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Description  |
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This invention relates to oral compositions containing an anticalculus
agent.
Calculus is a hard, mineralized formation which forms on the teeth. Regular
brushing prevents a rapid build-up of these deposits, but even regular
brushing is not sufficient to remove all of the calculus deposits which
adhere to the teeth. Calculus is formed on the teeth when crystals of
calcium phosphates begin to be deposited in the pellicle and extracellular
matrix of the dental plaque and become sufficiently closely packed
together for the aggregates to become resistant to deformation. There is
no complete agreement on the route by which calcium and orthophosphate
ultimately become the crystalline material called hydroxyapatite (HAP). It
is generally agreed, however, that at higher saturations, that is, above
the critical saturation limit, the precursor to crystalline hydroxyapatite
is an amorphous or microcrystalline calcium phosphate. "Amorphous calcium
phosphate" although related to hydroxyapatite differs from it in atomic
structure, particle morphology, and stoichiometry. The X-ray diffraction
pattern of amorphous calcium phosphate shows broad peaks typical of
amorphous materials, which lack the long-range atomic order
characteristics of all crystalline materials, including hydroxyapatite. It
is apparent therefore that agents which effectively interfere with
crystalline growth of hydroxyapatite will be effective as anticalculus
agents. A suggested mechanism by which the anticalculus agents of this
invention inhibit calculus formation probably involves an increase of the
activation energy barrier thus inhibiting the transformation of precursor
amorphous calcium phosphate to hydroxyapatite.
Studies have shown that there is a good correlation between the ability of
a compound to prevent hydroxyapatite crystalline growth in vitro and its
ability to prevent calcification in vivo.
A substantial number of different types of compounds and compositions have
been developed for use as antibacterial, and antiplaque and anticalculus
agents in oral compositions, including for example such cationic materials
as the bisbiguanide compounds and quaternary ammonium compounds, e.g.
benzethonium chloride and cetyl pyridinium chloride, disclosed in U.S.
Pat. No 4,110,429. These cationic materials however tend to stain the
teeth with continued use.
It is an object of this invention to provide an improved anticalculus oral
composition which will have relatively little or no tendency to stain the
teeth.
A further object of the invention is to provide an oral composition which
inhibits the transformation of amorphous calcium phosphate to
hydroxyapatite crystal structure normally associated with calculus.
Another object of this invention is the provision of an improved method for
inhibiting the formation of calculus.
Other objects and advantages will appear as the description proceeds.
In accordance with certain of its aspects, this invention relates to an
oral composition comprising oral (orally acceptable) vehicle containing in
an effective amount as an anticalculus agent a
2-phosphono-butane-1,2,4-tricarboxylic acid (PBTA) compound, of the
formula
##STR1##
wherein R is hydrogen, lower alkyl or carboxyl, and R.sup.1 is hydrogen or
methyl, or an orally acceptable salt thereof, preferably water soluble,
such as with an alkali metal (e.g. sodium and potassium), ammonium,
C.sub.1 -C.sub.18 mono-, di- and tri-substituted ammonium (e.g. alkanol
substituted such as mono-, di- and tri-ethanolammonium) cation.
Compounds of the above formula, and methods for their production, are
disclosed in U.S. Pat. Nos. 3,886,204 and 3,886,205, which disclosures are
incorporated herein by reference thereto. The preferred PBTA compound for
use in the present invention is the unsubstituted compound of the above
formula (I) in which R and R.sup.1 are each hydrogen. When R is lower
alkyl, it preferably contains 1 to 4 carbon atoms, especially methyl.
