Note: Descriptions are shown in the official language in which they were submitted.
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Methods for Protecting and Repairing Enamel
BACKGROUND OF THE INVENTION
1. Field of the Invention
. 5 .. The present invention is directed to advances in protecting and
repairing enamel by
administering to enamel, aqueous-free, stannous fluoride, brushing gels;
whereby the
protectant and repair ingredients are substantive to enamel surfaces, thereby
extending
the protecting and repairing processes with improved stannous fluoride
effectiveness.
Key protectant and repair combinations used in the methods of the present
invention
comprise brushing gels containing: stannous fluoride and calcium in aqueous-
free,
substantivity agents.
2. Description of the Related Art
The use of fluoride in anticaries drug products, marketed in the U.S., is
carried out
under the guidance of the FDA's Fluoride Monograph, 21 CFR 355.10 (revised
April 1,
2012).
Table 1
Concentration and Dosage of Stannous Fluoride In Dentifrice/Rinse/Gel products
according to the Federal Register 21 CFR 355.10
Dentifrices Dentifrices containing 850 to 1,150 ppm theoretical
total fluoride in a gel or paste dosage
form.
Stannous fluoride 0351 to 0.474% with an available fluoride ion concentration
. 700 ppm
for products containing abrasives other than calcium pyrophosphate.
Stannous fluoride 0.351 to 0.474% with an available fluoride ion concentration
.290 ppm
for products containing the abrasive calcium pyrophosphate.
Preventive treatment gel Stannous fluoride 0.4% in an anhydrous glycerin
gel, made from anhydrous glycerin and
the addition of suitable thickening agents to adjust viscosity.
Treatment rinse Stannous fluoride concentrate marketed in a stable form
and containing adequate
directions for mixing with water immediately before using to result in a 0.1%
aqueous
solution.
Dentrifices
.. Fluoride dentifrices have been shown in numerous clinical trials to be
effective
anticaries agents [Stookey, J. Dent. Res. 1990, 69(Special Issue): 805-812]
and have
been recognized as a major cause of the remarkable decline in caries
prevalence in
many developed countries. Dentifrices have been widely adopted around the
world as
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the principle means of delivering topical fluoride and obtaining caries
preventive
benefits.
"Washout" of various enamel protectant and enamel repair ingredients from
enamel
surfaces by saliva flow, eventually controls the effective residence time of
various
commercial fluoride, enamel protectant and enamel repair, brushing
compositions used
in the methods of the present invention. To improve enamel protectant and
enamel
repair effectiveness, commercial, professionally prescribed, fluoride,
brushing
compositions resort to high levels of fluoride, i.e. 5000 ppm for Rx
toothpastes, gels and
rinses and to approximately 22,000 ppm fluoride for "in-chair", professionally
applied
varnishes. In addition, standard OTC, fluoride toothpastes can contain up to
1150 ppm
fluoride under the FDA's Fluoride Monograph.
The current market for fluoride brushing products includes: professional and
consumer
.. oral care fluoride treatments, both OTC and Rx brushing products;
including:
toothpastes, gels, pastes and varnishes. As noted above, Rx fluoride
toothpastes and
Rx fluoride brushing gels are well outside fluoride Monograph levels
containing up to
5000 ppm fluoride. Professional oral care, in-chair, fluoride varnishes
contain up to
about 22,000 ppm fluoride, while OTC fluoride toothpastes can contain up to
1150 ppm
total theoretical fluorine, the maximum level provided for by the Monograph.
The American Dental Association (ADA); the Food & Drug Administration (FDA)
and
oral care professionals including: general practitioners, periodontists,
orthodontists,
pediatric dentists, etc. as a group; are generally concerned over the trend of
increasing
fluoride levels. These organizations and oral care professionals generally
favor using
lower levels of fluoride in various in-chair treatments and various OTC and
Rx, oral
care, topical, home treatments for patients, provided..., enamel protection
and repair,
achieved with lower fluoride levels, are comparable to the results reported
for brushing
products with higher levels of fluoride. This preference for lower fluoride-
brushing
products is driven by the concern over toxicity, fluorosis in children, etc.,
associated
with exposure to high fluoride levels, long term.
It is generally accepted, approximately 90% of the fluoride used in OTC and Rx
fluoride
brushing treatments is expectorated after use. Thus, the window for fluoride
treatment
of enamel is essentially limited to the time fluoride is being brushed onto
the enamel. In
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contrast, fluoride varnishes containing 22,000 ppm fluoride, applied to the
enamel by an
oral care professional, are designed to maintain substantive fluoride levels
on the
enamel after patient expectoration.
Fluoride varnishes are generally applied professionally, at a frequency of
about once
every six months with the target audience comprising primarily children.
Dietary fluoride levels have gradually increased due to fluoridated drinking
water and
the fluoride in water used in food preparation, etc. In addition, most
consumers use
fluoride: toothpastes, rinses, gels, etc. Extensive literature citations
indicate topical
fluoride treatments are more effective in protecting and repairing enamel than
treatment
with systemic fluorides.
See: Ripa, Public Health Dent., 1991; 51:23-41.
Yet, with all this fluoride available, caries continues to pose a challenge:
in children, as
well as adults including coronal caries in the elderly, caries in dry mouth
patients, caries
in immunocompromised patients, caries in patients undergoing medical or dental
treatment, etc.
There is a need to improve enamel protectant and enamel repair methods for
professional oral care, fluoride treatments, as well as for OTC fluoride for
patient
treatment, while reducing the risk associated with exposure to high fluoride
levels.
Additionally, there is a need to improve the efficacy of fluoride treatments
in the area of
enamel protection and enamel repair, where the efficacy of various fluoride
treatments
is assessed as a function of the fluoride level used to effect treatment of
various
conditions of the enamel.
OBJECTS OF THE PRESENT INVENTION
To provide methods for improving enamel protectant factor (EPF) values and
improved
enamel repair factor (ERF) values.
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To provide methods for improving EPF and ERF values, where improvements in EPF
and ERF values can be achieved with reduced fluoride content in the brushing
gels.
To provide methods for treating enamel with reduced fluoride levels in
brushing gels,
while attaining comparable or improved EPF and ERF values, compared to
current,
commercial, fluoride brushing products, as well as fluoride brushing products
described
in the prior art.
To provided methods for improving EPF and ERF brushing gels for "at-risk"
patients.
To provide methods that improve challenged enamel conditions of "at-risk"
patients
including immunocompromised patients; cancer therapy, cardio treatment,
diabetes,
COP patients; etc.
DEFINITION OF TERMS
The following terms used throughout this specification and claims to describe
features
of the brushing gels of the present invention are described below:
"Aqueous-free" is defined as: substantially free from water.
"Enamel Protectant Factor (EPF)" is defined as: the percent reduction in
enamel
solubility divided by the fluoride level in parts per million using FDA method
#40.
"Enamel Repair Factor (ERF)" is defined as: the average increase in enamel
fluoride
concentration divided by the fluoride level of the fluoride brushing product
tested using
FDA method #33.
"Stannous fluoride brushing gel" is defined: in the Federal Register 21 CFR
355.10 as
set out in Table 1 above.
"Mucoadhesive" is defined as: a substance that is retained for a period of
time onto
surfaces in the mouth that is not easily removed by the mechanical action of
the tongue
nor by flow of saliva.
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"Stable stannous fluoride" is defined as: compositions that, when chemically
assayed,
substantially retains the level of stannous and/or fluoride in an unreacted
state.
"Biofilm" is defined as: a surface adherent film comprised of bacteria, exuded
polysaccharides, etc., that is not easily removed by mechanical means or
saliva flow.
"Substantivity agent" is defined as: a composition that improves the mucosal
retention
of the desired agents.
"Cation bridging" is defined as: electrical attraction between two films or
membranes
initiated by cation moieties.
"Shift in calcium binding from bidentate to monodentate" is defined as: the
loss of
"chelate"-like binding by calcium cations with a corresponding increase in
single ligand
binding by calcium cations.
"Liquid nonionic surfactant" is defined as: a liquid composition that
indicates surface
active properties with the absence of charged species.
"Solid nonionic surfactant" is defined as: a solid composition that indicates
surface
active properties with the absence of charged species.
"Car moiety" is defined as: a monodentate calcium fluoride ion.
"Linear, polymeric, polycarboxylates, substantivity enhancer" is defined as: a
linear
polymer with carboxylate substituents that increases retention of compositions
onto
charged surfaces.
"Emulsion discontinuous phase" is defined as: the minor component in an
emulsion that
is surrounded by a continuous phase.
"Emulsion continuous phase" is defined as: an emulsion component that
surrounds
discontinuous phase component.
6
SUMMARY OF THE INVENTION
The present invention is directed to methods of treating enamel with aqueous-
free,
brushing gel compositions, wherein the brushing gels contain stannous fluoride
and
calcium in an aqueous-free, substantivity agent. The methods of the present
invention
protect and repair enamel more effectively than prior methods relying on
brushing gels
and toothpaste compositions containing comparable or substantially higher
levels of
fluoride, as indicated by comparative EPF and ERF values reported herein.
In at least one embodiment, the present invention provides methods of
treatment for
enamel using substantially aqueous-free, enamel protectant and enamel repair,
brushing gels containing: stannous fluoride and calcium in a substantivity
agent,
wherein:
(a) Substantivity of said stannous fluoride and calcium into biofilm present
on
enamel is enhanced through a shift in calcium binding from bidentate to
monodentate in
the presence of stannous fluoride;
(b) EP F and ERF values of at least about 2.5 and 200, respectively, are
achieved with periodic administration of said brushing gels onto enamel
surfaces with
biofilm present.
In at least one embodiment, said substantivity agent is selected from solid
and liquid,
nonionic poloxamers and combinations thereof.
