2:1 to about 5:1,
preferably from about 0.5:1 to about 3:1, more preferably from
about 0.6:1 to about 2:1, and most preferably from about 0.7:1 to
about 1:1.
[0052] In addition to binding stannous ions effectively, the
polymeric mineral surface active agent has been found to solubilize
insoluble salts. For example, Glass H polyphosphate has been found
to solubilize insoluble stannous salts as well as stannous oxides
and hydroxides.
[0053] Aqueous Carriers
[0054] In preparing the present compositions, it is desirable to
add one or more aqueous carriers to the compositions. Such
materials are well known in the art and are readily chosen by one
skilled in the art based on the physical and aesthetic properties
desired for the compositions being prepared. These aqueous carriers
may be included at levels which do not prevent the interaction
between the stannous and the polymeric mineral surface active
agent. The amounts of the polymeric mineral surface active agent,
stannous, and fluoride may be adjusted if necessary to compensate
for the additional carriers. Aqueous carriers typically comprise
from about 50% to about 99%, preferably from about 70% to about
98%, and more preferably from about 90% to about 95%, by weight of
the oral composition.
[0055] Total Water Content
[0056] Water employed in the preparation of commercially suitable
oral compositions should preferably be of low ion content and free
of organic impurities. In the oral composition, water will
generally comprise from about 5% to about 95%, and preferably from
about 10% to about 50%, by weight of the composition herein. This
water content may be in a single phase oral composition or may be
the resulting total water content of a dual phase oral composition.
If the oral composition comprises a polyphosphate having an average
chain length of about 4 or more, the composition or phase
containing the polyphosphate will comprise a lower level of water,
generally up to about 20% total water. Preferably, the total water
content is from about 2% to about 20%, more preferably from about
4% to about 15%, and most preferably from about 5% to about 12%, by
weight of the oral composition. The amounts of water include the
free water which is added plus that which is introduced with other
materials, such as with sorbitol, silica, surfactant solutions,
and/or color solutions.
[0057] Buffering Agent
[0058] The present compositions may contain a buffering agent.
Buffering agents, as used herein, refer to agents that can be used
to adjust the pH of the compositions to a range of about pH 3.0 to
about pH 10. The phase of the oral composition containing stannous
will typically have a slurry pH of from about 3.0 to about 7.0,
preferably from about 3.25 to about 6.0, and more preferably from
about 3.5 to about 5.5. The phase containing the polymeric mineral
surface active agent will typically have a slurry pH of from about
4.0 to about 10, preferably from about 4.5 to about 8, and more
preferably from about 5.0 to about 7.0. An oral composition
containing both stannous and a polymeric mineral surface active
agent in a single phase will typically have a pH of from about 4 to
about 7, preferably from about 4.5 to about 6.5, and more
preferably from about 5 to about 6.
[0059] The buffering agents include alkali metal hydroxides,
carbonates, sesquicarbonates, borates, silicates, phosphates,
imidazole, and mixtures thereof. Specific buffering agents include
monosodium phosphate, trisodium phosphate, sodium benzoate, benzoic
acid, sodium hydroxide, potassium hydroxide, alkali metal carbonate
salts, sodium carbonate, imidazole, pyrophosphate salts, citric
acid, and sodium citrate. Preferred buffers would be those that
control the pH in the target range without complexing stannous
ions. Preferred buffering agents include acetic acid, sodium
acetate, citric acid, sodium citrate, benzoic acid and sodium
benzoate. Buffering agents are used at a level of from about 0.1%
to about 30%, preferably from about 1% to about 10%, and more
preferably from about 1.5% to about 3%, by weight of the present
composition.
[0060] Additional Anticalculus Agents
[0061] Optional agents to be used in combination with the stannous
fluoride binding mineral surface active agent include such
materials known to be effective in reducing mineral deposition
related to calculus formation. These agents may be included at
levels, which do not prevent the formation of the stannous
fluoride/stannous fluoride binding mineral surface active agent
complex. Agents included are pyrophosphates, tripolyphosphates, and
synthetic anionic polymers including polyacrylates and copolymers
of maleic anhydride or acid and methyl vinyl ether, such as Gantrez
as described in U.S. Pat. No. 4,627,977 to Gaffar et al., and
polyamino propane sulfonic acid (AMPS). Also included are zinc
citrate trihydrate, diphosphonates such as EHDP and AHP and
polypeptides such as polyaspartic and polyglutamic acids, and
mixtures thereof.
[0062] Abrasive Polishing Materials
[0063] An abrasive polishing material may also be included in the
oral compositions. The abrasive polishing material contemplated for
use in the compositions of the present invention can be any
material which does not excessively abrade dentin. Additionally,
the abrasive polishing material should be formulated in the oral
composition so that it does not compromise the stability of the
stannous fluoride. For example, in a dual phase oral composition,
the abrasive polishing material is preferably in a separate phase
from the fluoride ion source and stannous ion source.
