Note: Descriptions are shown in the official language in which they were submitted.
'~
This invention relates to an antibacterial oral eomposition which ~'
promotes oral hygiene.
Cationic antibacterial materials are well known in the art as indi-
cated in a section on "Quaternary Ammonium and Related Compounds" in the
article on "Antiseptics and Disinfectants" in Kirk-Othmer Encyclopedia of
Chemical Technology 2nd edition (Vol. 2, p. 632-635). Cationic materials
which possess antibacterial activity (i.e. are germicides) are used against
bacteria. As bacteria are present in the oral cavity and lead to plaque
formation, cationic antibacterial agents have been used in oral compositions
to counter plaque formation.
Among the most common of these antibacterial antiplaque quaternary
ammonium compounds is benzethonium chloride, also known as Hyamine 1622 or
di-iso butyl (phenoxyethoxyethyl dimethyl benzyl ammonium chloride). In an
oral preparation this material is highly effective in promoting oral hygiene
by reducing formation of dental plaque and calculus. Reduction of plaque
and calculus is generally accompanied by reduction in caries formation. Other
cationic antibacterial agents of this type are those mentioned, for instanoe~
in United States Patents 2~982,639; 3,325,402, 3,703,583; and 3,431,208 and
British Patent 1,319,396.
Other antibacterial antiplaque quaternary ammonium compounds include
those in which one or two of the substituents on the quaternary nitrogen has a
carbon chain length (typically alkyl group) of some 8 to 20, typically 10 to
18, carbon atoms while the remaining substituents have a lower number of
carbon atoms (typically alkyl or benzyl group), such as 1 to 7 carbon atoms,
typically methyl or ethyl groups. Dodecyl trimethyl ammonium bromide, benzyl ~ ;
dimethyl stearyl ammonium chloride, cetyl pyridinium chloride and quaternized
5-amino-1,3-bis (2-ethyl-
Trade Mark ,
-- 1 ~ ~
:~:
~ 71~9~ ~
hexyl~-5-methyl hexa hydro-pyrimidine are typical quaternary am-
monium antibacterial agents. ~;
Other types of cationic antibacterial agents which are
desirably incorporated in oral compositions to promote oral
hygiene by reducing plaque formation are the amidines such as ;
th~bstituted guanidines e.g. chlorhexidine and the corre-
sponding compound, alexidine, having 2-ethylhexyl groups instead
of chlorphenyl groups and other bis-biguanides such as those
described in German patent application P 2,332,383 published
January 10~ 1974, which sets forth the following formula:
R NH NH NH NH R'
l ll 11 11 \1 I
A-~X)z-N-C-NH-C-NH~CH2)n-NH-C-NH-C-N-~X')zl-A'
in which A and A' signify as the case may be either (1) a phenyl
radical, which as subs*ituent can contain up to 2 alkyl or alkoxy
groups with 1 up to about 4C-atoms, a nitro group or a halogen
atom, (2) an alkyl group which contains 1 to about 12 C-atoms, ~,
or ~3) alicyclic groups with 4 to about 12C-atoms, X and X' as
the case may be may represent an alkylene radical with 1-3C-atoms,
z and z' are as the case may be either zero or 1, R and R' as the
case may be may represent either hydrogen, an alkyl radical with
1 to about 12C-atoms or an aralkyl radical with 7 to about 12C-
atoms, n is a ~hole number o 2 to inclusively 12 and the poly-
methylene chain ~C~l2)n can be interrupted by up to 5 ether,
thioether, phenyl- or naphthyl groups; these are available as
pharmaceutically suitable salts. Additional substituted guanidines
are: N'-~4-chlorobenzyl)-N5-(2,4-dichlorobenzyl) biguanide; p-
chlorobenzyl biguanide, 4-chlorobenzhydryl guanylurea; N-3-
lauroxypropyl-N5-p-chlorobenzyl biguanide; 5,6-dichloro-2-
guanidobenzimidazole; and N-p-chlorophenyl-N5-laurylbiguanide.