The concentration of the PBTA compound (or salt) in the oral compositions
can range widely, typically upward from about 0.01% by weight, with no
upper limit on the amount that can be utilized except as dictated by cost
or incompatibility with the vehicle. Generally, concentrations from about
0.01% to about 10% and preferably about 0.1% to about 3% by weight are
utilized. Oral compositions which in the ordinary course of usage could be
accidentally ingested preferably contain lower concentrations of the PBTA
compound. Thus, a mouthwash in accordance with this invention preferably
contains less than about 1.5% by weight of the PBTA compound. Other
dentifrice compositions, topical solutions and prophylactic pastes, the
latter to be administered professionally, can preferably contain about
0.1% to 2% by weight of the PBTA compound.
The PBTA compounds of this invention are anti-nucleating agents, oral
compositions of this invention containing them are effective in reducing
formation of dental calculus without unduly decalcifying the dental
enamel, and in contrast to the above-mentioned cationic antibacterial,
antiplaque and anti-calculus agents, such PBTA compounds and compositions
have little or no tendency to stain the teeth.
The PBTA compounds and compositions of this invention have additionally
been found to effectively reduce or inhibit gingivitis.
In certain highly preferred forms of the invention the oral composition may
be substantially liquid in character, such as a mouthwash or rinse. In
such a preparation the vehicle is typically a water-alcohol mixture
desirably including a humectant as described below. Generally, the ratio
of water to alcohol is in the range of from about 1:1 to about 20:1,
preferably about 3:1 to 10:1 and most preferably about 4:1 to about 5:1,
by weight. The total amount of water-alcohol mixture in this type of
preparation is typically in the range of from about 70% to about 99.9% by
weight of the preparation. The pH of such liquid and other preparations of
the invention is generally in the range of from about 4.5 to about 9 and
typically from about 5.5 to 8. The pH is preferably in the range of from
about 6 to about 8.0. It is noteworthy that the compositions of the
invention may be applied orally at a pH below 5 without substantially
decalcifying dental enamel. The pH can be controlled with acid (e.g.
citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered
(as with phosphate buffers). Such liquid oral preparations may also
contain a surface active agent and/or a fluorine-providing compound.
In certain other desirable forms of this invention, the oral composition
may be substantially solid or pasty in character, such as toothpowder, a
dental tablet, a toothpaste or dental cream. The vehicle of such solid or
pasty oral preparations generally contains polishing material. Examples of
polishing materials are water-insoluble sodium metaphosphate, potassium
metaphosphate, tricalcium phosphate, dihydrated calcium phosphate,
anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium
orthophosphate, trimagnesium phosphate, calcium carbonate, alumina,
hydrated alumina, aluminum silicate, zirconium silicate, silica,
bentonite, and mixtures thereof. Preferred polishing materials include
silica gel or colloidal silica, complex amorphous alkali metal
aluminosilicate and hydrated alumina.
Alumina, particularly the hydrated alumina sold by Alcoa as C333, which has
an alumina content of 64.9% by weight, a silica content of 0.008%, a
ferric oxide content of 0.003%, and a moisture content of 0.37%, at
110.degree. C., and which has a specific gravity of 2.42 and a particle
size such that 100% of the particles are less than 50 microns and 84% of
the particles are less than 20 microns, is very effective.
When visually clear gels are employed, a polishing agent of colloidal
silica, such as those sold under the trademark SYLOID as Syloid 72 and
Syloid 74 or under the trademark SANTOCEL as Santocel 100 and alkali metal
aluminosilicate complexes are particularly useful, since they have
refractive indices close to the refractive indices of gelling agent-liquid
(including water and/or humectant) systems commonly used in dentifrices.
Many of the so-called "water-insoluble" polishing materials are anionic in
character and also include small amounts of soluble material. Thus,
insoluble sodium metaphosphate may be formed in any suitable manner, as
illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th
Edition, pp. 510-511. The forms of insoluble sodium metaphosphate known as
Madrell's salt and Kurrol's salt are further examples of suitable
materials. These metaphosphate salts exhibit a minute solubility in water,
and therefore are commonly referred to as insoluble metaphosphates. There
is present therein a minor amount of soluble phosphate material as
impurities, usually a few percent such as up to 4% by weight. The amount
of soluble phosphate material, which is believed to include a soluble
sodium trimetaphosphate in the case of insoluble metaphosphate, may be
reduced by washing with water if desired. The insoluble alkali metal
metaphosphate is typically employed in powder form of a particle size such
that no more than about 1% of the material is larger than about 37
microns.
