Note: Descriptions are shown in the official language in which they were submitted.
1~)95414
This invention relates to an antibacterial oral composition which
promotes oral hygiene.
Cationic antibacterial materials are well known in the art. See,
for instance the 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 and have been used in oral compositions to counter plaque formation
caused by bacteria in the oral cavity.
Among the most common of these antibacterial antiplaque quaternary
ammonium compounds is benzethionium chloride, also known as Hyamine 1622 or
diisobutylphenoxyethoxyethyl 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, which is generally accompa-
nied by a reduction in caries formation and periodontal diseases. Other
cationic antibacterial agents of this type are those mentioned, for instance,
in United States patents 2,984,639, 3,325,402, 3,431,208 and 3,703,583, 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
* Trade ~lark
-- 2 --
.~;
lO9S414
ammonium bromide, benzyl dimethyl stearyl ammonium chloride, cetyl
pyridinium chloride and quaternized 5-amino-1,3-bis (2-ethyl-
hexyl)-5-methyl hexa hydro-pyrimidine are typical quaternary
ammonium antibacterial agents.
Other types of cationic antibacterial agents which are
desirably incorporated in oral compositlons to promote oral
hygiene by reducing plaque ~ormatlon are the amidines such as
the substituted guanidines e.g. chlorhexldine and the corres-
ponding compound, alexldine, having 2-ethylhexyl groups instead
of chlorophenyl group~ and other bis-biguanldes such as those
described in German patent appllcatlon P 2,332,383 published
January 10, 1974, which sets forth the ~ollowing formula:
R:NH NH NH NH`R'
~ A-(X)Z-N-C~NH-C-NH(CH2)n-NH-c-NH-c-N-(x )z -A
ib which A and A' slgni~y a8 the caee may be elther (1) a phenyl
radlcal, which as substltuentscan contaln up to 2 alkyl or alkoxy
groups with 1 up to;about 4C-atoms, a nltro group or a halogen
atom, (2) an alkyl group whlch contalns 1 to about 12 C-atoms, or
(3) allcycllc groups wlth 4 to about 12C-atoms, X and X' as the
case-may be may represent an alkylene radlcal wlth 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 elther hygrogen, an alkyl radical
with~l to about 12C-atoms or an aralkyl radlcal wlth 7 to about
12C-atoms, n 18 a whole number of 2 to lncluslvely 12 and the
polymethylene ch~in (CH2)n can be interrupted by up to 5 ether,
thloether, phenyl- or naphthyl groups; these are available as
pharmaceutically sultable salts. Addltlonal sub~tltuted guanldines
1095414
are: N~-(4-chlorobenzyl)-N5-(2,4-dlchlorobenzyl) biguanlde; p-
chlorobenzyl biguanlde, 4-chlorobenzhydryl guanylurea; N-3-
lauroxypropyl-N5-p-chlorobenzyl biguanlde; 5,6-dlchloro-2-
guanidobenzlmldazole; and N-p-chlorophenyl-N5-laurylblguanlde.
The long chaln tertlary amines also possess antl-
bacterlal and antiplaque activity. Such antlbacterial agents
lnclude tertlary amlnes having one fatty alkyl group ~typlcally
12 to 18 carbon atoms) and 2 poly(oxyethylene) groups attacbed bD
the ni~rogen (typically contalnlng a total Or rrom 2 to 50
ethenoxy groups per molecule) and salts thereof wlth aclds and
compounds Or the structure: i
,
(cH2cH2o)zH CH2CH20)xH ';
R-N-/CH2CH2CH2N` C_
~ cH2cH2o)yH
where R is a fatty alkyl group contalning ~2 to 18 carbon atoms
and x, y and z total 3 or higher, as well as salts thereo~.