[0064] Typical abrasive polishing materials include silicas
including gels and precipitates; aluminas; phosphates including
orthophosphates, polymetaphosphates, and pyrophosphates; and
mixtures thereof. Specific examples include dicalcium
orthophosphate dihydrate, calcium pyrophosphate, tricalcium
phosphate, calcium polymetaphosphate, insoluble sodium
polymetaphosphate, hydrated alumina, beta calcium pyrophosphate,
calcium carbonate, and resinous abrasive materials such as
particulate condensation products of urea and formaldehyde, and
others such as disclosed by Cooley et al in U.S. Pat. No.
3,070,510, issued Dec. 25, 1962, incorporated herein by reference.
Mixtures of abrasives may also be used. If the oral composition or
particular phase comprises a polyphosphate having an average chain
length of about 4 or more, calcium containing abrasives and alumina
are not preferred abrasives. The most preferred abrasive is
silica.
[0065] 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, issued Mar. 2, 1970, and DiGiulio, U.S.
Pat. No. 3,862,307, issued Jan. 21, 1975, both incorporated herein
by reference. Preferred are the silica xerogels marketed under the
trade name "Syloid" by the W. R. Grace & Company, Davison
Chemical Division. Also preferred are the precipitated silica
materials such as those marketed by the J. M. Huber Corporation
under the trade name, "Zeodent", particularly the silica carrying
the designation "Zeodent 119". 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, issued Jul. 29,
1982, incorporated herein by reference. Silica abrasives are also
described in Rice, U.S. Pat. Nos. 5,589,160; 5,603,920; 5,651,958;
5,658,553; and 5,716,601; herein incorporated by reference. The
abrasive in the oral composition compositions described herein is
generally present at a level of from about 6% to about 70% by
weight of the composition. Preferably, oral compositions contain
from about 10% to about 50% of abrasive, by weight of the oral
composition.
[0066] Peroxide Source
[0067] The present invention may include a peroxide source in the
composition. The peroxide source is selected from the group
consisting of hydrogen peroxide, calcium peroxide, urea peroxide,
and mixtures thereof. The preferred peroxide source is calcium
peroxide. Preferably, to maximize stability, the peroxide source is
not in the same phase as the stannous ion source. The following
amounts represent the amount of peroxide raw material, although the
peroxide source may contain ingredients other than the peroxide raw
material. The present composition may contain from about 0.01% to
about 10%, preferably from about 0.1% to about 5%, more preferably
from about 0.2% to about 3%, and most preferably from about 0.3% to
about 0.8% of a peroxide source, by weight of the oral
composition.
[0068] Alkali Metal Bicarbonate Salt
[0069] The present invention may also include an alkali metal
bicarbonate salt. Alkali metal bicarbonate salts are soluble in
water and unless stabilized, tend to release carbon dioxide in an
aqueous system. Sodium bicarbonate, also known as baking soda, is
the preferred alkali metal bicarbonate salt. The alkali metal
bicarbonate salt also functions as a buffering agent. Because of
the pH at which alkali metal bicarbonate salts buffer, the
bicarbonate salt is preferably in a phase separate from the
stannous ion source. The present composition may contain from about
0.5% to about 50%, preferably from about 0.5% to about 30%, more
preferably from about 2% to about 20%, and most preferably from
about 5% to about 18% of an alkali metal bicarbonate salt, by
weight of the oral composition.
[0070] Additional Aqueous Carriers
[0071] The present invention compositions are in the form of
toothpastes, dentifrices, topical oral gels, mouthrinse, denture
product, mouthsprays, lozenges, oral tablets or chewing gums and
typically contain some thickening material or binders to provide a
desirable consistency. The amount and type of the thickening
material will depend upon the form of the product. Preferred
thickening agents are carboxyvinyl polymers, carrageenan,
hydroxyethyl cellulose, and water soluble salts of cellulose ethers
such as sodium carboxymethylcellulose and sodium 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. Thickening agents
can be used in an of amount from about 0.1% to about 15%, by weight
of the oral composition.
[0072] Another optional component of the compositions desired
herein is a humectant. The humectant serves to keep oral
compositions from hardening upon exposure to air and certain
humectants can also impart desirable sweetness of flavor to
toothpaste compositions. Suitable humectants for use in the
invention include glycerin, sorbitol, polyethylene glycol,
propylene glycol, xylitol, and other edible polyhydric alcohols.
The humectant generally comprises from about 0% to 70%, and
preferably from about 15% to 55%, by weight of the oral
composition.
[0073] 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. 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 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,
incorporated herein in its entirety by reference. Nonionic
surfactants which can be used in the compositions of the present
invention can be broadly defined as compounds produced by the
condensation of alkylene oxide groups (hydrophilic in nature) with
an organic hydrophobic compound which may be aliphatic or
alkyl-aromatic in nature. Examples of suitable nonionic surfactants
include poloxamers (sold under trade name Pluronic),
polyoxyethylene, polyoxyethylene sorbitan esters (sold under trade
name Tweens), Polyoxyl 40 hydrogenated castor oil, fatty alcohol
ethoxylates, 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. The nonionic surfactant
poloxamer 407 is one of the most preferred surfactant because the
poloxamer has been discovered to help reduce the astringency of the
stannous. The amphoteric surfactants useful in the present
invention can be broadly described as derivatives of aliphatic
secondary and tertiary amines in which the aliphatic radical can be
a straight chain or branched and wherein one of the aliphatic
substituents contains from about 8 to about 18 carbon atoms and one
contains an anionic water-solubilizing group, e.g., carboxylate,
sulfonate, sulfate, phosphate, or phosphonate. Other suitable
amphoteric surfactants are betaines, specifically cocamidopropyl
betaine. Mixtures of amphoteric surfactants can also be employed.