The polishing material is generally present in amounts ranging from about
10% to about 99% by weight of the oral preparation. Preferably, it is
present in amounts ranging from about 10% to about 75% in toothpaste, and
from about 70% to about 99% in toothpowder.
In the preparation of toothpowders, it is usually sufficient to admix
mechanically, e.g., by milling, the various solid ingredients in
appropriate quantities and particle sizes.
In pasty oral preparations the PBTA compound should be compatible with the
other components of the preparation. Thus, in a toothpaste, the liquid
vehicle may comprise water and humectant typically in an amount ranging
from about 10% to about 90% by weight of the preparation. Glycerine,
propylene glycol, sorbitol, or polyethylene glycol 400 may also be present
as humectants or binders. Particularly advantageous liquid ingredients
comprise mixtures of water, glycerine and sorbitol.
In clear gels where the refractive index is an important consideration,
about 3-30% by weight of water, 0 to about 80% by weight of glycerine, and
about 20-80% by weight of sorbitol is preferably employed. A gelling
agent, such as natural or synthetic gums or gum-like materials, typically
Irish moss, sodium carboxymethylcellulose, methyl cellulose, or
hydroxyethyl cellulose, may be employed. Other gelling agents which may be
employed include gum tragacanth, polyvinylpyrrolidone and starch. They are
usually present in toothpaste in an amount up to about 10% by weight,
preferably in the range of from about 0.5% to about 5%. The preferred
gelling agents are methyl cellulose and hydroxyethyl cellulose. In a
toothpaste or gel, the liquids and solids are proportioned to form a
creamy or gelled mass which is extrudable from a pressurized container or
from a collapsible, e.g., aluminum or lead, tube.
The solid or pasty oral preparation which typically has a pH measured on a
20% slurry of about 4.5 to 9, generally about 5.5 to about 8 and
preferably about 6 to about 8.0, may also contain a surface active agent
and/or a fluorine-providing compound.
It will be understood that, as is conventional, the oral preparations are
to be sold or otherwise distributed in suitable labelled packages. Thus a
jar of mouthrinse will have a label describing it, in substance, as a
mouthrinse or mouthwash and having directions for its use; and a
toothpaste will usually be in a collapsible tube, typically aluminum,
lined lead or plastic, or other squeeze dispenser for metering out the
contents, having a label describing it, in substance, as a toothpaste or
dental cream.
Organic surface-active agents are used in the compositions of the present
invention to achieve increased prophylactic action, assist in achieving
thorough and complete dispersion of the anticalculus agent throughout the
oral cavity, and render the instant compositions more cosmetically
acceptable. The organic surface-active material is preferably anionic,
nonionic or ampholytic in nature, and it is preferred to employ as the
surface-active agent a detersive material which imparts to the composition
detersive and foaming properties. Suitable examples of anionic surfactants
are water-soluble salts of higher fatty acid monoglyceride monosulfates,
such as the sodium salt of the monosulfated monoglyceride of hydrogenated
coconut oil fatty acids, higher alkyl sulfates, such as sodium lauryl
sulfate, alkyl aryl sulfonates, such as sodium dodecyl benzene sulfonate,
higher alkyl sulfoacetates, higher fatty acid esters of 1,2 dihydroxy
propane sulfonate, and the substantially saturated higher aliphatic acyl
amides of lower aliphatic amino carboxylic acid compounds, such as those
having 12 to 16 carbons in the fatty acid, alkyl, or acyl radicals, and
the like. Examples of the last mentioned amides are N-lauroyl sarcosine,
and the sodium, potassium, and ethanolamine salts of N-lauroyl,
N-myristoyl, or N-palmitoyl sarcosine which should be substantially free
from soap or similar higher fatty acid material. The use of these
sarcosinate compounds in dentifrice compositions of the present invention
is particularly advantageous since these materials exhibit a prolonged and
marked effect in the inhibition of acid formation in the oral cavity due
to carbohydrate breakdown in addition to exerting some reduction in the
solubility of tooth enamel in acid solutions.