The long chain tertiary amines also possess antibacterial
and antiplaque activity. Such antibacterial agents include
-- 2 --
~ 37q~ 8 ~
tertiary amines having one fatty alkyl group (typically 12 to 18 ;~
carbon atoms) and 2 poly(oxyethylene) groups attached to the
nitrogen (typically containing a total o~ from 2 to 50 ethenoxy
groups per molecule) and salts thereof with acids and compounds
of the structure: (CH2cH2o)xH ;
(CH2cH2o)zH /
R-N-CH2CH2CH2N ~ ~`
(cH2cH2o)yH
wherein R is a fatty alkyl group containing 12 to 18 carbon atoms
and x, y and z total 3 or higher, as well as salts thereof.
Generally, cationic agents are preferred for their antiplaque -
effectiveness.
The antibacterial antiplaque compound is preferably one
which has an antibacterial activity such that its phenol coef-
ficient is well over 50, more preferably well above 100, such as
above about 200 or more for S. aureus; for instance the phenol
coefficient (A.O.A.C.) of benzethonium chloride is given by the
manufacturer as 410, for S. aureus. The cationic antibacterial
agent will generally be a monomeric ~or possibly dimeric)
material of molecular weight well below 2,000, such as less than ;
about 1,000. It is, however, within the broader scope of the
invention to employ a polymeric cationic antibacterial agent. ~ I
The cationic antibacter.ial is preferably supplied in the ~orm o
an orally acceptable salt thereof, such as the chloride, bromide,
sulfate, alkyl sulfonate such as methyl sulfonate and ethyl sul-
~onate~ phenylsulfonate, such as p-methyphenyl sulfonate,
nitrate, acetete, gluconate, etc.
The cationic antibacterial agents and long chain tertiary
amine antibacterial agents effectively promote oral hygiene, par-
ticularly by removing plaque. However, their use has been ob-
served to lead to staining of dental surfaces or discoloration
~ 3 ~
:
other than that which occurs from normal contact of dental sur-
faces with foods, beverages, tobacco etc.
The Teason for the formation of such dental stain in the
presence of antibacterial antiplaque agent has not been clearly
established. Human dental enamel is normally covered by a pro-
teinaceous pellicle derived from saliva protein over which there
may be a layer of bacterial plaque. The enamel contains a high
proportion ~about 95%) of hydroxyapatite which includes Cat2 and
P04 3 ions. In the absence of dental plaque additional Cat2 and
P04 3, particularly from saliva, can be deposited on tooth pel-
licle on the enamel and such deposits can include color bodies
which ultimately stain the tooth as a calcified deposit thereon.
It can be that as the cationic or long chain tertiary amlne
antibacterial agents remove plaque they also denature protein
from saliva in the oral environment and the denatured protein can
then act as a nucleating agent in which Ca+2 and PO4 3ions are
deposited and then crystallized as hydroxyapatite. Small crystals
of hydroxyapatite provide a high surface area upon which tooth
stain or discoloration is retained.
Previously employed additives which reduced dental staining
by cationic antibacterial antiplaque agents also generally
reduced the activity of the antibacterial agents or its ability
to act on dental plaque to measurable degrees. ~urther Victamide
~e.g., Victamine C) which is the condensation product of ammonia
with phosphous pentoxide actually increases staining even in the
absence o a cationic antibacterial antiplaque agent and it and
other known phosphous containing agents such as disodium-ethane-
l-h~droxy-l, l-diphosphonic acid (EHDP) salt precipitate in the
presence of antibacterial agent such as bis-biguanido compound,
thereby reducing the antiplaque effectiveness of the antibacterial
agent.
* Trade Mark 4
9~ ,
Moreover, a number of additives have been proposed to
retard "natural" discolorations, i.e., the discolorations which
occur as a result of contact between the teeth and the usual
foods and beverages. Such normal stain has been attributed to
ferric and manganous ions. Accordingly, published German
Application 26 13 5~0 taught the use of chelating agents having
relatively high a~finity for iron and manganese but relatively
low for calcium (a principal componen~ of dental enamel).