Many of the suitable nonionic and amphoteric surfactants are
disclosed by Gieske et al., U.S. Pat. No. 4,051,234, issued Sep.
27, 1977, incorporated herein by reference in its entirety. The
present composition typically comprises one or more surfactants
each at a level of from about 0.25% to about 12%, preferably from
about 0.5% to about 8%, and most preferably from about 1% to about
6%, by weight of the composition.
[0074] Titanium dioxide may also be added to the present
composition. Titanium dioxide is a white powder which adds opacity
to the compositions. Titanium dioxide generally comprises from
about 0.25% to about 5%, by weight of the composition.
[0075] Coloring agents may also be added to the present
composition. The coloring agent may be in the form of an aqueous
solution, preferably 1% coloring agent in a solution of water.
Color solutions generally comprise from about 0.01% to about 5%, by
weight of the composition.
[0076] A flavor system can also be added to the compositions.
Suitable flavoring components include oil of wintergreen, oil of
peppermint, oil of spearmint, clove bud oil, menthol, anethole,
methyl salicylate, eucalyptol, cassia, 1-menthyl acetate, sage,
eugenol, parsley oil, oxanone, alpha-irisone, marjoram, lemon,
orange, propenyl guaethol, cinnamon, vanillin, ethyl vanillin,
heliotropine, 4-cis-heptenal, diacetyl, methyl-para-tert-butyl
phenyl acetate, and mixtures thereof. Coolants may also be part of
the flavor system. Preferred coolants in the present compositions
are the paramenthan carboxyamide agents such as
N-ethyl-p-menthan-3-carboxamide (known commercially as "WS-3") and
mixtures thereof. A flavor system is generally used in the
compositions at levels of from about 0.001% to about 5%, by weight
of the composition.
[0077] Sweetening agents can be added to the compositions. These
include saccharin, dextrose, sucrose, lactose, xylitol, maltose,
levulose, aspartame, sodium cyclamate, D-tryptophan,
dihydrochalcones, acesulfame, and mixtures thereof. Various
coloring agents may also be incorporated in the present invention.
Sweetening agents and coloring agents are generally used in
toothpastes at levels of from about 0.005% to about 5%, by weight
of the composition.
[0078] The present invention may also include other agents in
addition to the stannous to provide antimicrobial benefits. These
agents may be included at levels which do not prevent the
interaction between stannous and the polymeric mineral surface
active agent. Included among such antimicrobial agents are water
insoluble non-cationic antimicrobial 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. The
water soluble antimicrobials include quaternary ammonium salts and
bis-biquamide salts, among others. Triclosan monophosphate is an
additional water soluble antimicrobial agent. The quaternary
ammonium agents 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. Dodecyl trimethyl ammonium bromide,
tetradecylpyridinium chloride, domiphen bromide,
N-tetradecyl-4-ethyl pyridinium chloride, dodecyl dimethyl
(2-phenoxyethyl) ammonium bromide, benzyl dimethylstearyl ammonium
chloride, cetyl pyridinium chloride, quaternized
5-amino-1,3-bis(2-ethyl-- hexyl)-5-methyl hexa hydropyrimidine,
benzalkonium chloride, benzethonium chloride and methyl
benzethonium chloride are examplary of typical quaternary ammonium
antibacterial agents. Other compounds are
bis[4-(R-amino)-1-pyridinium] alkanes as disclosed in U.S. Pat. No.
4,206,215, issued Jun. 3, 1980, to Bailey, incorporated herein by
reference. Other antimicrobials such as copper bisglycinate, copper
glycinate, zinc citrate, and zinc lactate may also be included.
Also useful are enzymes, including endoglycosidase, papain,
dextranase, mutanase, and mixtures thereof. Such agents are
disclosed in U.S. Pat. No. 2,946,725, Jul. 26, 1960, to Norris et
al. and in U.S. Pat. No. 4,051,234, to Gieske et al., incorporated
herein by reference. Specific antimicrobial agents include
chlorhexidine, triclosan, triclosan monophosphate, and flavor oils
such as thymol. Triclosan and other agents of this type are
disclosed in U.S. Pat. No. 5,015,466, issued to Parran, Jr. et al.
and U.S. Pat. No. 4,894,220, to Nabi et al., incorporated herein by
reference. The water insoluble antimicrobial agents, water soluble
agents, and enzymes may be present in either the first or second
oral compositions if there are two phases. These agents may be
present at levels of from about 0.01% to about 1.5%, by weight of
the oral composition.