In at least one embodiment, some of said stannous fluoride is present as Car.
In at least one embodiment, said substantivity agent contains linear,
polymeric
polycarboxylate, substantivity enhancers.
In at least one embodiment, the brushing gel contains stannous fluoride and
calcium in
a substantivity agent comprising an emulsion of polydimethylsiloxane polymer
at
viscosities from between about 10,000 cs and about 2.5 million cs as the
discontinuous
phase in a nonionic, liquid surfactant, continuous phase.
Date Recue/Date Received 2022-05-31
6a
In at least one embodiment, nonionic liquid poloxamer surfactants, suitable
for said
brushing gels, are represented by the structural formula:
HO[(C2H40)x /(C3I-160)y]- [C31-160]z - [(C21-140)x /(C31-160)y]H
wherein the sum of x, y and z is from between 125 and 175.
In at least one embodiment, nonionic liquid surfactants, suitable for said
brushing gels,
are represented by the structural formula:
HO[(C2H40)x /(C3H60)11- [C3H6O]z - [(C2H40)x /(C3H60)0H
wherein x = 76, y = 25 and z = 56.
In at least one embodiment, said brushing gel contains unreacted, calcium and
phosphate components.
In at least one embodiment, the present invention provides a method of
treatment for
enamel with substantially aqueous-free, enamel protectant and enamel repair,
brushing
gels containing stannous fluoride and calcium in a substantivity agent
comprising an
emulsion of polydimethylsiloxane polymer at viscosities from between about
10,000 cs
and about 2.5 million cs as the discontinuous phase in a nonionic, solid
poloxamer
surfactant, continuous phase and a linear polymeric polycarboxylates
substantivity
enhancer.
In at least one embodiment, nonionic, solid, poloxamer surfactants, suitable
for said
brushing gels, are represented by the structural formula:
HO[(C2H40)x /(C3H60)0- [C3H60]z - [(C2H40)x /(C3H60)0H
wherein the sum of x, y and z is from between 120 and 150.
In at least one embodiment, nonionic, solid, poloxamer surfactants, suitable
for said
brushing gels, are represented by the structural formula:
HO[(C2H40)x /(C3H60)j- [C3H60]z - [(C2H40)x /(C3H160)y]H
wherein x = 76, y = 0 and z = 56.
In at least one embodiment, the brushing gels contain unreacted, calcium and
phosphate components.
Date Recue/Date Received 2022-05-31
6b
In at least one embodiment, said nonionic surfactant is a liquid surfactant
selected from
the group consisting of liquid surfactants having the following, general,
structural
formula:
HO[(C2H40)x /(C3H60)11- [C3H60]z - [(C2H4.0)x /(C3H60)y]H
wherein the sum of x, y and z is from between 125 and 175.
In at least one embodiment, the present invention provides a method of
treatment for
enamel with substantially, aqueous-free, enamel protectant and enamel repair,
brushing gels, featuring monodentate-bidentate bonding of calcium in the
presence of
stannous fluoride; containing: stannous fluoride, calcium and phosphate
components,
and a substantivity agent emulsion containing liquid, nonionic, poloxamer
surfactant as
the continuous phase and polydimethylsiloxane polymer as the discontinuous
phase;
with an EPF of at least about 2.5 and ERF of at least about 200.
In at least one embodiment, said polydimethylsiloxane polymer discontinuous
phase
comprises up to 40% of said emulsion.
In at least one embodiment, the present invention provides a method of
treatment for
enamel with Substantially aqueous-free, enamel protectant and enamel repair,
brushing
gels containing stable stannous fluoride and calcium on a substantivity agent
substantive to biofilm coated enamel, wherein:
(a) substantivity of said stannous fluoride and calcium into said biofilm is
enhanced by a substantivity enhancer and by a shift from bidentate binding of
calcium
to monodentate in the presence of stable stannous fluoride; and
(b) said stannous fluoride, upon release from said substantivity agent,
converts
to the moiety CaF+ which effects EPF and ERF values of at least about 2.5 and
about
200, respectively.
In at least one embodiment, said stannous fluoride, upon release from said
substantivity agent, includes a CaF+ moiety in the presence of said calcium
monodentate binding to said biofilm present on enamel.
In at least one embodiment, the pH of said brushing gel, upon administration
to enamel
with biofilm, is at least about 3.
Date Recue/Date Received 2022-05-31
6c
In at least one embodiment, the level of said substantivity agent and said
substantivity
enhancers is between about 0.5 and about 5% by wt. and about 0.1 and about 3%
by
wt., respectively.
In at least one embodiment, said EPF and ERF values range from between about
380
and about 1070.
In at least one embodiment, said calcium is selected from the group of calcium
compositions comprising: calcium fumarate, calcium sulfate, calcium gluconate,
mixed
sodium and calcium salts of methylivinyliether/maleic copolymers and
combinations
thereof.
In at least one embodiment, said substantivity enhancer has the structural
formula:
_
OM "I
V OM
fair Go¨cw''"7" - cvir 4's tlf 'e"
-ci 441
Oita ON* i 0 1 . 0
- , m
CV*
where m is an integer that provides weight between about 60,000 and about
1,000,000.
In at least one embodiment, the total calcium level is between about 0.5 and
about 5Ø
In at least one embodiment, the present invention provides a method for
treating
enamel of "at-risk" patients including: immunocompromised, cancer therapy,
diabetes,
COP, mucositis and cardiovascular patients; comprising administering to the
patient:
enamel protectant and enamel repair, brushing gels containing: stannous
fluoride,
calcium and a substantivity agent emulsion containing nonionic surfactant as
the
continuous phase and polydimethylsiloxane polymer as the discontinuous phase;
.. comprising administering said gels at a frequency sufficient to effect EP F
and ERF
values of at least about: 2.5 and 200, respectively.
In at least one embodiment, the present invention provides a method of
treatment for
enamel of "at-risk" patients comprising administering enamel protectant and
repair,
brushing gels as described herein at a frequency sufficient to effect EP F and
ERF
values of at least about: 2.5 and 200, respectively.
Date Recue/Date Received 2022-05-31
6d
In at least one embodiment, said enamel protectant and repair, brushing gels
are
administered for up to two minutes, followed by expectoration; at a frequency
sufficient
to effect EPF and ERF values of at least about: 2.5 and 200, respectively.
In at least one embodiment, enamel protectant and repair, brushing gels are
administered: (a) throughout the day as required, and (b) prior to retiring
for the
evening; thereby establishing EP F and ERF values of at least about: 2.5 and
200,
respectively.
The unexpected enamel protectant and enamel repair features of the methods of
the
present invention, as detailed below in the Examples, Tables and Drawings; are
attributed to administering by brushing, unique, aqueous-free, brushing gel
compositions, which feature:
(a) stannous fluoride and calcium;
(b) a substantivity agent; and
(c) cation bridging associated with microbial fluoride binding.
The methods of administering enamel protectant and enamel repair, brushing gel
compositions onto enamel form substantive, mucoadhesive gels in the presence
of
saliva; which mucoadhesive gels gradually release stable stannous fluoride and
calcium onto enamel. This slow release continues until the mucoadhesive gel is
eventually totally solubilized by saliva. This gradual release minimizes the
"wash-out"
effect traditionally experienced with fluoride brushing products. The
resultant enamel
protectant and enamel repair increases in EPF and ERF values, resulting from
the
extended enamel residence time of stannous fluoride, calcium and cation
bridging
associated with microbial fluoride binding to biofilm. This improved stannous
fluoride
efficiency reduces the need to resort to elevated fluoride levels.
Traditionally, methods for treating enamel that rely on fluoride brushing
products with
strong taste characteristics have been reported to cause excessive salivary
stimulation,
which increases the rate of fluoride clearance from the mouth. In contrast,
the methods
of the present invention that rely on brushing gels with exceptionally strong,
taste
characteristics, including "tingle", mouthfeel and hedonic characteristics
that mask the
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metallic taste of stannous fluoride; surprisingly indicate increased
"residence time" and
extend the availability of stannous fluoride, thereby effecting enamel
fluoride uptake
and enamel protection values (ERF and EPF, respectively) superior to
commercial
methods that rely on stannous fluoride, brushing products.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 of the drawings summarizes comparative, in vitro, enamel protectant
factor
(EPF) values for methods of treatment of the present invention with a brushing
gel with
stannous fluoride at 970 ppm fluoride, as described in Example 1; compared
with: (a)
an Rx 5000 ppm, sodium fluoride toothpaste, and (b) an OTC, 1100 ppm, stannous
fluoride toothpaste.
Figures 2 and 3 of the Drawings illustrate enamel repair factor (ERF) values
for
methods of treatment of the present invention using brushing gels with
compositions, as
described in Examples 1 and 2; with stannous fluoride at 970 ppm compared with
toothpastes having stannous fluoride at 1100 ppm and sodium fluoride at 900
ppm or
sodium fluoride at 5000 ppm, respectively.
Figures 4 through 6 present ERF values for methods of treatment of the present
invention using brushing gels comprising compositions, as described in
Examples 3
through 5. These brushing gels of the present invention contain stannous
fluoride at a
level of 970 ppm, compared with: (a) a 900ppm sodium fluoride toothpaste, and
(b) an
1100 ppm stannous fluoride toothpaste or (c) a 5000 ppm sodium fluoride
toothpaste.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
Methods of the invention for protecting and repairing enamel with aqueous-
free,
stannous fluoride, calcium, brushing gels that comprise substantivity agents
that
contain various enamel protectant and enamel repair ingredients. These
substantivity
agents function as carriers for various enamel protectant and repair
ingredients. These
substantivity agents are characterized by their ability, in the presence of
saliva, to form
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mucoadhesive gels which are substantive to enamel with biofilm. These
substantive,
mucoadhesive gels are further characterized by their ability to: (a) gradually
dissolve
when exposed to saliva flow, and (b) gradually release various enamel
protectant and
enamel repair ingredients, in an unreacted state, onto enamel surfaces with
biofilm as
they dissolve. This gradual dissolution feature of these mucoadhesive gels
minimizes
saliva "wash-out" of enamel protectant and enamel repair ingredients by
gradually
releasing these ingredients onto enamel surfaces with biofilm. The
substantivity agents
extend the duration of enamel protectant and enamel repair treatments of the
present
invention, and support cation bridging associated with microbial fluoride
binding;
thereby enhancing the EPF and ERF values of various methods of treatment of
the
present invention, while simultaneously reducing the level of fluoride
required to
achieve the unexpected increases in EPF and ERF values.