Generally, cationic agents are pre~erred for their antiplaque
efrectlveness. ` ;~
The antlbacterlal antlplaque compound 18 prererably one
which has an antibacterial actl~ity such that its phenol co-
efficient 18 well over 50, more preferably well above 100, such
as above about 200 or more ior S. aureus; for lnstance the phenol
coefflcient (A.O.A.C.) o~ benzethonium chloride 18 glven by the
manu~acturer as 410, for S. aureus. me catlonic antlbacteri~l
agent wlll generally be a monomerlc (or posslbly dimerict material
molecular welght well below 2,000, such as less than about 1,000.
~ t
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lO9S41~
It i~, however, within the broader scope of the lnvention to
employ a polymeric cationic antibacterial agent. The cationic
antibacterial is preferably supplied in the form of an orally
accept~ble salt thereof, such as the chloride, bromide, sulfate,
alkyl sulfonate such as methyl sulfonate and ethyl sulfonate,
phenylsulfonate, such as p-methylphenyl sulfonate,-nitra$e,
acetate, gluconate, etc.
The cationic antibacterial agents and long chain
tertiary amine antibacterial agents efrectively promote oral
hygiene, partlcularly by removing plaque. However, their use
has been observed to lead to stalning of dental surraces or f
discoloratlon other than that which occurs from normal contact
of dental surfaces with roods, beverages, tobacco etc.
The reason for the formation Or such dental stain in
the presence of antibacterial antlplaque agent ha~ not been cloarly
established. Human dental enamel is normally covered by a
proteinaceous pellicle (derived from saliYa protein) over which
there may be a layer Or bacterial plaque. The enamel contains
a high proportion (about 95%) of hydroxyapatlte whlch includes
Ca+2 and P04~3 ions. In the absence of dental plaque additional
Ca+2 and P04~3, particularly from saliva, can be deposited on
tooth pellicle on the enamel and such deposits can include color
bodles which ultimately stain the tooth as a calcified deposit
thereon. It can be that as the cationic or long chain tertiary
amine 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
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~09S414
P04 ions 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. Further Victamide (Victamine C) which is the conden-
sation product of ammonia with phosphous pentoxide actually increases staining
even in the absence of a cationic antibacterial antiplaque agent and it and
other known phosphous containing agents such as disodium-ethane-l-hydroxy-
l,l-diphosphonic acid (EHDP) salt precipitate in the presence of antibacterial
agent such as bisbiguanido compound, thereby reducing the antiplaque effective-
ness of the antibacterial agent.
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 agents without
substantially adversely affecting antibacterial and antiplaque activity of
such agent. Other advantages will be apparent from consideration of the
following disclosure.
In accordance with certain of its aspects this invention relates to
an oral composition comprising an oral vehicle, at least one nitrogen contain-
ing antibacterial antiplaque agent selected from the group consisting of
cationic antibacterial antiplaque agent and long chain amine antibacterial
antiplaque agent containing a fatty alkyl group of 12 to 18 carbon atoms and
a stain reducing agent which reduces stain formed by said nitrogen containing
antibacterial antiplaque agent, selected from the group consisting of:
(A) a water soluble quaternary aminoalkylene phosphonic compound of the
formula:
R3-n R' R" pO3 = M 2
* Trade Mark - 6 -
~'
1~9541~1
wherein R is Cl to C20 alkyl, alkenyl, cycloa:Lkyl or aralkyl; R' is Cl to C20
alkyl or alkenyl; R" is Cl to C6 alkylene or alkenylene; n is an integer from
1 to 3; and M is an orally acceptable cation,
(B) a water soluble diphosphono pyrrolidone compound of the formula:
R R
R - C - C - R
X203P ~ C C = O
x2o3p N
R
whèrein the R's are independently H, Cl 6 alkyl or C2 6 hydroxyalkyl and
X is an orally acceptable cation;
(C) a water soluble N-methylene phosphonate compound of the formula:
~ A'
N \ CH2P3X
A"
wherein A' is -CH2CH20H, -CH2COOX or CH2P03X2; A" is -CH2CH20H or -CH2COOX;
A' equals A" when A' is not -CH2P03X2, and X is an orally acceptable cation;
(D) phosphonoacetic acid (PAA), of the formula H203P-CH2-COOH, or an orally
acceptable salt
and (E) a water soluble phosphono-containing compound of the formula:
lO9SA14
fOOH COOH
(a) H-C C R
Rl Rl
wherein Rl is hydrogen, Cl to C4 alkyl or (CH2)1 2 COOH; and R is
/ R1 P3H2
P3H2' C , -C - PO3H2 , -C - R
\ COOH \ Rl CH2 3 2
and mixtures thereof, and preferably of the formula:
(b) CIH2 CH R2
COOH COOH
PO3 2
wherein R2 is -PO3H2 -CH / , and mixtures thereof,
P03H2
or an orally acceptable salt thereof.