Examples of water-soluble nonionic surfactants are condensation products of
ethylene oxide with various reactive hydrogen-containing compounds
reactive therewith having long hydrophobic chains (e.g. aliphatic chains
of about 12 to 20 carbon atoms), which condensation products
("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as
condensation products of poly (ethylene oxide) with fatty acids, fatty
alcohols, fatty amides, polyhydric alcohols (e.g. sorbitan monosterate)
and polypropyleneoxide (i.e. Pluronic materials).
In certain forms of this invention a fluorine-providing compound is present
in the oral preparation. These compounds may be slightly soluble in water
or may be fully water-soluble. They are characterized by their ability to
release fluoride ions in water and by substantial freedom from reaction
with other compounds of the oral preparation. Among these materials are
inorganic fluoride salts, such as soluble alkali metal, alkaline earth
metal and heavy metal salts, for example, sodium fluoride, potassium
fluoride, ammonium fluoride, a copper fluoride such as cuprous fluoride,
zinc fluoride, a tin fluoride such as stannic fluoride or stannous
chlorofluoride, barium fluoride, sodium fluorsilicate, ammonium
fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate,
aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium
pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous
fluorides, sodium monofluorophosphate and mixtures thereof, are preferred.
The amount of the fluorine-providing compound is dependent to some extent
upon the type of compound, its solubility, and the type of oral
preparation, but it must be a nontoxic amount. In a solid oral
preparation, such as toothpaste or toothpowder, an amount of such compound
which releases a maximum of about 1% by weight of the preparation is
considered satisfactory. Any suitable minimum amount of such compound may
be used, but it is preferably to employ sufficient compound to release
about 0.005% to 1%, and preferably about 0.1% of fluoride ion. Typically,
in the cases of alkali metal fluorides and stannous fluoride, this
component is present in an amount up to about 2% by weight, based on the
weight of the preparation, and preferably in the range of about 0.05% to
1%. In the case of sodium monofluorophosphate, the compound may be present
in an amount up to 7.6% by weight, more typically about 0.76%.
In a liquid oral preparation such as a mouthwash, the fluorine-providing
compound is typically present in an amount sufficient to release up to
about 0.13%, preferably about 0.0013% to 0.1% and most preferably about
0.0013% to 0.5%, by weight, of fluoride ion.
Various other materials may be incorporated in the oral preparations of
this invention such as whitening agents, preservatives, silicones,
chlorophyll compounds, other anticalculus agents, antibacterial antiplaque
agents, and/or ammoniated material such as urea, diammonium phosphate, and
mixtures thereof. These adjuvants, where present, are incorporated in the
preparation in amounts which do not substantially adversely affect the
properties and characteristics desired.
Any suitable flavoring or sweetening material may also be employed.
Examples of suitable flavoring or sweetening material may also be
employed. Examples of suitable flavoring constituents are flavoring oils,
e.g., oil of spearmint, peppermint, wintergreen, sassafras, clove, sage,
eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate.
Suitable sweetening agents include sucrose, lactose, maltose, sorbitol,
xylitol, sodium cyclamate, perillartine, APM (aspartyl phenylanine, methyl
ester), saccharine and the like. Suitably, flavor and sweetening agents
may together comprise from about 0.01% to 5% or more of the preparation.
In preparing the oral compositions of this invention, it is preferred but
not essential to add the PBTA after the other ingredients (except perhaps
some of the water) are mixed or contacted with each other to avoid a
tendency for the PBTA to be precipitated.