In as preferred embodiment of the invention, phosphate components are also
included
in the brushing gels. These are described by Ming Tung in U.S. Patents:
5,037,639;
5,268,167; 5,427,768; 5,437,857; 5,460,803; 5,562,895; by Tung in the American
Dental Association Foundation publication, "ACP Technology,"; by Schemehorn,
et. al.,
in The Journal of Clinical Dentistry Vol. XXII: No 2. 51-54, 2011; by the 19
references
cited by Schemehorn, et. al.; and by the description of various Gantrez
resins
containing calcium, including Gantreze MS-955 available from International
Specialty
Products, Wayne, NJ, USA.
The aqueous-free, substantivity agents used in the methods of treatment of the
present
invention hold the various enamel protectant and enamel repair ingredients,
including
stannous fluoride, calcium and phosphate components, in a condition where
these
ingredients remain stable and unreacted. When this aqueous-free, substantivity
agent
is exposed to saliva, it forms a mucoadhesive gel that is substantive to
enamel with
biofilm. This mucoadhesive gel continues to hold the enamel protectant and
enamel
repair ingredients onto enamel surfaces with biofilm without the ingredients
reacting.
These ingredients eventually react upon being released onto saliva- and
biofilm-coated,
enamel surfaces.
Eventually, this mucoadhesive, substantivity agent is totally dissolved by
saliva,
releasing the balance of unreacted enamel protectant and enamel repair
ingredients
onto saliva- and biofilm-coated, enamel surfaces.
9
Aqueous-free, brushing gels used in the treatment methods of the present
invention
contain enamel protectant and enamel repair ingredients, suitable for
protecting and
repairing dental enamel; wherein:
(1) said aqueous-free, brushing gels inhibit premature reaction of the
enamel
protectant and enamel repair ingredients;
(2) the enamel protectant and enamel repair ingredients are released onto
enamel with biofilm via saliva that solubilizes substantivity agents that are
substantive to: enamel, dentin, biofilm and pellicle;
(3) the enamel protectant and enamel repair ingredients contained in the
substantivity agents are gradually released onto the enamel in an unreacted
state as the saliva soluble, substantivity agent undergoes saliva dissolution
at
rates, which are controlled by saliva flow and the composition of the
substantivity agent; and
(4) bidentate binding of calcium shifts to monodentate binding of calcium
in the
presence of stannous fluoride.
For purposes of the methods of treatment of the present invention, saliva
soluble,
aqueous-free emulsions used as substantivity agents include those emulsions
that are
comprised of polydimethylsiloxane polymers in solid nonionic surfactants, as
described
in U.S. Patents: 5,032,387; 5,098,711; 5,538,667; 5,651,959; having the
structural
formula:
HORC2F140)x /(C31160)yi- [C31160]z - [(C2F140)x /(C31-160)0H
wherein the sum of x, y and z is between 120 and 150. In a preferred
embodiment, x =
76, y = 0 and z = 56;
liquid, nonionic surfactants, having the structural formula:
HORC21-140)x /(C3F160)0- [C31-160]: - [(C2F140)x /(C3F160)0H
wherein the sum of x, y and z is between 125 and 175. In a preferred
embodiment, x =
76, y = 25 and z = 56;
and combinations of solid and liquid, nonionic surfactants, wherein the
mixture is liquid.
Date Recue/Date Received 2021-09-15
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In a preferred embodiment of the invention, liquid, nonionic surfactants
comprise the
continuous phase of the aqueous-free emulsions. These liquid, nonionic
surfactants are
selected from the group consisting of: poloxamer, having the structural
formula set out
.. above, as well as mixtures of such liquid, nonionic surfactants with solid,
nonionic
surfactants; wherein the mixture is liquid, including: solid, nonionic
surfactants having
the structural formula set out above.
Preferred aqueous-free, saliva soluble emulsions for use as substantivity
agents in the
methods of treatment of the present invention include aqueous-free emulsions
comprising a liquid, nonionic, continuous phase and a discontinuous phase of
polydimethylsiloxane (PDMS) at viscosities ranging from between about 1500 cs
and
about 2.5 million cs. Particularly preferred, aqueous-free emulsions include a
liquid,
nonionic, surfactant, continuous phase and a discontinuous phase PDMS at
viscosities
between about 10,000 cs and 2.5 million cs.
Solid surfactants, useful as adjuncts to liquid, nonionic, surfactant,
continuous phase
are described in detail in U.S. 5,651,959. These liquid and liquid/solid,
nonionic,
surfactant emulsion mixtures are liquid and form mucoadhesive gels in the
presence of
saliva.
Preferred polydimethylsiloxanes are selected from the group consisting of
polydimethylsiloxane; at 1500 cs, at 10,000 cs, at 100,000 cs, at 250,000 cs,
at 500,000
cs, at 750,000 cs, at 1.5 million cs, at 2.2 million cs, at 2.5 million cs and
combinations
thereof.
Foam modulators are useful in the methods of treatment of the present
invention.
These include, without limitation: materials operable to control amount,
thickness or
stability of foam generated by the brushing gel composition upon agitation.
Any orally
acceptable foam modulator can be used, including polyethylene glycols (PEGs),
also
known as polyoxyethylenes. High molecular weight PEGs are suitable, including
those
having an average molecular weight of about 200,000 to about 7,000,000, for
example
about 500,000 to about 5,000,000 or about 1,000,000 to about 2,500,000. One or
more
PEGs are optionally present in a total amount of about 0.1% to about 10%, for
example
about 0.2% to about 5% or about 0.25% to about 2%.
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Humectants useful for the brushing gels used in the methods of treatment of
the
present invention include, without limitation: polyhydric alcohols such as
glycerin,
sorbitol, xylitol or low molecular weight PEGs. In various embodiments,
humectants can
prevent hardening of the brushing gels upon exposure to air. In various
embodiments,
humectants also function as sweeteners.
Any other desired components may be added to the compositions used in the
methods
of treatment of the present invention, including, for example, additional:
mouth-feel
agents, pH modifying agents, flavorants, sweeteners, antimicrobial (e.g.,
antibacterial)
agents such as those described in U.S. Pat. No. 5,776,435, saliva stimulants,
anti-
inflammatory agents, nutrients, vitamins, proteins, antioxidants, colorants,
etc.
Tables 2 through 10 summarize:
(a) EPF or ERF data for methods of treatment of the present invention using
brushing gels at varying compositions, as described in Examples 1 through 5,
compared with commercial, fluoride, brushing products;
(b) Illustrative Examples of methods of treatment of the present invention
using
brushing gels; and
(c) Illustrative methods of treatment of the present invention using
brushing gels.
In a preferred embodiment, the methods of treatment of the present invention
using
brushing gels contain ingredients that substantially effect enamel protection
factor
(EPF) and enamel repair factor (ERF) values, based on bidentate binding of
calcium
shifting to monodentate binding of calcium in the presence of stannous
fluoride. These
include:
Stannous fluoride calcium, phosphate components, and
Substantivity agents and substantivity enhancers including mixed sodium and
calcium
salt copolymers of methyl/vinyl/ether/maleic acid;
wherein the stannous fluoride, calcium and phosphate components remain
unreacted
and the pH of the brushing gel when administered to saliva coated enamel is at
least
about 3.
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The foregoing methods of treatment of the present invention using the above
ingredients are described in detail below.
Stannous Fluoride Concentration
The amount of stannous fluoride, used in the methods of treatment of the
present
invention, where stannous fluoride brushing gels are applied to the toothbrush
(dose) is
not as important as the concentration of available stannous fluoride in the
brushing gel.
Heretofore, reducing fluoride concentration in brushing products has been
reported not
to be as effective as regular concentration fluoride products.
Petersson, et. al., Swed. Dent. 1982, 6:233-238
Metropoulos, et. al., Community Dent. Health, 2002, 1:193-200.
The extraordinary EPF and ERF values reported for methods of treatment of the
present invention using brushing gels allow for reducing stannous fluoride
concentrations while effecting acceptable fluoride protection and uptake
results.
The fluoride dose is important in regard to enamel fluorosis in children under
six years
of age, due to fluoride brushing gel ingestion. For this reason, reducing the
amount of
stannous fluoride applied in the methods of treatment of the present invention
using
brushing gels is a preferred strategy over lowering the dose of stannous
fluoride
brushing gels intended for use by children under six years of age.
While fluoride brushing products have a long history of safety, there is a
continuing
concern associated with dental fluorosis due to fluoride ingestion in children
under age
six. Dendrys, J. Am. Dent. Assoc. 2000, 131(6): 746-755.
Studies have shown that for children 1-3 years of age, 30 to 75% of the
fluoride
brushing product is ingested; and for children 4-6 years of age, 14 to 48% is
ingested.
Warren and Levy, Pediatr. Dent., 199, 21:265-271.
The methods of treatment of the present invention using stannous fluoride
brushing
gels, with their improved efficacy can be used at reduced stannous fluoride
levels, and
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thereby substantially lower the risk of overdosing and the onset of fluorosis,
while
delivering effective EPF and ERF results.