[0079] A dentifrice composition may be a paste, gel, or any
configuration or combination thereof. If a dual phase dentifrice is
desired, the first and second dentifrice compositions will be
physically separated in a dentifrice dispenser. It is generally
preferred that the first dentifrice composition be a paste and the
second dentifrice composition be a gel. The dispenser may be a
tube, pump, or any other container suitable for dispensing
toothpaste. Dual compartment packages suitable for this purpose are
described in U.S. Pat. No. 4,528,180; U.S. Pat. Nos. 4,687,663; and
4,849,213, all to Shaeffer, all incorporated herein in their
entirety. The dispenser will deliver approximately equal amounts of
each dentifrice composition through an opening. The compositions
may intermix once dispensed. Alternatively, the oral formulation
may be delivered from a kit containing two separate dispensers
which are used to deliver two dentifrice compositions that are both
used simultaneously.
Efficacy Measures
[0080] Overall performance of the present compositions may be
defined in terms of an efficacy score/stain score ratio, wherein
efficacy is measured using the in vitro Plaque Glycolysis and
Regrowth Model (i-PGRM), and stain is measured using the in vitro
Pellicle Tea Stain Model (i-PTSM). The present compositions provide
an efficacy score to stain score ratio of at least 1.2, which
represents a realistic improvement in that sufficient therapeutic
efficacy is maintained while achieving a reduction in staining.
Improvement in formulation astringency is defined as greater than
50% increase in formulation mouth feel parameters such as dry
mouth, and clean mouth indices as defined in controlled consumer
testing. Effectiveness for control of supragingival calculus is
defined by activity in prevention of plaque calcification using the
Modified Plaque Growth and Mineralization assay.
[0081] Antimicrobial Activity
[0082] The stannous ion concentration and bioavailability required
for the provision of therapeutic actions may differ for different
clinical actions, for example, caries vs. gingivitis. However, it
is critical to establish a minimum antimicrobial activity level,
since the therapeutic activity of stannous can be compromised below
this level. It is especially important to maintain efficacy in
compositions wherein binding of stannous occurs, since stannous
binding can easily lead to loss of antimicrobial activity. Herein,
the minimum efficacy provided by the stannous ion source is defined
in terms of effects in producing metabolic inhibition of dental
plaque bacterial biofilms, which are responsible for numerous
undesirable intraoral conditions. Efficacy is thus defined in terms
of a noticeable and significant reduction in in situ plaque
metabolism as measured using the in vitro Plaque Glycolysis and
Regrowth Model (i-PGRM), developed in our laboratories. The i-PGRM
has been demonstrated to provide an excellent correlation to
bioavailability of stannous fluoride required to produce clinical
antimicrobial, antigingivitis and antiplaque activity of oral
compositions containing stannous fluoride. The efficacy of stannous
containing compositions for gingivitis can be directly compared to
a stannous-containing dentifrice formulation such as described in
U.S. Pat. No. 5,004,597 to Majeti, et al. and shown in Example II
below as Comparative Example or to a currently marketed dentifrice
containing stannous fluoride, Crest Gum Care.
[0083] The i-PGRM is a technique where plaque is grown from human
saliva, and treated with agents designed to produce various levels
of antimicrobial activity. The purpose of this technique is to
provide a simple and quick method for determining if compounds have
a direct effect on the metabolic pathways that plaque
microorganisms utilize for the production of toxins which adversely
affect gingival health. In particular, the model focuses on the
production of organic acids including lactic, acetic, propionic,
and butyric. This method utilizes plaque grown on polished glass
rods which have been dipped in saliva overnight, soy broth and
sucrose for 6 hours, and saliva again overnight. The plaque mass
grown on the glass rods is then treated for 1 minute with a 3:1
water to dentifrice slurry. The mass is then placed in a soy
broth/sucrose solution for 6 hours and the pH of the incubation
solution is measured at the end of the 6 hours. Thus, there are
measures of pre-incubation pH and post incubation pH for both test
formulations and controls. This testing is typically done with a
number of replicates to minimize experimental variances, and a mean
pH is calculated from the replicates. Due to strong reactivity with
saccharolytic organisms, compositions containing high levels of
bioavailable stannous produce significant inhibition of plaque acid
generation in the i-PGRM assay. This enables formulation variations
to be compared for stability and bioavailability of stannous with
relative ease.
[0084] Stannous fluoride and/or other stannous salts are found in
the oral compositions described herein in an effective amount to
provide a desired i-PGRM score. The desired i-PGRM score is
measured relative to non-stannous containing formulations (negative
control) and to stannous-containing formulations (positive control)
such as described in U.S. Pat. No. 5,004,597 to Majeti et al. Most
preferable i-PGRM scores are significantly different from placebo
controls and ideally similar to those provided by conventional
stannous fluoride compositions proven effective for reducing plaque
and gingivitis. Research has demonstrated that effective gingivitis
efficacy can be anticipated for compositions providing at least
about 60%, preferably at least about 70%, and more preferably at
least about 80% of an effective stannous-containing dentifrice such
as shown in Example II, Comparative Example below.
[0085] The i-PGRM score is calculated according to the formula: 1 i
- PGRM Score = 100 % .times. ( Test product mean pH - Non -
Stannous Control mean pH ) ( Stannous Control mean pH - Non -
Stannous Control mean pH )
[0086] The mean pH values refer to incubation media pH's obtained
following treatment and sucrose challenge. The non-stannous control
plaque samples produce large amounts of acid, and hence their pH's
are lower than that of plaque samples treated with the positive
control (stabilized stannous fluoride dentifrice as shown in
Example II, Comparative Example). The effectiveness of a
formulation prepared from the combination of a stannous ion source
and polymeric mineral surface active agent will ideally be
comparable to the stannous-containing control, and hence ideal
i-PGRM score should approach 100%.