For instance, a mouthrinse or mouthwash may be prepared by mixing ethanol
and water with flavoring oil, surfactant, humectant, gum or thickener such
as sodium carboxymethylcellulose or hydroxyethyl cellulose, and sweetener
and adding thereto polishing agent, flavor, additional water, and then the
PBTA compound.
In the practice of this invention an oral composition according to this
invention such as a mouthwash or toothpaste containing the PBTA compound
in an amount effective to inhibit calculus on dental surfaces is applied
regularly to dental enamel, preferably from about 5 times per week to
about 3 times daily, at a pH of about 4.5 to about 9, generally about 5.5
to about 8, preferably about 6 to 8.
The following examples are further illustrative of the nature of the
present invention, but it is understood that the invention is not limited
thereto. All amounts and proportions referred to herein and in the
appended claims are by weight unless otherwise indicated.
EXAMPLE 1
Inhibition of Crystal Growth of HAP
This is evaluated by a pH Stat method. 1.0 ml of an aqueous solution of
1.times.10.sup.-4 M to 1.times.10.sup.-5 M of the anticalculus agent being
tested and 0.1 M sodium dihydrogen phosphate is placed in a reaction flask
with 22 to 23 ml. of distilled water with continuous stirring in an
atmosphere of nitrogen. To this is added 1 ml. of 0.1 M CaCl.sub.2 and the
pH adjusted to 7.4.+-.0.05 with NaOH (final conc. of Ca.sup.++ and
PO.sub.4.sup.3- =4.times.10.sup.-3 M). Consumption of 0.1 N NaOH is
recorded automatically by a pH Stat (Radiometer). In this test, the
formation of HAP occurs in 2 distinct phases. First rapid base consumption
(1-4 min.) then diminishes until 15-20 minutes when second rapid uptake
takes place. A delay in the time of second rapid consumption or a total
absence of the second rapid consumption indicates an interference with the
crystal growth of HAP. Agents which interfere with HAP crystal growth are
effective anticalculus agents. When PBTA is tested by the foregoing
procedure, the following results are obtained.
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Anticalculus Time for Delay in
Agent (cone) HAP Formation HAP Formation
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Water (control)
15 min. --
PBTA (4 ppm) 25 min. 10 min.
PBTA (8 ppm) 75 min. 60 min.
PBTA (10 ppm)
129 min. 114 min.
PBTA (20 ppm)
33.8 hrs.
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The above results show that PBTA effectively inhibits crystal growth of HAP
in vitro and that the inhibition is not due to complexation or chelation
of calcium since sub-stoichiometric ratios of PBTA:calcium are employed.
In the following examples illustrative of mouthwash formulations according
to the invention, Pluronic F108 is a polyoxyalkylene block polymer.
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Example
2 3 4 5
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Flavor 0.22% 0.22% 0.22% 0.22%
Ethanol 15.0 15.0 15.0 15.0
Pluronic F108
3.0 3.0 3.0 3.0
Glycerine 10.0 10.0 10.0 10.0
Na Saccharin
0.03 0.03 0.03 0.03
PBTA 0.1 0.2 0.5 1.0
Water q.s. to
100 100 100 100
pH (with NaOH)
7.4 7.4 7.4 7.4
Appearance Clear Clear Clear Clear
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The following examples are illustrative of anticalculus toothpastes
according to the invention:
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Example
6 7
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Silica 30 30
Glycerine 16 16
Sorbitol (70%) 6 6
Pluronic F-108 3 3
Hydroxyethyl cellulose
1.2 1.2
PBTA 2 2
Sodium saccharin 0.17 0.17
Flavor 0.8 0.8
Water q.s. to 100 100
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This invention has been described with respect to preferred embodiments and
it will be understood that modifications and variations thereof obvious to
those skilled in the art are to be included within the spirit and purview
of this application and the scope of the appended claims.
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