See also Zero, BMC Oral Health, 2006, 6(Suppl 1): 59; 1-13.
Monitoring the fluoride-mineral phase formed on enamel using the methods of
treatment of the present invention establishes the function of the
concentration of fluoride ions (F] in the demineralizing medium
See: Mohammed, et. al., Caries Res., 2013; 47:421-428.
= At below 45 ppm [F ] in the solution 19F MAS-NMR showed fluoride-
substituted
apatite formation, 1B 19F magic angle, spinning nuclear magnetic resonance was
used to characterize the solid phase precipitated on enamel as a function of
fluoride concentration during exposure of the enamel to an in vitro
demineralization system. The cariostatic effect of fluoride is due to the
formation
of Fsa HAP and CaF2 depending on the [F] level in the solution.
= Above 45 ppm, calcium fluoride (CaF2) is formed in increasing
proportions.
= Further increases in [F 1 caused no further reduction in
demineralization, but
increased the proportion of CaF2 formed.
= As to the mechanism of fluoride anticaries efficacy.... fluoroapatite
formation in
enamel is investigated.
Advantages of 19F MAS-NMR:
(1) selectively probes the local environment of only fluorine atoms in the
sample,
permitting direct identification of the possible structural forms in which [F
may exist within the enamel.
(2) detects all fluorine present, whether:
crystalline,
amorphous, or
adsorbed.
(3) measures very low concentration of fluoride in the order of 0.1%.
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19F MAS-NMR established the effects of varying fluoride concentrations on
fluoride-
enamel interactions under acidic conditions using bulk enamel blocks rather
than
powder.
For the samples demineralized in the presence of [F ]:
(1) chemical shifts were identified;
(2) formulation of fluoride-substituted apatite: (a)(CaloCP04)6F2-x,
(F5-HAP); and
(3) formation of CaF2;
= were observed in approximately aged proportion at 45 ppm [F] solutions.
- At [F ] above 45 ppm less F5-HAP forms and an increased signal for CaF
= For [F 1 above 136 ppm mostly CaF2 was identified.
The present study demonstrates that the addition of fluoride produces Fs-HAP
as a
major chemical species only at low concentrations of fluoride.
There is overwhelming evidence that low fluoride levels found in:
(a) saliva can significantly reduce enamel demineralization, and
(b) plaque have the potential to remineralize even at pH values typically
regarded as demineralizing.
Calcium, CaF2, Car and Phosphate
According to Walton, et. al., "Textbook of Dental Pharmacology and
Therapeutics"
(Oxford University Press 1994), pp. 149 and 154:
Tin Salts:
The ability of the tin ions to inhibit plaque formation has been studied
primarily using
stannous fluoride mouthrinses. Daily rinsing with a 0.1 percent stannous
fluoride
solution significantly reduces bacterial accumulation on the teeth.
The action of stannous ions is mediated through their ability to bind to
lipotechoic acid
on the surface of Gram-positive bacterial. The surface net charge of the
organisms is
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therefore reversed and the adsorption of the cells onto teeth is consequently
reduced.
Furthermore, the effectiveness of stannous fluoride solution in reducing
bacterial
adhesion I related to the stability of the stannous ions in aqueous solution
and the rate
at which they are taken up and retained by specific bacteria. The accumulation
of tin in
bacteria may alter their metabolism and other physiochemical characteristics.
Stannous fluoride:
This also reduces dentine sensitivity. In solution it undergoes spontaneous
hydrolysis
and oxidation, so it is applied in the form of a gel mixed with
carboxymethylcellulose or
glycerin. Stannous fluoride acts as an enzyme poison and may inactivate
enzymic
activity in the odontoblastic process. Like sodium fluoride, stannous fluoride
induces
mineralization within the dentinal tubules, which creates a calcific barrier
in the dentine
surface.
Christofferson, et. al., in ACTA ODONTOL. SCAND. 1988, 46:325-336, reports:
"It is suggested that the calcium fluoride-like material formed on dental
enamel during
treatment of enamel with acidified solutions of high fluoride content is a
phosphate-
containing calcium fluoride."
"The aims of the present work are to determine the rates of growth and
dissolution of
pure calcium fluoride in aqueous suspensions and possible mechanisms
controlling
these processes, and to study the properties of the calcium fluoride-like
material formed
by adding fluoride to systems containing hydroxyapatite crystals and/or
dissolved
calcium and phosphate, simulating the type of calcium fluoride-like material
formed on
dental enamel as a result of topical treatment with acidified solutions of
high fluoride
content."
"From our results of dissolution of pure CaF2 in systems containing phosphate
it can be
seen that 1 um phosphate has a dramatic effect on the rate of dissolution of
CaF2-"
"The calcium fluoride-like materials containing phosphate appear to be more
likely
candidates to serve as slow fluoride release agents."
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B. Ogaard's "CaF2 Formation: Cariostatic Properties and Factors of Enhancing
the
Effect," Caries Res., 2001; 35 (Suppl) 11:40-41, teaches:
"CaF2 or a CaF2-like material/phosphate-contaminated CaF2 is a major reaction
product
during topical treatment of dental hard tissues. Recently, evidence has
suggested that
CaF2 is formed not only on surfaces but also to some extent in the enamel. The
minimum concentration of fluoride required for CaF2 formation is not well
known and
may depend on whether calcium is available from plaque fluid or only through
dissolution of the dental hard tissue. Furthermore surface adsorption of
fluoride to
crystals may cause local concentrations necessary for CaF2 formation. It has
been
suggested that CaF2 acts as a pH-controlled reservoir of fluoride. The rate-
controlling
factor appears to be phosphate, which controls the dissolution rate of CaF2 at
high pH.
Increasing fluoride concentration, prolonging the exposure time or using a
fluoride
solution with low pH can increase CaF2 formation. CaF2 formed at low pH
contains less
internal phosphate which has been shown to be less soluble. This may be of
clinical
significance for fluoride applied topically a few times per year."
"The interaction between the fluoride ion and dental hard tissues has been
investigated
extensively since modern fluoride research started in the 1940s. The chemistry
of this
process is complicated due to many impurities in hydroxyapatite-like carbonate
and
magnesium and to a large variety of fluoride concentrations, pH and
composition of the
agents used in caries prevention. During pH cycling in plaque, fluoride may
exchange
with hydroxyl in the apatite and a series of solids with intermediate
composition and
crystallographic properties are formed known as fluorhydroxyapatite."
"CaF2 is the major or probably the only reaction product on dental hard
tissues from
short treatments with relatively concentrated fluoride agents (Cruz et. al.,
Scand. J.
Dent. Res., 1992; 100:154-158). Without doubt, this pH-controlled depot of
CaF2 plays
a major role in the cariostatic effect of topical fluoride. CaF2 has been
detected on
dental hard tissues weeks and months after a single topical fluoride treatment
(Caries
Res., 1991, 25:21-26) and is the only logical way to explain that such
treatments have a
cariostatic effect. By treating enamel samples subjected to topical fluoride
treatment
with KOH, the cariostatic effect is lost (Ogaard, et al., J. Dent. Res., 1990,
69:1505-
1507)."
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J.M. ten Cates "Review on Fluoride, with special emphasis on calcium fluoride
mechanisms in caries prevention", Eur. J. Oral Sc., 1997, 105:461-465,
teaches:
"For treatments to be effective over periods longer than the brushing and the
following
salivary clearance, fluoride needs to be deposited and slowly released.
Calcium fluoride
(or like) deposits act in such a way, owing to a surface covering of phosphate
and/or
proteins, which makes the CaF2 less soluble under in vivo conditions than in a
pure
form in inorganic solutions. Moreover, due to the phosphate groups on the
surface of
the calcium fluoride globules, fluoride is assumed to be released with
decreasing pH
when the phosphate groups are protonated in the dental plaque."
"In the presence of low concentrations of fluoride in solution (such as saliva
or plaque
fluid), hydroxyapatite might be dissolved below the critical pH (for
hydroxyapatite), but
the released mineral ions could be reprecipitated as fluoroapatite or a mixed
fluor-
hydroxyapatite. This mechanism prevents the loss of mineral ions, while
providing
additional protection to mineral crystallites by laying fluoride-rich other
layers onto the
apatite crystallites."
"These observations point to the presence of slowly releasing fluoride
reservoirs, either
on the dentition or the mucosal surfaces. Recent work has shown that in
particular the
oral mucosa, both by its chemical and morphological nature and the large
surface area,
is an underestimated retention site of fluoride."
"Research has shown that small amounts of fluoride in plaque and saliva are
sufficient
to shift the de, remineralization balance favorably. Such levels should then
be available
throughout the day, in particular during periods of carbohydrate fermentation
in the
plaque. A fluoride-releasing reservoir system, effective at low pH, such as
shown for
calcium fluoride, would be a preferred system."
Vogel, et al., in "No Calcium-Fluoride-Like Deposits Detected in Plaque
shortly after a
Sodium Fluoride Mouthrinse", Caries Res., 2010; 44:108-115, reported:
"Plaque 'calcium-fluoride-like' (CaF2-like) and fluoride deposits held by
biological/bacterial calcium fluoride (Ca-F) bonds appear to be the source of
cariostatic
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concentration of fluoride in plaque fluid. The aim of this study was to
quantify the
amounts of plaque fluoride held in these reservoirs after a sodium fluoride
rinse."
"The results suggest that either CaF2-like deposits were not formed in plaque
or, if
these deposits had been formed, they were rapidly lost. The inability to form
persistent
amounts of CaF2-like deposits in plaque may account for the relatively rapid
loss of
plaque fluid fluoride after the use of conventional fluoride dentifrices or
rinses."
"Based on laboratory [Margolis and Moreno, J. Dent. Res., 1990, 69 (Spec.