[0087] Staining Reduction
[0088] Tooth staining is a common undesirable side effect of the
use of stannous fluoride compositions. Improved stannous fluoride
dentifrices described herein provide reduced dental stain formation
resulting from more efficient stannous delivery from stannous bound
to the polymeric mineral surface active agent. The staining of the
tooth surface typically caused by stannous is measured in the
clinical situation by using a stain index such as the Lobene or
Meckel indices described in the literature. The present inventors
have also developed an in vitro staining model which provides
quantitative estimates for stannous fluoride formulation staining
potential which correlate well with clinical observations.
Formulations can thus be tested in advance of clinical examination
using these methods.
[0089] The in-vitro Pellicle Tea Stain Model (i-PTSM) is a
technique where an in vitro plaque biomass is grown on glass rods
from pooled human stimulated saliva over the course of three days.
The plaque biomass is treated with 3:1 water to dentifrice
supernatants, where abrasive and insoluble solids have been removed
via centrifugation, to determine potential dental staining levels
of the various agents. The purpose of this technique is to provide
a simple and quick method for determining if compounds have a
direct effect on the amount of dental plaque stain. This method
utilizes plaque grown on polished glass rods from pooled human
saliva with treatments of 5 minutes each, followed by a 10 minute
tea treatment. The treatment regimen is repeated at lest three
times before the plaque mass is digested off the rods, filtered and
absorbance at 380 nm is measured. This testing is typically done
with a number of replicates to minimize experimental variances, and
a mean absorbance is calculated from the replicates.
[0090] The present inventors have found that the stain, which is
typically produced by effective stannous fluoride is reduced by
combining the stannous fluoride with one or a mixture of the
polymeric surface active agents discussed above. The benefit of
reducing the staining caused by stannous is achieved with the
present compositions without significantly compromising the
efficacy of the stannous, fluoride, and polymeric surface agent.
The amount of staining resulting from the oral compositions of the
present invention is significantly lower than the amount of
staining resulting from typical dentifrices containing stannous.
The term "reduced" as used herein means a statistically significant
reduction. Therefore, reducing the staining of stannous means that
the amount of stain is statistically significantly reduced relative
to a stannous-containing positive control. Not reducing the
efficacy of the stannous means the efficacy of the stannous is not
statistically significantly reduced relative to a
stannous-containing positive control. Alternatively, stain may be
measured relative to typical oral compositions, which do not
contain stannous fluoride or another antimicrobial agent which is
known to stain. Therefore, the compositions may be measured
relative to very little to no stain.
[0091] The i-PTSM score can be calculated from this staining assay
according to the formula: 2 i - PTSM Score = 100 % .times. Test
Product Mean Absorbance ( Stannous Control Mean Absorbance )
[0092] The mean absorbance values refer to digested plaque
calorimetric values obtained following dentifrice treatments and
tea rinsing challenge. The stannous control used is typically a
high staining stannous fluoride formulation such as illustrated in
Example II, Comparative Example below. The stannous control samples
produce large amounts of tea absorption and hence increased
colorimetric absorbance. Thus, the i-PTSM score is a measure of the
relative level of staining. The lower the score, the lower the
level of staining. The combination of a stannous ion source and
polymeric mineral surface active agent provides a reduction in
staining and will ideally have a i-PTSM score of less than about
75%, preferably less than 60%, more preferably less than 50%, most
preferably less than 25%.
[0093] Ratio of i-PGRM Score to i-PTSM Score
[0094] A key descriptor of the improvement in stannous compositions
provided herein is the ratio of efficacy of stannous in comparison
to staining potential, these being key consumer concerns. The
effectiveness of the oral composition of the present invention will
be measured by a ratio of i-PGRM score to i-PTSM score.
[0095] The ratio of i-PGRM score to i-PTSM score is calculated
according to the formula:
Ratio=i-PGRM score/i-PTSM score
[0096] In accordance with the present invention, the ratio
developed using these methods should be at least about 1.2 for
significant improvements in stannous formulation efficacy relative
to tooth staining side effects. The ratio is preferably above about
1.3, more preferably above about 1.5, and most preferably above
about 2.0. If there is little to no stain occurring, the ratio
approaches infinity, which is preferred.
[0097] Binding of Stannous
[0098] As discussed above, effective delivery of improved stannous
and stannous fluoride reactivity (efficacy with reduced side
effects) requires significant in situ binding or complexation of
stannous ion with the mineral surface active (MSA) polymer. In
mixed compositions containing stannous fluoride, evidence of
significant binding of stannous is readily observed by
potentiometric detection of available ionic fluoride. For example,
binding of stannous with polyphosphate MSA ligand results in
exchange of fluoride from stannous fluoride and release as ionic
fluoride into solution. Relevant measures of stannous binding can
be assessed by this technique because fluoride is the strongest
ligand in the system after the MSA binding agent. Thus, fluoride
release is illustrative of stannous binding by the polymeric MSA
under these conditions.