The invention also provides a method for preparing the above
defined composition wherein said staining reducing agent is added to the
remaining components of said composition after said components have been
contacted with each other.
Typical orally acceptable cations include H, metal (e.g. sodium
and potassium), ammonium, or Cl-C18 mono-, di- and tri-substituted ammonium
(e.g. alkanol substituted such as mono-, di- and tri-ethanolammonium).
The preferred compounds of Group (A) are those wherein n=3; R' is
lower alkyl of Cl to C6, more preferably Cl to C4, and most preferably methyl;
and R" is methylene. Such compounds have the formula
CH2P03H2
Cl_6 alkyl N ~ CH2PO3H2
CH2P03H
In the above formulae, the cation M may for example be hydrogen,
alkali metal (e.g. sodium, potassium, lithium), ammonium or substituted
ammonium such as Cl 18 mono-, di- or tri-substituted ammonium (e.g. alkanol
substituted such as mono-, di- and tri-ethanolammonium).
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ll~9S4~4
Illu~tratlve operative phosphonocarboxyllc acld~ of~ormula (~ above include:
(a) l-phosphonoethane-1,2-dicarboxyllc acid,
(b) 2-phosphonopropane-2,3-dicarboxylic acid;
(c) 2-pho~phonobutane-2,3-dicarboxylic acid;
(d) l-phosphonopropane-1,2-dicarboxylic acid;
(é) l-phosphonopropane-1,2,3-tricarboxylic acid;
(f) l-phosphonobutane-2,3,4-tricarboxyllc acid;
(g~) 2-phoaphonobutane-2,3,4-tricarboxyllc acid;
(h) l-phosphonobutane-1,2,3-tricarboxylic acid;
(i) 2-phosphonopentane-2~3~4-tricarboxyllc acld;
(~) 1,1-dlphosphonopropane~2,3-dlcarboxylic acid;
(k) 1,1-diphosphonobutane-2,3-dicarboxyllc acid;
(1) 2,2-diphosphonobutane-3,4-dicarboxyllc acid; and
(m) 1,1-dlphosphono-2-methylpropane-2,3-dlcarboxyllc acid.
Compounds (a) and (~) above are preferred.
Antlbacterial agents whlch are catlonlc or long chaln
amlne germlcldes which may be employed in the practice o~ this
invention are descrlbed above. They are typlcally employed ln
amounts such that the oral product contains between about 0.001~ ;
and 15% by weight o~ the agent. Preferably ~or desired levels
of antlplaque ef~ect, the flnlshed oral product contains about
0.01% to about 5%, and most pre~erably about 0.25~ to 1.0% by
welght of the agent. mese amounts refer to the quantlty of
the free base form o~ the agent.
me staln whlch generally occurs on dental enQmel 18
unexpectedly pre~ented when the quaternary amlnoalkylene phos-
phonic acld or water-soluble salt thereof, i8 employed. Theee
_g_
109541~
materials are anti-nucleating agents. [n 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 while permitting such agents to retain the antiplaque
activity.
United States Patent 3,934,002 discloses combining
the above-described bis-biguanide antiplaque agents with various
anticalculus agents, some of which contain phosphono groups,
but none corresponding to the phosphono-containing additives
employed herein.