Issue) 606-
.. 613; J. Am. Dent. Assoc., 2000, 13:887-889; and clinical observations
(reviewed by
Featherstone, J. American Dent. Assoc., 2000, 13:887-889; the current models
for
increasing the anticaries effects of fluoride (F) agents emphasize the
importance of
maintaining a cariostatic concentration of F in oral fluids."
"This inability to form potentially more persistent calcium fluoride deposits,
which
appears to be due to the low concentration of oral fluid Ca, may account for
the
relatively rapid loss of F in plaque after the use of current over-the-counter
topical F
agents. It should be noted in this regard that (1) studies in which a Ca
preapplication
was used to ameliorate this situation have produced very large and persistent
increases
in both plaque fluid and that salivary fluoride (Vogel, et. al., Caries Res.,
2006, 40:449-
454; Vogel, et. al., Caries Res. 2008 (a) 421;401-404; and Vogel, et. al., J.
Dent. Res.
2008(b) 87:466-469; and that (2) preliminary studies (unpubl.) using
modifications of
the techniques described here confirm that the use of a Ca prerinse prior to a
F rinse
indeed forms large amounts of CaF2-like deposits."
Substantivity Agents
For purposes of the present invention, substantivity agent refers to a
composition or
combination of compositions that, when administered to oral cavity surfaces
with
biofilm, using the methods of treatment of the present invention enhance the
retention
of stannous fluoride and calcium to said oral cavity surfaces.
The unexpected enamel protectant and enamel repair features of the methods of
treatment of the present invention, using aqueous-free, brushing gels are
attributed to
the unique substantivity properties indicated by the brushing gels of the
invention.
19
For purposes of the present invention, preferred substantivity agents for the
brushing
gels include various aqueous-free emulsions of polydimethylsiloxane/polymers
in
nonionic surfactants at viscosities of at least about 10,000 cs.
These substantivity agents form mucoadhesive gels in the presence of saliva,
which
are substantive to biofilm-coated enamel and gradually dissolve under saliva
flow,
releasing stannous fluoride onto the biofilm on the enamel at a pH of at least
about 3;
thereby effecting EPF and ERF values of at least about 2.5 and about 200,
respectively, using the methods of treatment of the present invention.
For purposes of the present invention, substantivity agents include saliva
soluble,
aqueous-free emulsions comprised of:
polydimethylsiloxane polymers in solid, nonionic surfactants, as described in
U.S.
Patents: 5,032,387; 5,098,711; 5,538,667; 5,645,841; 5,651,959; having the
following
structural formula:
HORC2H40)x /(C31-160)y]- [C31-160]z - [(C2H40)x /(C31-160)0H
wherein y = 0 and the sum of x and z is between 120 and 150. In a preferred
embodiment, x = 76, y = 0 and z = 56;
and liquid nonionic surfactants having the following structural formula:
HO[(C21-140)x /(C3H60)11- [C3H60]: - [(C21-140)x /(C3H60)0H
wherein the sum of x, y and z is between 125 and 175. In a preferred
embodiment, x =
76, y = 25 and z = 56.
Combinations of solid and liquid, nonionic surfactants are also suitable for
purposes of
the present invention, provided the resultant emulsion remains liquid.
Date Recue/Date Received 2021-09-15
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In a preferred embodiment of the invention, liquid nonionic surfactants
comprise the
continuous phase of the aqueous-free emulsions. Preferred liquid nonionic
surfactants
are represented by the structural formula:
HORC21140)x /(C31160)J- [C311601z - RC2I-140)x /(C3H60)0H
wherein x = 76, v = 26 and z = 56.
Combinations of liquid, nonionic surfactants with solid, nonionic surfactants
are also
preferred, including solid nonionic surfactants having the structural formula:
HONC2H40)x /(C3H60)11- [C3H6Olz - [(C21140)x 4C3H60)0H
wherein x = 76, y = 0 and z = 56, are suitable.
Preferred aqueous-free, saliva soluble emulsions for use in the substantivity
agents in
the methods of treatment of the present invention include aqueous-free
emulsions
comprising a liquid, nonionic, continuous phase and a discontinuous phase of
polydimethylsiloxane (PDMS) at viscosities ranging from between about 1500 cs
and
about 2.5 million cs. Particularly preferred are aqueous-free emulsions with a
liquid,
nonionic surfactant continuous phase and a discontinuous PDMS phase at
viscosities
between 10,000 cs and 2.5 million cs. Solid surfactants, useful as adjuncts to
the liquid
nonionic surfactant continuous phase are described in detail in U.S.
5,651,959. These
liquid and liquid/solid nonionic surfactant emulsions form mucoadhesive gels
in the
presence of saliva.
Preferred polydimethylsiloxanes are selected from the group consisting of
polydimethylsiloxane: at 1500 cs, at 10,000 cs, at 100,000 cs, at 250,000 es,
at 500,000
es, at 750,000 es, at 1.5 million cs, at 2.2 million cs, at 2.5 million cs and
combinations
thereof.
In a preferred embodiment of the invention, copolymers described below are
useful as
substantivity enhancers; when combined with the aqueous-free, substantivity
agents in
the methods of treatment of the present invention. These substantivity
enhancers
include various linear polymeric, polycarboxylates, such as: copolymers of
sodium and
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calcium salts of methyl/vinyl/ether/maleic acid including those copolymers
available
commercially as Gantrez MS-955 polymer, a mixed sodium and calcium salt of
methyl/vinyl/ether/maleic acid copolymer; where the cations form salt bridges
which
cross-link the polymer chains.
The chemical structure of this copolymer is represented by the following
chemical
structure:
0cHa. I at-A43
1.31 0=C C=0
oisia 4:irtaJ b. .1;
where m is an integer that provides molecular weight for the polymer between
about
60,000 and about 1,000,000.
Preferred are 1:4 to 4:1 copolymers of maleic anhydride or acid with another
polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether
(maleic
anhydride) having a molecular weight of about 30,000 to about 1,000,000.
Sodium and calcium salts of carboxymethyl cellulose ether polymers can also be
used
including sodium and calcium salts of carboxymethyl cellulose ether,
hydroxyethyl
cellulose ether, sodium cellulose ether, etc.
The contribution of Ca ++ from the copolymer substantivity enhancer to ERF
values is
illustrated in Figures 5 and 6 of the Drawings and Tables 6 and 7.
Examples 1 through 5
The following stannous fluoride brushing gel samples, used in the methods of
treatment
of the present invention, were prepared, as described below; and subsequently
tested
for EPF and/or ERF values, as described in Tables 2 through 8 below:
Examples 1 and 2
Example 1
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In a stainless steel 1 L mixing vessel, using an overhead stirrer, 26.966 gm
of PEG 400
were added along with 82.768 gm of glycerin, and 48.78 gm of 1.64% stannous
fluoride
in glycerin. Stirring was begun at a low speed while heating to 809C. Then
2.84 gm of L-
1220/2.5 million PDMS cs (10%) ULTRAMULSION substantivity agent was added
with stirring for 15 minutes. The overhead stirrer speed was increased to
medium and
1.88 gm of Gantrez MS-955 substantivity enhancer was added with stirring for 5
minutes. Then Crodasinic L, 1.42 gm; Sucralose, 0.18 gm; and insoluble
saccharin,
0.56 gm were added with continued stirring for 10 minutes. TEGO betaine CKD,
1.42
gm, was added and stirred for 5 minutes. Calcium fumarate, anhydrous,
micronized,
2.84 gm, was added with stirring for 5 minutes followed by addition of sodium
dihydogen phosphate, anhydrous, micronized, 0.612 gm, was added with continued
stirring for 5 minutes.
In multiple increments, Sipernat 225, 28.3 gm was added with stirring 2
minutes
between each addition. When the Sipernat 22S was all added, stirring continued
for 15
minutes after which Vanillamint, 1.32 gm, and Multisensate flavor, 0.114 gm,
were
added with continued stirring for 5 minutes. The stirrer was removed and the
gel was
filled into dispensing tubes. When used as a brushing gel, a pleasant,
refreshing
mouthfeel and very little metallic taste is perceived.
Example 2
Using the procedure described in Example 1, a second brushing gel was
formulated
without the Gantrez MS-955 substantivity enhancer.
Examples 3 through 5
Three STANNOUS FLUORIDE BRUSHING GEL formulations, used in the methods of
treatment of the present invention, described below; were prepared using the
method
described above for Examples 1 and 2. These brushing gel formulations were in
vitro
tested. The results are reported in Tables 5 through 7 and in
Figs. 4 through 6 of the Drawings.