[0099] The binding chemistry occurring is illustrated in the
following experiment using the dentifrice composition described in
Example 1 herein. In this experiment, the stannous
fluoride/stannous chloride toothpaste phase (second dentifrice
composition) was slurried at a 1:2.5 ratio with distilled water
(representing 1/2 dilution in real brushing). In like manner, a
paste phase (first dentifrice composition) was slurried. This paste
phase included either a placebo (conventional) dentifrice control
with no MSA polyphosphate or a paste phase containing 15% Glass H
polyphosphate according to Example I, first dentifrice formulation
A. The two slurries were mixed and ionic fluoride readings made by
ISE fluoride electrode on a digital pH meter. Following reading, a
standard addition of 10 and 100 fold excess ionic fluoride (from
neutral NaF) was added to the mixed slurries enabling calibration
within matrix through the standard additions technique. Results
shown below illustrate stannous binding by polyphosphate as added
to the paste in these mixed compositions.
1 Free Ionic Fluoride in Mixed 20% Formulation Slurry Theoretical F
Release from 1100 ppm Total .about.190 ppm Fluoride in System NaF
Control Paste (all ionic F) - Total 185 ppm Fluoride = 1100 ppm
SnF.sub.2 Slurry (Comparative Example Mixed 42 ppm as Phase 1 and
Phase 2) Total Fluoride = 1100 ppm Mixed Polyphosphate Stannous
Fluoride 195 ppm System Total Fluoride = 1100 ppm
[0100] Results show significant and complete stannous binding by
MSA in formulations according to this invention. Note that only
about 25% of fluoride is available as ionic fluoride in
conventional compositions, which demonstrates the strength of
stannous binding to fluoride ions. Likewise, evidence of
significant stannous ion binding can be demonstrated in single
phase compositions, although in these cases binding may occur in
situ within compositions prior to dilution. Importantly, stannous
binding to mineral surface active polymeric agents occurs within
the oral cavity on brushing, that is, when the composition is
diluted with saliva during the course of toothbrushing.
[0101] Astringency Reduction
[0102] Astringency is an additional side effect of many stannous
containing compositions which is significantly improved in the
present compositions comprising the polymeric mineral surface
active agents in combination with stannous and fluoride. The
astringency of formulations can be measured in intraoral panels,
where subjects assess mouth condition before and after tooth
brushing with the test formulations. In these studies, time
dependent studies can be made of dentifrice effects on consumer
subjective responses. In one protocol, panelists began a
conditioning series by having teeth cleaned with vigorous self oral
hygiene including brushing for two three minute periods, flossing
and disclosing to ensure complete plaque removal. Subjects are then
assigned their test product and instructed to brush with twice per
day as usual. For these tests, subjects reported in the morning to
a clinic prior to any oral hygiene or food or beverage consumption.
Panelists are then asked to fill out a subjective mouth feel
assessment questionnaire including questions on tooth clean
feeling, smooth teeth feeling and clean mouth feeling as well as
assessments of mouth moisture. Panelists then brushed for one
minute with assigned oral product. At this point, before lunch and
before dinner (late p.m.) subjects again filled out subjective
mouth feel questionnaire. Results of these tests show that the
present formulations containing stannous salts in combination with
a polymeric mineral surface active agent such as the Glass H
polyphosphate produce a marked improvement in formulation
astringency post brushing. Astringency is reduced compared to
conventional stannous formulations without the polymeric surface
active agent. Acceptability of the present formulation is
comparable to conventional sodium fluoride (NaF) and tartar control
dentifrices respectively.
[0103] Reduction and Control of Calculus
[0104] The provision of anticalculus benefits is another desirable
aspect of the present stannous fluoride formulations. Anticalculus
activity can be predicted from mineral surface activity
measurements and the application of plaque growth and
mineralization assays. The present compositions include certain
polymeric mineral surface active agents, such as polyphosphates
that bind stannous ions. Preferred compositions contain mineral
surface active phosphate polymers with significant affinity for
dental surfaces, which are comprised of calcium hydroxyapatites.
Preferred polymeric surface active agents will include phosphate
polymers which produce significant reductions in calcium phosphate
mineralization as established in controlled mineralization assays.
Polyphosphates (in particular linear polyphosphates with average
chain lengths greater than about 4) have been found by the present
inventors to produce superior activity and substantivity to oral
surfaces compared to pyrophosphate and some other commonly used
dental cleaning ingredients. The increased activity and
substantivity translate into significant improvements in the
prevention of dental stains and supragingival calculus and in the
non-abrasive removal of dental stains. Without wishing to be bound
by theory, it is believed that the polyphosphates prevent formation
of supragingival calculus by essentially disrupting the
mineralization process, which is the formation of hard calcium
phosphate mineral deposits on tooth enamel. By binding to tooth
surfaces, polyphosphates disrupt the mineral building process,
because their structures do not adequately fit the developing
mineral lattice, which becomes the calculus.
[0105] Method of Treatment
[0106] The present invention also relates to a method of treating
gingivitis and plaque with reduced staining, by using the present
compositions comprising a stannous ion source, a fluoride ion
source and particular polymeric mineral surface active agents.