Preferred chelating agents therein were maltol, kojic acid,
thylene diamine diacetic acid (EDDA) and calcium dihydrogen
ethylene diamine tetraacetate (Ca-EDTA) and water-soluble
pharmaceutically acceptable salts thereof. However, the
chelating activity of such agents or other agents mentioned in
that disclosure appears to be unrelated to the ability of an
agent to retard dental stain which occurs due to the antibac-
terial antiplaque agent. Indeed, chelating agents such as maltol
and the calcium disodium salt of EDTA are essentially without
effect in reducing stain formed in the presence of antibacterial
antiplaque agent such as cetyl pyridinium chloride. This may be
attributable to the lack of antinucleation properties of che-
la~ing agents such as maltol and calcium disodium EDTA.
It is an advantage of this invention that an antinucleating
additive is provided which prevents the staining of dental enamel
resulting from the use of the cationic or long chain tertiary
` amine antibacterial agent without substantially adversely af-
fecting antibacterial and antiplaque activity of such agent. Other
advantages will be apparent from consideration of the following
disclosure.
- 5 -
' .
:, 10~
In accordance with the present invention there is provided an oral
composition comprising an oral ~ehicle~ about 0.001% to about 15% by weight
based on its free base form of a nitrogen containing antibacterial anti-
plaque agent selected from the group consisting o~ cationic antibacterial anti-
plaque agent and long chain amine antibacterial antiplaque agent containing a
fatty alkyl group of 12 to 18 carbon atoms and at least about 0.01% by weight
of a water soluble polyamine polyphosphonic compound of the formula:
X203P-H2C \ / 2 P03X2
N~~CH2)n~N
X203P-H2C / \ CH2~P03X2
wherein n is a number from 1 to 10 and X is selected from the group consisting
of hydrogen and an orally acceptable cation and said polyamine polyphosphonic
compound reduces stain formed by said nitrogen containing antibacterial anti-
plaque agent. When X is an orally acceptable cation it may be alkali metal
(e.g., sodium and potassium), ammonium, Cl~C18 mono-, di- and tri-substituted
ammonium (e.g., mono-, di- and tri-ethanolammonium) salts.
Antibacterial agents which are cationic or long chain amine germi-
cides which may be employed in the practice of this invention are described
above. They are typically employed in amounts such that the oral product con-
tains between about 0.001% and 15% by weight of the agent. Preferably for
desired levels of antiplaque effect, the finished oral product contains about
0.01 to about 5%, and most preferably about .025% to 1.0% by weight of the
agent. These amounts refer to the quantity of the free base Eorm of the
agent.
The stain which generally occurs on dental enamel is unexpectedly
prevented when the polyanline polyphosphonic acid or water-soluble salt thereo~,
is employed. These materials are anti-nucleating agents. In themselves (even
in the absence of cationic antiplaque antibacterial agents) they are effective
to reduce formation of dental calculus without unduly decalcifying enamel.
However, not all anti-nucleating agents are effective
to prevent stain by cationic antibacterial agents are permitting
such agents to retain their antiplaque activity. For instance,
antiplaque activity o cationic antibacterial agent is substan-
tially reduced in the presence of E~IDP.
The polyamine polyphosphonic compounds which are most
preferred are ethylenediamine tetra(methylenephosphonic acid),
~hereinafteT EDITEMPA) and its water-soluble salts, (e.g., so-
dium, potassium, and ammonium and other pharmaceutically
acceptable salts; most preferably the tri-, ~etra- or penta-
sodium salts). Other polyamine polyphosphonic compounds include:
tetramethylenediamine tetra~methylenephosphonic acid), penta-
methylene diamine tetra ~methylenephosphonic acid), octa- '~
methylenediamine tetra~methylenephosphonic acid) and the water-
soluble salts of these acids, e.g., sodium, potassium, ammonium
and other pharmaceutically acceptable salts. It is noted that
EDITEMPA and its water-soluble salts are among the chelating
agents disclosed for retarding normal stain formation which may
involve iron and manganese. However, as mentioned earlier the
stain formed by antibacterial antiplaque agents is quite
different in character and origin from the so-called "natural"
discolorations which occur asa result of contact between the
teeth and the usual oods and beverages.