Example 3
Stannous Fluoride Brushing Gel
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Ingredients Percent Grams
PEG 400 13.653 68.265
Glycerin 41.384 206.92
1.64% Stannous Fluoride in Glycerin 24.39 121.95
L-1220 / 2.5 million CS ULTRAMLILSIONO 10% 1.42 7.1
(substantivny agent)
Multisensate (flavor enhancer) 0.057 0.285
Gantrez MS-955 (substantivity agent) 0.94 4.7
Vanillamint P 0.66 3.3
Insoluble Saccharin 0.28 1.4
Tego Betaine CKD 0.71 3.55
Sipe rnat 228 14.15 70.75
Crodasinic L 0.71 3.55
Sucralose 0.09 0.45
Calcium Sulfate 1.25 6.25
Sodium Phosphate Monobasic Anhy. 0.306 1.53
Total 100 100
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Example 4
Stannous Fluoride Brushing Gel
Ingredients Percent Grams
PEG 400 13.483 67.415
Glycerin 41.384 206.92
1.64% Stannous Fluoride in Glycerin 24.39 121.95
2.5 million CS ULTRAMULSIONC) 10% 1.42 7,1
(substantivity agent)
Multisensate (flavor enhancer) 0.057 0.285
Gantrez MS-955 (substantivity agent) 0.94 4.7
Vanillamint P 0.66 3.3
Insoluble Saccharin 0.28 1.4
Tego Betaine CKD 0.71 3.55
Sipernat 228 14.15 70.75
Crodasinic L 0.71 3.55
SuCralose 0.09 0.45
Calcium Fumarate 1.42 7.1
Sodium Phosphate Monobasic Anhy. 0.306 1.53
Total 100 100
Example 5
Stannous Fluoride Brushing Gel
Ingredients Percent Grams
PEG 400 15.149 75.745
Glycerin 42.384 211.92
1.64% Stannous Fluoride in Glycerin 24.39 121.95
1-1220 / 2.5 million CS ULTRAMULSIONO 10% 1,42 7.1
(substantivity agent)
Multisensate (flavor enhancer) 0.057 0.285
Vanillamint P 0.66 3.3
Insoluble Saccharin 0.28 1.4
Tego Betaine CKD 0.71 3.55
Sipernat 228 14.15 70.75
Crodasinic L 0.71 3.55
Sucralose 0.09 0.45
Total 100 100
In Vitro Testing of the Methods of Treatment of embodiments of the present
invention:
In vitro determination of EPF values attributed to administration of various
fluoride
containing: toothpastes and a test brushing gel onto human enamel subjected to
acid
challenge.
The following study was carried out according to the FDA Monograph on
Anticaries
Drug Products for over-the-counter, human use. The study was performed
following
FDA good laboratory practices.
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Purpose of the following in vitro study: to determine the effect of acid
challenge to
human enamel treated with various fluoride containing brushing products. The
effect of
the acid challenge was established by measuring the resistance of enamel
specimens
treated with various fluoride brushing products to an acid challenge; before
and after
treatment with various fluoride brushing products.
Tooth Preparation:
Three sound human molars were placed in a disc of red boxing wax so that only
the
enamel surfaces were exposed. Twelve set of three teeth each were prepared for
the
study. All specimens were cleaned and polished with a flour of pumice slurry
and a rag
wheel to remove any deposits or stains.
Preparation of Buffered Lactic Acid Challenge Solution:
Two moles (203.58 g of 88.5% pure lactic acid were diluted with approximately
500 ml
of distilled water. To this was added a solution of 84 g NaOH dissolved in
about 600 ml
of distilled water. The total volume was then adjusted to 2000 ml. This was
the buffered
1.0 M lactic acid challenge solution.
Another lactic acid solution was prepared by diluting two moles lactic acid to
2000 ml
with distilled water. The solution of lactic acid and sodium hydroxide was
placed in a
4000 ml beaker, and pH electrodes placed in the solution. The 1.0 M lactic
acid solution
was used to adjust the pH of the buffered solution to 4.5. To obtain a 0.1
working
concentration (for all decalcifications) the 1.0 M buffer was diluted by a
factor of 10 with
distilled water.
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Deprotection:
Before every use, any residual anti-solubility protection afforded by the
previous
treatment was eliminated. Deprotection of these specimens was accomplished by
etching the teeth in the above prepared 0.1 M lactate buffer solution for a
two-hour
.. period. Each disc of three specimens was agitated (450 rpm) in about 50 ml
of lactate
buffer at room temperature during the deprotection period. The teeth were
rinsed well
with distilled water immediately following deprotection.
Pre-Treatment Etch:
The test was performed using preheated (37 C) tooth sets and lactate buffer.
The
deprotected tooth sets were mounted on 1/4 inch diameter acrylic rods with
molten red
boxing wax. Multiplaced stirrers were used for treatments and the etches. All
slurries
and solutions were pre-heated to 37 C. The actual treatments and etches were
carried
out on the bench top with the preheated solutions. Plastic specimen containers
(120 ml)
were used for the etching procedure. A 1/4 inch hole was drilled in each
container lid to
accommodate the plastic rod to which the tooth sets were mounted. A 40 ml
portion of
0.1 M lactic acid buffer was placed in each container along with a one-inch
magnetic
stirring bar. The rod of the first tooth set was pushed through the hole in
the lid, placed
in the first container and adjusted so that all enamel surfaces were immersed
into the
.. buffer solution. The container was then placed on the first magnetic
stirrer and stirring
was begun. The timer was started at this time. At 30-second intervals the
other tooth
sets were started in the same manner. After 15 minutes of exposure to the
buffered
lactate solution, the first set was stopped and the lid and tooth set
immediately removed
from the container and placed in a tray of distilled water to terminate
etching. The other
sets were similarly removed at 30 second intervals in the same order that they
were
initiated and the lactate buffer solutions was retained for phosphorus
analysis. The
tooth sets were placed back in the 37 C water bath in preparation for the
fluoride
treatment step.
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Treatment:
The treatments were performed using slurries of the fluoride brushing
products. The
slurries consisted of 1 part fluoride brushing product and 3 parts preheated
(370C)
distilled water (9g:27m1). Each slurry was mixed for exactly one minute after
adding the
water. The slurries were NOT prepared ahead of time. They were NOT
centrifuged. All
tooth sets were treated at the same time (one for each fluoride brushing
product). The
treatment procedure was similar to the etching procedure with the exception of
the
slurry in place of the acid. A 30 ml portion of the preheated fluoride
brushing slurry was
added to the first tooth set, the teeth were immersed in the slurry and the
container
placed on the first stirrer. The stirrer and timer were started. At 90-second
intervals (to
allow time for stirring), the other tooth sets were started in the same
manner. At the end
of the five minutes of treatment, the first set was stopped, the tooth set
removed and
rinsed well with distilled water. The other sets were removed at 90-second
intervals and
rinsed well. The treatment fluoride brushing slurries were discarded.
Post-Treatment:
A second acid exposure was then performed by the same method as the pre-
treatment
etch and the lactate buffer solutions were again retained for phosphorus
analysis. The
pre and post-treatment solutions were analyzed using a Klett-Summerson
Photoelectric
Colorimeter.
Repeat Analyses:
The tooth sets were deprotected and the procedure repeated additional times so
that
each fluoride brushing product was treated and assayed on each tooth set. The
treatment design was a Latin Square design so that no treatment followed
another
treatment consistently.
Calculation of Enamel Solubility Reduction:
The percent of enamel solubility reduction was computed as the difference
between the
amount of phosphorus in the pre and post acidic solutions, divided by the
amount of
phosphorus in the pre solution and multiplied by 100.
Treatment Groups:
A. Placebo (deionized water)
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B. Positive control 1 Crest PRO-HEALTH Toothpaste with stannous fluoride @
1100 ppm fluoride
C. Positive control 2 ClinProe 5000 Toothpaste with sodium fluoride at 5000
ppm
fluoride
D. Test Gel with stannous fluoride at 970 ppm fluoride composition as
described
hereinafter in Example 1 was used in a method of treatment of the present
invention.
Statistical Analyses:
Statistical analyses of the individual means were performed with a one-way
analysis of
variance model using Sigma Stat (3.1) Software. Since the ANOVA indicated
significant
differences, the individual means were analyzed by the Student Newman-Keuls
(SNK)
test.
Results and Discussion:
The deionized water negative control was not effective in reducing enamel
solubility.
The positive fluoride containing controls and the test gel were significantly
more
effective than the deionized water negative control. The Clinpro 5000
toothpaste was
significantly more effective than the negative control. The method of
treatment of the
present invention using the Test Gel was significantly more effective than the
other two
positive controls in reducing enamel solubility.
The results are shown in Table 2 below:
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Table 2
ENAMEL SOLUBILITY REDUCTION
Summary of Results
Pre-Etch Post-Etch Della Percent EPF *1'
Group Treatment P P PP pP Reduction
A Deionized Water 583 24* 633 22 -50 13 -9.06
2.28
B Crest PRO-REALM() (stannous 645 23 488* 14 158* 18
23.83* 2.27 2.2
fluoride @ 1100)
C Clinpro 5000 (sodium fluoride @ 617 21 582 21 35 14
5.49 2.28 0.1
5000 ppm)
D Brushing Gel (stannous fluoride @ 654 39 409 12 245 32
35.79 2.91 3.7
970 ppm fluoride) used in a method
of treatment of the presen1 invention
See Example 1
* Mean SEM (N=12)
** To establish the enamel protection factor (EPF) values for each fluoride
brushing
product tested, the percent reduction in enamel solubility was divided by the
fluoride
level in parts per million of the brushing product tested. The resultant
number was
multiplied by 100.
See Fig. 1 of the Drawings.
In vitro determination of ERF values attributed to administration of various
fluoride
containing toothpastes and the method of treatment of the present invention,
applying
brushing gel of the present invention onto incipient enamel lesions in bovine
enamel.
The following study was carried out according to the FDA Monograph on
Anticaries
Drug Products for over-the-counter, human use, following FDA good laboratory
practices.
Purpose of the following in vitro study: to determine the fluoride uptake into
incipient
enamel lesions in bovine incisors, treated with various fluoride containing,
brushing
products and the methods of treatment of the present invention.
The test procedure was identical to the procedure identified as Procedure 40
in the
FDA anticaries Monograph, except the lesions were formed using a solution
comprising
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0.1 M lactic acid and 0.2% Carbopol 907, wherein the solution was saturated
with HAP
(hydroxyapatite) at a pH of 5Ø
The fluoride uptake was established by analyzing fluoride and calcium levels
of enamel
pre-treatment and enamel post-treatment to determine the change in enamel
fluoride
attributed to treatment with fluoride containing brushing products.
Procedure:
Sound, upper, central, bovine incisors were selected and cleaned of all
adhering soft
tissue. A core of enamel 3mm in diameter was prepared from each tooth by
cutting
perpendicularly to the labial surface with a hollow-core diamond drill bit.