Additionally provided are methods of providing oral compositions,
which have caries, gingivitis, plaque, tartar, stain, sensitivity,
aesthetics, breath, mouthfeel, and cleaning benefits. The benefits
of these compositions may increase over time when the composition
is repeatedly used. Specifically, the method of treatment will
include reducing the gingivitis and plaque, as measured by the
i-PGRM, while reducing the staining caused by oral composition
containing stannous, as measured by the i-PTSM. The ratio of the
i-PGRM score to i-PTSM stain model score is above about 1.2.
[0107] The present invention also relates to methods for reducing
the incidence of calculus on dental enamel and to methods for
providing desirable mouth aesthetic benefits including reduced
astringency and oral surface conditioning effects. The benefits of
these compositions may increase over time when the composition is
repeatedly used.
[0108] Methods of treatment include preparing an oral composition
containing the stannous ion source, the fluoride source and the
polymeric mineral surface active agent and administering the
composition to the subject. Administering to the subject may be
defined as having the oral composition contact the tooth surfaces
of the subject by brushing with a dentifrice or rinsing with a
dentifrice slurry. Administration may also be by contacting the
topical oral gel, mouthrinse, denture product, mouthspray, oral
tablet, lozenge, or chewing gum with the tooth surfaces. The
subject may be any person or lower animal whose tooth surfaces
contact the oral composition.
[0109] It should be understood that the present invention relates
not only to methods for delivering the present polymeric surface
active agent containing compositions to the oral cavity of a human,
but also to methods of delivering these compositions to the oral
cavity of other animals, e.g., household pets or other domestic
animals, or animals kept in captivity.
[0110] 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 the rinsing of 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 including
the polymeric surface active agent is 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 & METHOD OF MANUFACTURING
[0111] The following examples and descriptions further clarify
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 as many
variations thereof are possible without departing from the spirit
and scope.
Example I
[0112] Example I illustrates dual phase dentifrice compositions
incorporating sodium polyphosphate (Glass H supplied by FMC
Corporation, n=21 unit condensed phosphate polymer) in the First
Dentifrice composition and incorporating stannous fluoride and
other stannous salts in the Second Dentifrice composition.
2 First Dentifrice Compositions Formula Formula Formula Formula
Ingredient 1a 2a 3a 4a Carboxymethycellulose 0.500 0.200 0.200
0.300 Water 2.210 -- -- 1.400 Flavor 1.500 1.100 1.100 1.100
Glycerin 29.890 45.550 43.550 39.850 Polyethylene Glycol 1.500 --
-- 6.000 Polyoxyethylene 0.200 -- -- -- Propylene Glycol 8.000 --
-- -- Sodium Lauryl Sulfate.sup.(a) 10.000 8.000 10.000 6.000
Silica 15.000 18.150 18.150 26.000 Polyoxyl 40 Hydrogenated 2.500
-- -- Castor Oil Benzoic Acid 0.600 -- -- 0.300 Sodium Benzoate
0.600 -- -- 0.300 Sodium Saccharin 0.400 0.400 0.400 0.350 Titanium
Dioxide 1.000 0.500 0.500 0.400 Glass H Polyphosphate 25.800 26.000
26.000 18.000 Xanthan Gum 0.300 0.100 0.100 -- Second Dentifrice
Compositions Formula Formula Formula Formula Ingredient 1b 2b 3b 4b
Polyoxyethylene -- 0.200 -- -- Water 21.840 49.0388 56.348 12.000
Flavor 1.500 1.300 1.200 1.100 FD&C Blue #1 Dye Sol'n 0.300
0.300 0.100 0.500 Glycerin 30.550 22.000 22.000 -- Polyethylene
Glycol -- -- -- 6.000 Poloxamer 407 15.500 17.500 16.500 7.000
Sodium Lauryl Sulfate.sup.(a) -- 2.500 -- 7.500 Silica 23.000 -- --
20.000 Sodium Gluconate 3.290 2.940 1.840 4.135 Stannous Fluoride
0.908 1.062 1.062 -- Stannous Chloride -- 1.510 0.370 -- Stannous
Sulfate 2.016 -- -- 2.851 Sodium Hydroxide.sup.(b) 0.746 0.600
0.280 0.900 Sodium Saccharin 0.350 0.400 0.300 0.400 Sodium
Fluoride -- -- -- 0.486 Sorbitol.sup.(c) -- -- -- 35.528 Xanthan
Gum -- 0.850 -- 1.100 Hydroxyethyl Cellulose -- -- -- 0.500
.sup.(a)27.9% solution .sup.(b)50% solution .sup.(c)70%
solution
[0113] The first dentifrice compositions are prepared as follows.
Add the water and/or sodium lauryl sulfate solution and water
soluble salts to main mixing vessel. In a separate vessel, disperse
thickeners in glycerin. Add this glycerin slurry to the mixing
vessel, mixing well. Add the propylene glycol and polyethylene
glycol to the mixing vessel and mix until well dispersed. Next add
titanium dioxide and silica. Mix well. Cool the mixing vessel to
less than 30.degree. C. and add the polyphosphate. Mix until
homogeneous.