Mixtures o any o the oregoing polyamine polyphos-
phonates can be used in the practice o this invention.
The polyamine polyphosphonates and suitable salts there-
o can be prepared in any convenient manner, for example,
according to the teachings o United States Patent 3,928~956 or
Moedritzer and Irani~ Journal o Organic Chemistry, May 1966,
pages 1603-1607. ;
The concentration o polyamine polyphosphonates in the
oral compositions can range widely, typically upward from 0.01%
-- 7 --
by weight. There is 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~ by weight are utili~ed. Oral compositions which in the
ordinary course of usage could be accidentally ingested pref-
erably contain lower concentrations of polyamine polyphos-
phonates. Thus, a mouthwash in accordance with this invention
preferably contains less than 3% by weight of polyamine poly-
phosphonate. Dentifrice compositions, topical solutions and
prophylactic pastes, the latter to be administered profession-
ally, can contain from 0.01% to 10% by weight, preferably
from 0.1% to 5% by weight of polyamine polyphosphonate. Most
desirably, the polyamine polyphosphate is present in a molar
excess to the amount of antibacterial antiplaque agent (based
on the free base thereof), in order to best prevent staining
by the antibacterial antiplaque agent.
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. Generally, ~he ratio of
water to alcohol is in the range of from about 1:1 to about
20:1 preferably from 3:1 to 20:1 and most preferably about
17:3, ~yweight. The total amount of water-alcohol mixture in
this type of preparation is typically in the range of Erom
about 70% to about 99.9% by weight of the preparation. The
pH of such liquid preparations is generally in the range of
Erom about 4.S to about 9 and typically from about 5.5 to 8.
The p~l is preferably in the range of from about 6 to about
8,0. It is noteworthy that the composition of the invention
permits the use of the polyamine polyphosphate at a pH
below 5 without substantially decalcifying dental enamel.
-- 8 --
g~70~
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 a toothpowder, a dental tablet or a tooth-
paste or dental cream. The vehicle of such solid or pasty -
oral preparations 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,
æirconium silicates, silica, bentomite, and mixtures thereof. /'~`
Preferred polishing materials include crystalline silica
having particle sizes of up to 5 microns, a mean particle size
of up to 1.1 microns, and a surface area of up to 50,000
cm2/gm, silica gel, complex amorphorus alkali metal alumino- -
silicate and hydrated alumina (e.g., alpha-alumina trihydrate).
Alumina, particularly the alpha-alumina trihydrate 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 110C, and which
has a specific gravity of 2.42 and a particle size such that
100% o~ the particles are less than 50 microns and 84% of the
particles are less than 20 microns, is particularly desirable.
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-
~ ~:
` ~
~ 7~
liquid ~including water and/or humectant) systems commonly used ;~ ~
in dentifrices. ~ ;
~ any o 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 so~luble phosphate material as impurities, usually a
few percent such as up to 4% by weight. The amount o:E solublc
phosphate material, which is believed to include a soluble
sodium trimetaphosphate in the case of insoluble sodium meta-
phosphate, 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 1%
of the material is larger than 37 microns. ;
.
It is further noted that the polyamine polyphosphonate
exerts a stabllizing effect on calcium phosphate polishing
material as is disclosed in United States Patent 3,792,152. `
The polishing material is generally present in amounts
ranging from about 20% to about 99% by weight of the oral
preparation. Preerably, it is present in amounts ranging from
about 20% to about 75% in toothpaste, and from about 70~ to
about 99% in toothpowder.
In the preparation of toothpowdersJ it is usually suffi-
cient to admix mechanically, e.g., by milling, the various
solid ingredients in appropriate quantities and particle sizes.