This was
performed under water to prevent overheating of the specimens. Each specimen
was
embedded in the end of a plexiglass rod (1/4" diameter x 2" long) using
methylmethacrylate. The excess acrylic was cut away exposing the enamel
surface.
The enamel specimens were polished with 600 grit wet/dry paper and then micro-
fine
Gamma Alumina. The resulting specimens were a 3mm disk of enamel with all but
the
exposed surface covered with acrylic. Twelve specimens per group were
prepared.
Each enamel specimen was then etched by immersion into 0.5 ml of 1M HC104 for
15
seconds. Throughout the etch period, the etch solutions were continuously
agitated. A
sample of each solution was then buffered with TISAB(fluoride ion probe
buffer) to a
pH of 5.2 (0.25 ml sample, 0.5 ml TISAB and 0.25 ml 1N NaOH) and the fluoride
content of the solution determined by comparison to a similarly prepared
standard
curve (1 ml std + 1 ml TISAB). For use in depth of each calculation, the Ca
content of
the etch solution was determined by taking 50 I and analyzing for Ca by
atomic
absorption (0.05 ml qs to 5 ml). These data was the indigenous fluoride level
of each
specimen prior to treatment.
The specimens were once again ground and polished as described above. An
incipient
lesion was formed in each enamel specimen by immersion into a 0.1M lactic
acid/0.2 /0
Carbopol 907 solution for 24 hours at room temperature. These specimens were
then
rinsed well with distilled water and stored in a humid environment until used.
The treatments were performed using slurries of the various fluoride
containing
brushing products. The flurries consisted of 1 part fluoride containing
brushing product
and 3 parts distilled water (9g:27m1). Each slurry was mixed for exactly one
minute after
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adding the water. The slurries were NOT prepared ahead of time. They were NOT
centrifuged. The 12 specimens of each group were then immersed into 25 ml of
their
assigned slurry with constant stirring (350 rpm) for 30 minutes. Following
treatment, the
specimens were rinsed' with distilled water. One layer of enamel was then
removed
from each specimen and analyzed for fluoride and calcium as outlined above
(i.e. 15
second etch). The pretreatment fluoride (indigenous) level of each specimen
was then
subtracted from post treatment, fluoride value to determine the change in
enamel
fluoride due to the last treatment.
Statistical Analyses:
All raw data (individual specimen Enamel Fluoride Uptake (EFU) values were
reported.
In addition, the mean, S.D. (standard deviation) and SEM(scanning electron
micrograph) for each group was calculated. Statistical analysis were performed
by a
one-way analysis of variance model using Sigma Stat Software (3.1). Since
significant
.. differences are indicated, the individual means were analyzed by the
Student Newman
Keuls (SNK) test.
Test Products:
The test fluoride containing brushing products were coded as follows:
1. Placebo (deionized water)
2. Positive Control 1 Crest PRO-HEALTH with stannous fluoride at 1100 ppm
fluoride
3. Positive control 2 Clinpro 50000 with sodium fluoride at 5000 ppm fluoride
The method of treatment of the present invention using a brushing Gel of the
present
invention with stannous fluoride at 970 ppm fluoride composition as described
in
Example 1.
Results:
The results are shown in Table 3 below:
Table 3
Change in Incipient Lesion Enamel Fluoride Content
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PCT/US21115/025375
Enamel Fluoride C,oncentration (ppm)
Fluoride Containing Pre Post ERF ***
Brushing Product Treatment Treatment Increase Etch Depth
Placebo, deionized water 41 4' 44 3 3 2 17.88 0.70
Crest PRO-HEALTHO 1100 44 5 1888 81 1843 83 10.06 0.25
170
stannous fluoride
Clinpro 50000 (ilt 5000 ppm sodium 52 6 3310 88 3258 88
15.28 0.56" 65
fluoride
A method of treatment of the 47 5 3003 212 2956 212 13.36
0.26 300
present invention using a Brushing
Gel (4 970 ppm stannous fluoride
See Example 1
* Mean SEM (N=12)
¨ Values 15.32 and 15.28 are not significantly different
¨ To establish the enamel repair factor (ERF) values for each fluoride
brushing
product tested, the increase in enamel fluoride concentration was divided by
the
fluoride level of the fluoride brushing product. The resultant number was
multiplied by
100.
See Fig. 2 of the Drawings.
In vitro determination of ERF values attributed to using methods of treatment
of the
present invention of various fluoride containing: toothpastes and a brushing
gel are
administered onto incipient enamel lesions in human enamel was carried out
following
the Enamel Fluoride protocol described above for the results reported in Table
3. Some
of the fluoride containing brushing products tested in this fluoride uptake
study are
different than those reported on in Table 3 above.
Table 4
Change in Incipient Lesion Enamel Fluoride Content
Enamel Fluoride Concentration (ppm)
Fluoride Containing Pre Post
Brushing Product Treatment Treatment Increase Etch Depth
ERF "
Placebo, deionized water 41 4" 89 5 47 5 17.88
0.70
Crest PRO-HEALTH Toothpaste 44 5 1530 69 1486 66 10.06
0.25 140
(stannous fluoride,1100 ppm
fluoride)
A method of treatment of the 52 6 2656 80 2615 79 15.26
0.56 270
present invention using a brushing
Gel (stannous fluoride at 970 ppm
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fluoride)
See Example 2
* Mean .1: SEM (N=12)
** To establish the enamel repair factor (ERF) values for each fluoride
brushing
product tested, the average increase in enamel fluoride concentration (post
treatment
was divided by the fluoride level of the fluoride brushing product tested. The
resultant
number was multiplied by 100).
See Fig. 3 of the Drawings
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Table 5
Change in Incipient Lesion Enamel Fluoride Content
Enamel Fluoride Concentration (ppm)
Fluoride Containing Pre Post
Brushing Product Treatment Treatment Increase Etch
Depth ERF **
Placebo, deionized water 46 4* 56 4 9 4 17.55 0.28
Crest PRO-HEALTH Toothpaste 57 6 2338 73 2280 76 9.51
0.35 210
(stannous fluoride,1100 ppm
fluoride)
A method of treatment of the 48 5 3034 117 2987 114 11.15
0.18 380
present invention using a brushing
Gel (stannous fluoride at 970 ppm
fluoride)
See Example 5
* Mean SEM (N=12)
** To establish the enamel repair factor (ERF) values for each fluoride
brushing
product tested, the average increase in enamel fluoride concentration (post
treatment
was divided by the fluoride level of the fluoride brushing product tested. The
resultant
number was multiplied by 100).
See Fig. 4 of the Drawings.
Table 6
Change in Incipient Lesion Enamel Fluoride Content
Enamel Fluoride Concentration (ppm)
Fluoride Containing Pre Post
Brushing Product Treatment Treatment Increase Etch
Depth ERF **
Placebo, deionized water 46 4* 56 4 9 4 17.55 0.28
Crest PRO-HEALTH Toothpaste 57 6 2338 73 2280 76 9.51
0.35 210
(stannous fluoride,1100 ppm
fluoride)
A method of treatment of the 56 4 4032 216 3976 217
10.84 0.24 410
present invention using a brushing
Gel (stannous fluoride at 970 ppm
fluoride)
See Example 3
* Mean SEM (N=12)
** To establish the enamel repair factor (ERF) values for each fluoride
brushing
product tested, the average increase in enamel fluoride concentration (post
treatment
was divided by the fluoride level of the fluoride brushing product tested. The
resultant
number was multiplied by 100).
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See Fig. 5 of the Drawings.
Table?
Change in Incipient Lesion Enamel Fluoride Content
Enamel Fluoride Concentration (ppm)
Fluoride Containing Pre Post
Brushing Product Treatment Treatment Increase Etch Depth
ERF **
Placebo, deionized water 46 4* 56 4 9 4 17.55 0.28
Crest PRO-HEALTH Toothpaste 57 6 2338 73 2280 76 9.51
0.35 210
(stannous fluoride,1100 ppm
fluoride)
A method of treatment of the 57 5 10462 357 10406 363 13.95
0.39 1070
present invention using a brushing
Gel (stannous fluoride at 970 ppm
fluoride)
See Example 4
* Mean SEM (N.12)
** To establish the enamel repair factor (ERF) values for each fluoride
brushing
product tested, the average increase in enamel fluoride concentration (post
treatment
was divided by the fluoride level of the fluoride brushing product tested. The
resultant
number was multiplied by 100).
See Fig. 6 of the Drawings.
Table 8
Summary of Stannous Fluoride Brushing Gel
ERF data, based on using methods of the present invention with various
brushing gel compositions, as described in Tables 3 through 7 and in Figs. 2
through 6 of the Drawings
Methods of pH
Treatment of the Substantivity SnF2 Calcium Phosphate Fluoride
Substant- Additional Total upon
present invention Agent in PPM F Content Content
Uptake ivity Cat' Ca '+ applic- ERF
using Stannous (% by wt) Enhancer % ation to
Fluoride (% by wt) enamel
Brushing
Gels, as
described in:
Table No/
Fig No.
3/2 L-1220& 970 0.369 0.242 2956 0.94 0.1
0.469 4.0 300
(Example 1) PDMS
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2.5 million cs
(1.42)
4/3 L-1220& 970 0 0 2615 0 0 0 ¨ 270
(Example 2) PDMS
2.5 million cs
(1.42)
5/4 L-1220/ 970 0 0 2987 -- 0 0 380
(Example 5) 2.5 million cs
ULTRAMUL-
' SIONO 10%
(1.42)
6/5 L-1220/ 970 1.25 0.306 3976 0.94 0.1 1.35
410
(Example 3) 2.5 million cs
ULTRAMUL-
SIONIO 10%
(1.42)
. . ,
7/6 2.5 million cs 970 1.42 0.306 10406 0.94
0.1 1.52 1070
(Example 4) ULTRAMUL-
SIONO 10%
(1.42)
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Illustrative Examples of Brushing Gels used in the methods of treatment of
the present invention
Table 9
Methods of
Example treatment of the Poloxamer PDMS
Substantivity pH of GEL in
No. present invention (% by wt.) (0,1 by WI.)