[0114] The second dentifrice compositions are prepared as follows.
Add glycerin and/or to the main mix tank. Add thickeners, non-ionic
surfactants, flavors, stannous salts and/or fluoride salts to the
main mix vessel. Mix/homogenize until well dispersed and
homogeneous. Add water to the main mix tank and mix/homogenize
until the salts and surfactants have dissolved, the thickeners are
hydrated and the mix is homogeneous. Add sodium hydroxide and color
and mix well. Add sodium lauryl solution and mix until homogeneous.
Cool batch to less than 30.degree. C.
[0115] Measured i-PGRM scores, i-PTSM scores and i-PGRM/1-PTSM
ratios are shown below for various combinations of dual phase
formulations containing stannous ions, fluoride sources and
polyphosphate mineral surface active agent.
3 Test Method 1a + 1b 2a + 2b 3a + 3b 4a + 4b i-PGRM Score 77.9
78.1 92.2 135.6 i-PTSM Score 51 50 69 66 Efficacy Score/Stain Score
Ratio 1.53 1.56 1.34 2.05
EXAMPLE II
[0116] Example II illustrates single phase dentifrice compositions
incorporating stannous ion salts, dispersions of suspended Glass H
polyphosphates or polyphosphonate polymer and various fluoride ion
sources all formulated within low water base to facilitate
polymeric MSA stability and stannous ion stability. Also shown is
an example of a stannous-containing dentifrice as described in U.S.
Pat. No. 5,004,597 to Majeti et al.
[0117] Example II compositions (Formula A-D below) are prepared as
follows. Add the glycerin and thickening agents to the main mix
tank and mix until homogeneous. If applicable, add the sodium
gluconate to the main mix tank and mix until homogeneous. Add the
sodium lauryl sulfate solution and flavor to the main mix tank and
mix until thickeners are hydrated/dissolved. Add the silica and
titanium dioxide to the main mix tank and mix until homogeneous.
Add stannous and/or fluoride salts to the main mix tank and mix
until homogeneous. Finally add the polymeric surface active agent
(Glass H or polyphosphonate) to the main mix tank. Mix until
homogeneous.
[0118] The comparative example of a stannous-containing dentifrice
is prepared as follows as described in U.S. Pat. No. 5,004,597 to
Majeti, et al. Sorbitol and one half of the water are added to the
mix tank and heating to 77.degree. C. initiated. Saccharin,
titanium dioxide, and silica may be added to the mixture during
this heating period. Sufficient agitation is maintained to prevent
the settling of the insoluble components. The glycerin is added to
a separate vessel and is also heated to 77.degree. C. When both the
solutions have attained the required temperature, the carboxymethyl
cellulose (CMC) is slowly added to the glycerin under vigorous
agitation. When the CMC is sufficiently dispersed in the glycerin,
this mixture is added to the sorbitol/water mixture. The resulting
mixture is then blended for a period of time sufficient to allow
complete hydration of the binders (about 15 minutes). When the
paste is of acceptable texture, the flavor, sodium alkyl sulfate,
and color are added. One half of the remaining water is then added
to a separate mix tank and allowed to heat to 77.degree. C. After
the water attains the necessary temperature, the sodium gluconate
is added under medium agitation and allowed to dissolve completely.
The stannous chloride dihydrate is then added to the gluconate
solution and also allowed to dissolve. This mixture is added to the
main mix. The stannous fluoride is added to the remaining water
(also at 77.degree. C.) and the resulting solution is added to the
main mix and allowed to blend thoroughly before final pH adjustment
with sodium hydroxide. The completed paste is agitated for
approximately 20 minutes before being milled and deaerated.
4 Compara- Formula Formula Formula Formula tive Ingredient A B C D
Example Flavor 1.000 1.200 1.500 1.150 1.000 Glycerin 53.166 54.300
52.872 9.000 14.425 Poloxamer 407 5.000 3.000 8.000 -- -- Stannous
Chloride 0.680 -- -- 1.500 1.500 Stannous Sulfate -- 1.460 -- -- --
Stannous Fluoride 0.454 -- -- 0.454 0.454 Sodium Fluoride -- 0.320
-- -- -- Sodium -- -- 1.128 -- -- Monofluorophosphate 7.500 6.000
4.000 4.000 5.000 Sodium Lauryl Sulfate 20.000 18.000 22.000 22.000
20.000 Silica 0.200 0.200 0.400 0.350 0.600 Carboxymethyl -- 1.470
-- -- 2.100 Cellulose Sodium Gluconate 0.400 0.350 0.500 0.460
0.300 Sodium Saccharin 0.500 0.500 0.500 -- 0.525 Titanium Dioxide
0.100 0.200 0.100 0.350 0.700 Xanthan Gum 11.000 13.000 9.000 -- --
Glass H 5.000 -- Polyphosphonate -- 0.600 Na hydroxide.sup.(b) --
0.300 FD&C Blue #1.sup.(c) 30.430 37.496 Sorbitol.sup.(d)
25.306 15.000 Water .sup.(a)27.9% solution .sup.(b)50% solution
.sup.(c)1% solution .sup.(d)70% solution
* * * * *