.,
In pasty oral preparations the combination of the anti~
bacterial antiplaque agent and polyamine polyphosphonic
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, sorbitol, or polyethylene glycol 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 hydroxy-
ethyl 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 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
con~ainer or Erom a collapsible, e.g., aluminum or lead, tube.
The solid or pasty oral preparation which typically has
a p~l measured on a 20% slurry of about ~.5 to about 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 suitably
- 11 -
o~
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 collapsibl~ tube, typically aluminum or lined lead, or
other squeeze dispenser for metering out the contents, having
a label describing it, in substance, as a toothpaste or dental
cream.
In oral compositions such as mouthrinses and toothpastes,
a surfactant is often present, e.g.,to promote foaming. It
will be understood that it is preferable to employ nonionic
surfactants rather than their anionic counterparts. Examples
of water-soluble nonionic surfactants are condensation products
of ethylenoxide with various compounds reactive therewith
having long hydrophobic chains (e.g. aliphatic chains of 12
to 20 carbon atoms) which condensation products t"ethoxamers")
have hydrophobic polyoxyethylene moieties, such as condensation
products of ethylene oxide and fatty acids, fatty alcohols,
fatty amides, including alcohols such as sorbitan monostearate
or polypropyleneoxide (that is 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-woluble.
They are characterized by their ability to release fluoride ions
in water and by substantial freedom from reaction with other
compounds ~ the oral preparation. Among there materials are
inorganic fluoride salts, such as soluble alkali metal, alkaline
earth metal and heavy metal salts, for example, sodium fluoride,
potassium fluoride, ammonium fluorideJ lead fluoride, a copper ~:
fluoride such as cuprous fluoride, zinc fluoride, a tin fluoride
such as stannic fluoride or stannous chlorofluoride, barium - -
fluoride, sodium fluorosilicate, ammonium fluorosilicate,
* Trade Mark - 12 -
. . . ' ~ 1 , . . '; ;. ,' , ' ; ` . ' I .
sodium fluorozirconate, sodium monofluorophosphate, aluminum
mono- and di- fluorophosphate. Alkali metal and tin fluorides, `;
such as sodium and stannous fluorides, sodium monofluorophosphate
and mixtures thereo~, are preferred. A mixture of sodium `
fluoride and sodium monofluorophosphate is particularly desirable.
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 a toothpaste or tooth-
powder, an amount of such compound which releases a maximum
of ab~ut 1% by weight of the prepara-tion is considered satis-
factory. Any suitable minimum amount of such compound may be
used, but it is preferable to employ sufficient compound to ;~
release from 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 2% by weight, based on the weight of the preparation, and
preferably in the range of from 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 0.76%. When
present in mixture the ratio of sodium monofluorophosphate to
sodium fluoride is desirably about 1:1 to 3:1 based on fluorine
provided by each.
In a liquid oral preparation such as a mouthwash, the
~uorine-providing compound is typically present in an amount
sufficient to release up to 0.13%, preferably from 0.0013% to
0.1% and most preferably from 0.0013% to 0.05%, by weight, of
flouride ion.
Various other materials may be incorporated in the oral
preparations of this invention. Examples are whitening agents,
preservatives, silicones, chlorophyll compounds, and ammoniated
- 13 -
- . - : . .: , . :
, , , ,, " , ; , , , , , ,, : , , ~,:
material such as urea, diammonium phosphate, monoammonium gly-
crrhizinate and mixtures thereof. These adjuvants, where
present, are incorporated in the preparations in amounts which
do not substantially adversely affect the properties and charac- ;
teristics desired.
Any 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, sodium cyclamate,
perillartine, and sodium saccharin. Suitably, flavor and
sweetening agents may together comprise from 0.01% to 5% or more
of the preparations.
Oral preparations of the invention may be prepared by
dispersing the cationic antibacterial agent and the polyamine
polyphosphonic compound in an oral vehicle which typically includes
water.