Enhancer saliva
using Brushing (% by wt.)
Gels with
Stannous Fluoride
level in ppm
fluoride
6 970 L-1220 (1.8) 2.5 million cs MS-955 3.5
(0.2) (1.1)
7 1100 F-127(2.7) 800,000 cs MS-955 3.0
(0.3) (0.94)
8 600 L-1220 (2.25) 1.5 million cs MS-955 5.6
(0.25) (0.97)
9 800 L-1220 (1.8) 1.2 million MS-955 4.5
(0.2) (0.94)
500 F-127 (2.25) 1 million cs MS-955 5.0
(0.25) (1.0)
11 400 F-1271-1220 (0.8) 2.5 million cs MS-955
5.8
(0.2) (0.94)
12 1000 F-127/L-1220 (2.85) 2 million cs MS-955
3.7
(0.71) (1.16)
,
13 700 L-1220 (2.5) 1,8 million cs MS-955 4.8
(0.63) (1.0)
14 850 F-127 (2.1) 2.5 million cs MS-955 4.3
(0.23) (0.94)
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Table 10
Methods of Treatment of the present invention for "at-risk" patients
with Brushing GELS
Specific Brushing GEL Frequency of Duration of
"At-risk" Patient Formulation Recommended Treatment
Treatment
Once daily for 2 minutes To De determined by
pediatric
Children under 7 years of age Example 4 followed by expectorating
dentist
Undergoing medical and/or Duration of
professional oral care Example 4 At least twice daily
medical/professional oral
treatments with prescribed care treatment
medications
lmmunocompromised with Example 5 At least twice daily For term of
chronic condition
chronic conditions
Diabetes, heart disease, etc. Example 3 Several times daily
For term of chronic condition
Cancer treatment Example 4 As required To be determined by oral
care professional
Example 15
A 5 liter Ross/Olsa vacuum mixer with internal homogenizer was heated to 80
degrees
C while the vessel was charged with 647.15 gm of PEG 400, 2069.2 gm of
anhydrous
glycerin and 1219.5 gm of 1.64% stannous fluoride/glycerin. Anchor stirring at
slow
speed was begun and continued for 7 minutes. ULTRAMULSION [(Plurocare L-1220
(90%)) and 2.5 million cs polydimethylsiloxane (10%)], 71 gm, was added with
homogenizer speed adjusted to 2500 rpm for 15 minutes. The anchor stirrer was
increased to medium speed and Gantrez MS-955. 47 gm, was added with stirring
and
homogenizing for 5 minutes. Crodasinic L, 35.5 gm, was added with continued
stirring
for 5 minutes. TEGO Betaine CKD, 35.5 gm, was added and stirring continued for
5
minutes. Micronized (20 micron D50) calcium fumarate, anhydrous, 71 gm, was
added
with stirring for 5 minutes. Micronized (20 micron) sodium phosphate
monobasic,
anhydrous, 15.3 gm, was added with stirring for 5 minutes. Sident 22S, 707.5
gm, was
added in increments at 2 minutes between additions until all was added.
Stirring was
continued for 15 minutes.
Vanillamint P flavor, 33 gm, and spilanthes extract, 2.85 gm, were added with
continued
stirring for 5 minutes. The vessel was cooled to ambient temperature over 15
minutes.
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The contents were dispensed into tubes for use. Upon dispensing, the brushing
gel was
pleasant testing with no stannous fluoride aftertaste. Stannous fluoride
stability testing
was performed on the product.
Discussion of EPF and ERF values established by in vitro testing
The methods of treatment of the present invention using stannous fluoride
brushing
gels show substantial improvement in EPF and ERF values compared to methods
using commercial toothpastes at various fluoride levels as reported in: Tables
2 through
7, Figs. 1 through 6 of the Drawings and Summary Table 8.
For example, the ERF values, reported in Table 3 and Fig. 2 for using Crest
PRO-
HEALTH and Clinpro 50009 toothpastes are 170 and 65 respectively, compared to
an ERF for the methods of treatment of the present invention using a stannous
fluoride
brushing gel of 300. The ERF values reported in Table 7 and Fig. 6 of the
Drawings for
Crest PRO-HEALTH toothpaste is 210 compared to an ERF for the methods of
treatment of the present invention using a Stannous Fluoride Brushing Gel,
1070.
These 2X and 5X improvements, respectively, in ERF value over commercial
toothpastes represent a major advance in methods of treatment of the present
invention
for fluoride uptake and enamel hardening. Such an advantage in enamel
hardening
efficiency is particularly critical to children as well as to patients
experiencing: rampant
caries, coronal caries, cancer therapy treatments, mucositis treatments,
immune
deficiency treatments, bone marrow transplants, etc.
Proposed Mechanism of Action for the methods of treatment of the present
invention
The enamel protectant and/or enamel repair (EPF and/or ERF) data reported for
methods of treatment of the present invention using formulations described in
Examples 1 through 5, as detailed in Tables 2 through 8 and in Figs. 1 through
6 of the
Drawings, suggest the substantivity of stannous fluoride and calcium to the
biofilm
present on enamel surfaces is enhanced by the methods of treatment to effect a
shift
from bidentate to monodentate calcium binding in the presence of stannous
fluoride.
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This shift in calcium binding in the presence of stannous fluoride results in
a most
effective binding site configuration. See:
Dudey and Lim, J. Phys. Chem B, 2004, 108:4546.
Vogel, et. al., Caries Res., 2010, 94:108-115.
Rolla and Bowen, Scand. J. Dent. Res., 1977; 85:149-151.
Rose, et. al., J. Dent. Res., 1993; 72:78-84.
See also:
Turner, et. al, Ceramics, Silikaty 57(1):1-6 (2013)
Mohammed, et. al., Caries Res., 47:421-428 (2013)
Calcium-bridge, fluoride binding
Calcium binding to biofilm shifts from a bidentate chelation to a monodentate
chelation
in the presence of fluoride, freeing up calcium to bind with fluoride, Car
pair, thereby
doubling the calcium binding capacity; using the methods of treatment of the
present
invention.
In the methods of treatment of the present invention, stable fluoride in the
brushing gels
produces marked reduction in calcium binding affinity and approximately
doubles
calcium binding capacity. In the absence of fluoride, calcium binding to
biofilm is
bidentate. Stable fluoride in these brushing gels compete with biofilm causing
calcium
binding to biofilm to become monodentate. This allows the binding of about
double the
quantity of calcium and of Car bound to biofilm. Release of fluoride bound by
calcium
bridging into biofilm fluid as a result of fluoride clearance into saliva will
always be
accompanied by a corresponding release of calcium which, in turn, potentiates
the
cariostatic effect of fluoride as indicated in the in vitro testing described
in Tables 2
through 7 and Figs. 1 through 6 of the Drawings.
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At least some of the stable fluoride present in the brushing gels used in the
methods of
treatment of the present invention is bound to calcium ions (sourced from
various
calcium salts in the present invention and/or calcium present in the copolymer
substantivity enhancer, such as Gantrez MS-955. These calcium ions, in turn,
are
bound to biofilm associated with enamel.
A drop in pH follows exposure of plaque to sucrose which removes some anionic
groups by neutralization, thereby liberating calcium and fluoride (as Car) at
the very
sites where these moieties can do the most good.
The effectiveness of the methods of treatment of the present invention using
brushing
gels depends on three factors:
(1) substantivity of the formulation to biofilm,
(2) stannous fluoride as the source of CaF+, and
(3) retention of fluoride in a form on biofilm which allows release of
Car ions
into hydroxyapatite.
Stannous fluoride produces a marked reduction in calcium binding affinity
accompanied
by an approximate doubling of the calcium binding capacity. In the absence of
fluoride,
divalent cation binding to plaque is bidentate. Fluoride competes with
macromolecular
anionic groups, causing binding to become monodentate. Release of fluoride
formed by
calcium bridging, is accompanied by release of calcium, which potentiates the
cariostatic effect of fluoride.
The presence CaF+ is required to deliver the enamel protection and repair (EPF
and
ERF) results required for the methods of treatment of the present invention
using
Brushing Gel formulations.
Summary as to the role of cation bridging in microbial fluoride binding
In the methods of treatment of the present invention, fluoride binding
produces a
marked reduction in calcium binding affinity, along with a doubling of calcium
binding
capacity. This indicates that calcium binding changes from bidentate to
monodentate.
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This shift from bidentate to monodentate is a consequence of fluoride
replacing an
anionic group as one of the calcium ligends.
The anionic groups to which calcium is no longer bound are then free to bind a
CaF+
ion pair, resulting in a doubling of the calcium binding capacity. Release of
fluoride,
bound by calcium bridging into plaque fluid, may be accompanied by a release
of
calcium which will potentiate the cariostatic effect of fluoride.
Car is taken up by hydroxyapatite and is responsible for the EPF and ERF in
vitro
data reported for the methods of treatment of the present invention. The ERF
values
reported in Tables 3 through 8 and Figures 2 through 6 of the Drawings suggest
that
the CaF+ moiety is incorporated into the hydroxyapatite lattice during
remineralization
methods of treatment of the present invention.
The methods of treatment of the present invention using brushing gels set a
new, oral
care standard for Enamel Protection and Enamel Repair, while dramatically
reducing
exposure to elevated fluoride levels in various fluoride varnishes, gels and
toothpastes.