The additives of Group (A) most preferred are N-
methyl aminotri(methylene phosphonic acid) (hereafter
QUMATMP) and its water-soluble salts, (e.g. sodium, potassium,
and ammonium salts). Other preferred compounds include: N-
ethyl aminotri~methylene phosphonic acid), N-n-propyl aminotri
(methylene phosphonic acid), N-methyl aminotri~ethylene phos-
phonic acid), and the water soluble salts of these acids, e.g.,
sodium, potassium and ammonium salts.
Mixtures of any of the foregoing can be used in the
practice of this invention.
These quaternary aminoalkylene phosphonates can be
prepared in any convenient manner, for example, according to
the teachings of United States Patent 3,925,453.
The phosphono compound of Group (B) which is most
preferred is pyrrolidone-5,5-diphosphonic acid and its water-
soluble salts, (e.g. sodium, potassium and ammonium salts).
.~`f'j_ ~ -
- 10 -
C
l~9S4~9~
Other comp~unds lnclude: N-methyl pyrrolldone-5,5-dlphosphonic
acid, N-ethyl pyrrolidone-5,5-diphosphonic acid, N-isopropyl
pyrrolidone-5,5-diphosphonic acid, N-2 hydroxyethyl pyrrolidone
-5,5-diphosphonic acid and the water soluble salts of these
acids, e g. sodium, potasslum and ammonium salts.
Mixtures of any of the foregoing diphosphono
pyrrolidones can be used in the practice of this invention.
These diphosphono p~rrolidone compounds can be prepared in any
convenient manner, for example, according to the teachings
of published German Specification 2,343,147.
The N-methylene phosphonic compounds of Group (C)
which are most preferred herein are iminodiacetic-N-methylene
phosphonlc acid (hereinafter IDANMPA) and its water-Eoluble
salts, (e.g. sodlum, potassium and ammonium salts). Other
N-methylene phosphonate compounds include: N-carboxymethyl-amlno-
di-methylene phosphonic acid; monoethanol-amlno-di-methylene
phosphonic acid; diethanol-amino-methylene phosphonic acid and
the water soluble salts of these acids, e.g., sodium~ potassium
and ammonium salts.
Mixtures of any of the foregoing can be used in the
practice of th~s invention.
These N-methylene phosphonic acid compounds can be
prepared in any convenient manner, for example, according to
the teachings of British Patent 1,394,035.
me phosphonocarboxylic acids of Group (E) and
suitable salts thereof employed herein can be prepared in any
conveni~nt manner, for example, accordlng-to the teachings of
British Patent 1,394,172.
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1~954il4
The concentration o~ the agent which remove~ stain
caused by the nitrogen centainlng antLbacterial antiplaque agent
in the oral composltlorls can range widely, ~cypically upward
from 0.01~ by weight. There i~ no upper limit on the amount
that can be utillzed except a~ dictated by cost or incompatibility
with the vehicle~ Generally, concentration~ from about 0.01% to
about 10~ by weight are utilized. Oral compositions which in
the ordinary course of usage could be accidentally ingested
preferably contain lower concentrations of the stain reduction
agent. Thus, a mouthwa~h in accordance with this invention
preferably contain~ le~s than 3~ by welght of the stain reduction
agents. Dentifrice composition~, topical solutions and
prophylactic pastes, the latter to be administered professlonally,
can contain from 0.01~ to 10~ by weight, preferably from 0.1~ to
5~ by weight of the staln reduction agent. Most desirably, the
stain reduction agent i8 pre~ent in a molar excess relative to
the amount of antibacterial antiplaque agent (ba~ed on the free
base thereof), ln order to best prevent staining by ~he anti-
bacterlal antiplaque agent.