For instance, a mouthrinse or mouthwash may be prepared by
mixing ethanol and water with flavoring oil, nonionic suractant,
humectant, cationic antibacterial antiplaque agent, such as
ben~ethonium chloride, ce~yl pyridinium chloride or chlorhexidine,
sweetener and color and then adding the polyamine polyphosphonic
compound, such as ED~TEMPA or a water-soluble salt ~e.g., tri-
tetra- or penta- sodium salt) thereof and a~ditional water as desired.
It is desirable to add the polyamine polyphosphonate after the other
ingredients are contacted with each other.
A toothpaste may be prepared by forming a gel with humectant,
gum or thickener such as hydroxyethyl cellulose, sweetener
and adding thereto polishing agent, flavor, antibacterial agent,
such as benzethonium chloride, cetyl pyridinium chloride or
- 14 -
chlorhexidine~ and additional water, followed by addition o~
flavoring oil and the polyamine polyphosphonic compound such
as F~ITEMPA or water-soluble salt thereof. It is preferable
to add the polyamine polyphosphonic compound after the other
components are contacted with each other. If sodium carboxy-
methyl cellulose is employed as the gelling agent the procedure `
of either United States Patent 3,842,168 or United States
Patent 3,843,779, modiied by the inclusion of the polyamine
polyphosphonic compound is followed. ~-
In the practice of this invention an oral composition
such as a mouthwash or toothpaste containing cationic or long
chain amine antibacterial antiplaque agent in amount effective to
promote oral hygiene and polyamine polyphosphonic compound in ~ '
amount efective to reduce staining o dental surfaces otherwise
resulting rom the presence of the antibacterial antiplaque
agent is applied regularly to dental enamel, preferably from -
about 5 times per week to about 3 times daily.
The ollowing specific examples are further illustrative
o the nature of the present invention; but it is understood
that the invention is not limited thereto. The compositions
are prepared in the usual manner and all amounts of the various
ingredients are by weight unless otherwise indicated.
EXAMPLE 1
The following mouthwash is prepared by mixing the ~ol-
lowing ingredients.
Parts
Flavored alcohol 15
Pluronic*F-108 3
Glycerine 10
Benzethonium chloride 0.1
Sodium saccharin 0,03
EDITEMPA trisodium salt
* Trade Mark - 15 -
~37~
water Q.S. to 100
pH 8.0 (adjusted with 5 N sodium hydroxide)
The seve~al ingredients are mixed with the EDITEMPA
trisodium salt and about 10 parts of water being withheld to the
end.
The pH of the mouthwash is also adjusted with 5 N sodium
hydroxide to prepare additional compositions having pH values
of 5.0, 6.6, 6.9, 7Ø With sodium hydroxide~ the pH is 4.6.
As the pH is adjusted the amount of sodium ion associated with
EDITEMPA inherently varies (from 3 to 6).
All compositions are clear without visible evidence of
precipitation. `;
The antiplaque activity and staining levels of the mouth-
washes of the same pH and composition except for the absence of
the polyamine polyphosphonate salt are determined.
Tests are made of the ability of the compositions to in-
hibit in vltro plaque formation by allowing plaque to form
~for 48 hours at 37C) on the surfaces of cleaned and pumiced
teeth in a preinoculated sucrose broth containing Strep mutans.
The pre-grown plaque is then immersed in the test composition
and rinsed with a buffer 1-5 times for one minute each. The `-
teeth carrying the plaque are then transferred to a sucrose broth
containing lmg/100 ml of bromocresol green indicator and incu-
bated at 37C anaerobically for 18 hours~ An antibacterial com- ~;
pound is considered e~fective if the indicator does not turn
yellow (which begins when pH reachas 5.5~ and there is not further
growth of the plaque as judged by the increase in turbidity. It
is found that on the clean teeth, plaque formation and plaque
growth are effectively inhibited.