In certaln highly preferred forms of the invention
oral composition may be substantially liquid in character, such
as a mouthwash or rinse. In such a preparation ~he vehlcle 1B
typically a water-alcohol mixture. Generally, the ratio of water
to alcohol 18 in the range of from about l:l to about 20:1
preferably from 3:1 to 20:1 and most preferably about 17:3, by
weight. me total amount of water-alcoholmi~ture in this type
of preparation 18 typically in the range of from about 70~ to
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109541.4
about 99.9~ by welght of the preparation. The pH of such liquid
preparations 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 ln the
range of from~about 6 to about 8.o. It 16 noteworthy that the
composition of the invention permits the use of these phosphono
compounds at a pH below 5 without substantially decalcifying
dental enamel.
Such liquld oral preparations may also contain a 6urface
active agent and/or a fluorins-provldin~ compound.
In certain other desirable forms of thls invention,
the oral compo6ition may be substantially solid or pasty in
character, such as a toothpowder, a dental tablet or a toothpaste
or dental cream. The vehicle o~ such solld or pasty oral prepara-
tions eontains polishing ma~erial. Examples of polishing materials
are water-insoluble 80diu~ metapho~phate, pota~sium metaphosphate,
tricalcium phosphate, dihydrated calcium phosphate, anhydrous
dicalc um phosphate, ealcium pyrophosphate, magnesium ortho-
phofiphate, trimag~esium phosphats, calcium carbonate, alumina,
hydrated alumina, &l~minum silicate, zirconium 6ilicates, silica,
bentonite, and mixtures thereof. Pre~erred polishing materials
include crystalline silica having pa~ticle sizes of up to 5
microns, a mean particle size o up to l.l microns, and a surface
area of up to 50,000 cm2/gm. silica ~el, complex amorphoru6 alkall
metal aluminosilicate and hyàrated alumina (e.g. alpha-alumina
trihydrate).
Alumina, particularly the alpha-aluminatrihydrate Gold
by Alcoa as C333, which has an alumina content of 64.9% by weight,
* Trade Mark
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loss4l~a
a silica content of o.oo8%, 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% of
the particles are le~ than 50 microns and 84~ of the particles
are less than 20 microns, i8 particularly de6irable.
~ hen vi~ually clear gels are employed, a polishing
agent of colloidal silica5 such as those sold under the trademark
SYLOID as Syloid 72 and Syloid 74 or under the trademark SA~TOCEL
as Santocel 100 and alkali metal ~luminosillcate complexes are
particularly ~se~ul, since they have refractive indice~ close to
the refractive indices of gelling agent-liquid (including water
and/or humectant) system~ commonly used in dentifrices.
Many of the so~called "water-insoluble" poli6hing
material~ are anionic in character and also include small amounts
of soluble material. mus, insoluble sodium metaphosphate may be
formed in any suitable manner, as illustrated by morpe's
Dictionary o~ Applied Chem-lstry, Volume 9, 4th Edition, pp. 510-511.
The forms of insoluble sodium metaphosphate known as Madrell's
salt and ~urrol's salt are further examples of suit~ble materials.
These metaphosphate salts exhibit a minute solubility in water,
and therefore are commonly referred ~o a6 insoluble metaphosphates.
There is present therein a minor amount of soluble phosphate
m~terialsas impurities, usually a few percent such as up to 4
by wei~ht. The amount o4 soluble phosphate material, whlch is
believed to include a ~oluble sodium trimetaphosphate in the case
of insoluble sodium metaphosphate, may be reduced by washing with
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109S414
water lf d2slred. The inæoluble alka:Li metal metapho6phate 1B
typically employed ln powder form of a particle size ~uch that
no more than 1~ o~ the m~ierial is larger than 37 mlcrons.
The polishing mater~al is generally present in amounts
ranglng from about 20~ to about 99~ by welght of the oral prepara-
tion. Preferably, lt is present in amounts ranging from about 20
to about 75~ ln toothpaste, and from about 70% to about 99% ln
toothpowder.
In the preparation of toothpowders, lt i6 uæually
sufflcient to admlx mechanlcally, e.g., by mllling, the varlous
solld lngredlents ln approprlate quantities and particle sizes.