The tooth staining characteristics of the composition are
tested as follows: Stain Test - 250 mgs. bovine albumin ~crys-
- 16 -
B
:
tallized three times) are added to 2 grams of hydroxy apatite
(HAP) powder (siogel) which serves as a substrate for a stain
while the proteins simulate dental pellicle and provide an ;
"amine source." The mouthrinse is added to the mixture followed
by a 7.5% of buffered acetaldehyde which serves as a carbonyl
source. The mixture is shaken at 37C for 18 hours. The
stained HAP is separated from the solution via filteration and
dried at 37C. The color on the powder is read on Gardner Color -
Difference Meter.
Color levels are determined on a Gardner Color Difference
Meter before and after the test composition is applied to the
colored material.
The antiplaque results reveal that with and without
EDITEMPA salt at each of pH 8.0, 7.0,6.9,6.6, 5.0, and 4.6, the
rinse is active ater 5 rinses with buffer and 3 day plaque
growth and acid produc~ion are inhibited.
, Thus, it is observed that EDITEMPA does not reduce the in
vitro antiplaque activity of benzethonium chloride.
The antistain results are as follows with the mouthwashes
at pH 4.9, 7.0 and 8.0 (these mouthwashes were at pH 5.0, 7.0
and 8.0 before applying to the in vitro stain):
Composition
EDITEMPA sodi~m Reflectance
p~l salt Presence Reflectance Dlfferenco
Control- No EDITEMPA sodium
5.0 to 8.0 salt and no Benze-
thonium Chloride 38.5
5,0 yes 33.9 1.1
5 .0 No 32.8
7.0 Yes 39.8 5.9
7.0 No 33.9
8.0 Yes 40.4 7.0
8.0 No 33.4
- 17 -
Thus, it is observed the EDITEMPA sodium salt substan-
tially reduces stainin~ by ben~ethonium chloride particularly at
pH 7.0 and 8.0 and also to a noted degree at pH 5Ø
Similar antiplaque and antistain results are observed
with corresponding mouthwashes containing 0.05 to 0.1% sodium
salt at pH of 4.8 to 8Ø In mouthwashes of the same formulation
at pH 7 containing 1% cetyl pyridinium chloride and 0.6, 0.9 and
1$, EDITEMPA sodium salt, the cetyl pyridinium chloride remains
active and the stain resulting therefrom is reduced by 12-13
reflectance units.
EXAMPLE 2 -
Mouthwashes similar to those of Example 1 are prepared
except that chlorhexidine diacetate and chlorhexidine digluconate
in amount corresponding to 0~1 part of chlorhexidine free base
and 0.1 part o EDITEMPA sodium salt are present. The p~l o the
mouthwashes without sodium hydroxide adjustment is 5.0 (EDITEMPA
being present as the tetra-sodium salt). These mouthwashes are
active against plaque in vitro after four rinses with the buffer
and inhibit plaque growth and acid as do the corresponding
mouthwashes without EDITEMPA. In the antistain test the stain
level caused when 0.1 part of EDITEMPA is present is less than
the stain level when it is absent. Similar reductions are
observed when 0.05 to 1 part o EDITEMPA are used with the pH
being rom 5.0 to 7Ø
Alexidine also maintains its antiplaque eect witll reduced
staining in the presence o EDITEMPA, as do other antibacterial
antiplaque agents including cetyl pyridinium chloride and a
C12-C18 alkyl tertiary amine o the formula:
CH2CH20H CH2CH20H
cl2-cl8Alkyl-NcH2-cH2N ~ CH2CH2H
- 18 -
98 -:
When EDITEMPA is replaced by other polyamine polyphosphon-
ates including tetramethylene diamine tetra~methylene phosphonic
acid), pentamethylene diamine tetra(methylene phosphonic acid),
hexamethylenediamine tetra(methylene phosphonic acid) and
octamethylenediamine tetra(methylene phosphonic acid) similar
desirable results are obtained.
On the other hand, other antinucleating agents including
Victamide, ethane-l-hydroxy-l,l-diphosphonic acid disodium salt
and 8-hydroxyquinoline precipitate in the presence of the anti-
bacterial antiplaque agen* and reduce its antiplaque effective-
ness. Moreover, Victamide actually increases staining.
EXAMPLE 3
The following mouthrinse is prepared with EDITEMPA and a
portion of the water added last:
Parts
Ethanol 5
Flavor 0.073
Pluronic*F-108 3
Glycerine 10
Sodium saccharin 0-03
Ben~ethonium chloride 0.075
~DITEMPA - trisodium salt 0.75
Water Q.S. to 100
p~l-8.0 (adjusted with 5 N sodium hydroxide)
This mouthwash) a placebo without benzethonlum chloride
and EDITEMPA and a control without EDITE~PA are applied to the
teeth of beagles which are first subjected to dental prophylaxis
to remove existing so~t and hard dental deposits. A disclosing
solution is used to insure complete removal. Three groups of
five beagles each are subjected to gentle oral sprays twice a
day, 5 days a week, for two weeks with the mouthrinses. Plaque
is evaluated after spraying the teeth with disclosing solution.
* Trade Mark - 19 -
: ;,
qO~8
The results are:
Group Mean Plaque % Reduction
Placebo 1.7
0.075 Benzethonium
chloride 1.2 29
0.075 Benzethonium
chloride
0.75 EDITEMPA 1.3 28
Thus, plaque is reduced to essentially the same degree when
EDITEMPA is present as when it is not. The same mouthrinse is
applied to humans, as is the mouthrinse without EDITEMPAJ to
groups of 20 each following dental prophylaxis. Rinsing is
twice a day under supervision, 7 days a week for 6 weeks. The
results in plaque reduction and stain reduction are as follows:
Group Mean Plaque Stain Quotient
:
0.07S% Benzethonium
Chloride 1.685 0.1287
0.075% Benzethonium -
Chloride ~
0.75% EDITEMPA 1.824 0.0851
Thus, the quantity of plaque formation is comparable in
both groups while the amount of stain developed when BDITEMPA
is present is substantially less (33.9%).
While the stain level in both cases is higher than the
stain formed naturally in vivo in the absence of benzethonium
chloride, the presence of the EDITEMPA substantially recluccs
the stain level resulting from the presence of benzethonium
chloride. Similar results are obtained after 12 weeks.
Similar desirable reductions in stain are present when
chlorhexidine and cetyl pyridinium chloride replaces benze-
thonium chloride.
- 20 -
EXAMPLE 4
The following toothpastes with reduced staining from :~
an~iplaque agent~
P A R T S
A B C D E
Hydrated alumina 30 30 42 42 42 -
Anhydrous alumina -- -- 10 10 10
Glycerine 16 16 26 22 22
Sorbitol ~70%) 6 6 -- -- --
Pluronic*F-108 3 3 -- ~- ~~
Polyoxyethylene (20)
sorbitan monoisostearate --- --
P A R T S ~:
A B C D E
Hydroxyethyl cellulose 1.2 1.2 1.3 1.3 1.3
Benzethonium chloride 0.5 ~ -- 0.5 --
Chlorhexidine digluconate ~20%) -- 4.725 -- -- -- ~
Cetyl pyridinium chloride -- -- 0.75 -- 0.75 ..
EDITEMPA (as acid) 1.69 1.69 1.69 1.69 1.69 ' `
Monoammonium glycyrrhizinate -- - -- 0.1 0.1
Sodium saccharin 0.17 0.17 0.2 0.2 0.2
Sodium fluoride -- -- -- -- 0.11
Sodium monofluorophosphate -- -- 0.76 -- 0.76
Flavor 0.8 0.8 1 1 1
Water and Sodium Hydroxide Q .S. ~S. Q.S. Q.S. Q.S. . .to pH 7 ~20% slurry) to 100 to 100 to 100 to 100 to 100
It will be apparent to one skilled in the art that modi-
fications of the above examples may be made thereto.
;: * Trade Mark - 21 -
~: ':.