In pasty oral preparations the above described
com~ination of the antibacterial antiplaque agent and phosphonic
compound should be compatible with the other components of the
preparation. Thus, in a toOthpa~te, the liquid vehicle may
comprise water and humectant typically in an amo~nt ranging from
about 10~ to about 90~ by weight of the prepatation. Glycerine,
sorbitol, or polyethylene glycol may also be present as humectants
or binders. Particularly adv~ntageous liquid ingredients comprise
mixtures of water, glycerine and sorbitol.
In clear gels where the refra¢tive index is an important
consideration, about 3-30% by weight of water, O to about 80~ by
weight of glycerine, and about 20-80~ by weight o~ sorbitol iB
preferably employed A gelling agent, such as natural or synthetic
gums or gum-like materials, typically Irish moss, sodium carboxy- ;
methylcellu~ose~ methyl cellulose, or hydroxyethyl cellulose, may
be employed. Other gelling agentæ which may be employed include
-~5-
i
lO9S414
gum tragacanth, polyvinylpyrrolldone and starch They are
usually present in toothpaste in an amount up to 10% by welght,
preferably in the ran~e of from about 0.5~ to about 5%. The
preferred gelling agents are methyl cellulose and hydroxyethyl
cellulose. In a toothpaste or gel, the llq~ids and sollds are
proportioned to form a creamy or gelled mass which 18 extrudable
from a pressurized contalner or ~rom a collapsible, e.g.,
aluminum or lead, tube.
me solid or pasty oral prepatation which-typlcally
has a pH measured on a 20~ slurry of about 4.5 to about 9,
generally about 5.5 to about 8 and preferably about 6 to about
8.o, may also contain a surface active agent and/or a fluorine-
providlng compound.
It will be understood that, as is convention~l, the
oral preparatlons are to be sold or otherwlse ~i~gributed in
suitably labelled packages. Thus a ~ar Or mouthrlnse wlll~lhave
a label describing it, in 6ubstance, as a mouthr1nse or mouthwash
and havlng dlrections for its use; and a toothpaste will usually
be in a collapsible tube, typlcally aluminum or lined lead, or
other squeeze dispenser for metering out the contents, having a
label describing i$, in substance, as a toothpaste or dental cream.
In oral composltions such as mouthrinses and toothpastes,
a surfactant is often present, e.g. to7promote foaming. It will
be understood that it is preferable to employ nonionic surfactants
rather than their anlonic counterparts. Examples of water-~oluble
nonionic surfactants are condensation products of ethyleneoxide
with various compounds reactive therewith having long hydrophobic
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1095'114
chains (e.g. aliphatic chain~ of 12 to 20 carbon ato~ ) which
condensation product~ ("etho~amers") have hydrophi~ic polyoxy-
ethylene moieties, such as conden~atlon products of ethylene oxide
and fatty acids, fatty alcohols, ~atty amides, including alcohols
such as sorbitan monostearate or polypropyleneoxide (that 15
Pluronic materials).
In certain forms of this invention a fluorine-providing
compound i8 present in the oral preparation. These compounds may
be slightly soluble in water or may be fully water-soluble. mey
are characterized by thelr ability to release fluorlde lons in
water and by substantial freedom from reaetion with other compounds
of the oral preparation. Among these materials are lnorganic
fluoride salts, such as soluble alkali metal, alkallne earth
metal and heavy metal salts, for example, sodium fluoride~
potassium fluoride, ammonium fluoride, lead fluoride, a copper
fluoride sueh as cuprous flubride, zinc fluoride, a tin fluoride
sueh as stannic fluoride or stannous chloroflu'oride, barlum
fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium
fluorozirconate, sodium monofluorophosphate, aluminum mono-~and
di-fluorophosphate, and fluorinated soaium calcium pyrophosphate.
Alkali metal and tin fluorides, such as sodium and stannous
fluoride6, sodium monofluorophosphate and mixtures thereof,
particularly of sodium fluoride and sodium monofluorophosphate,
are prefèrred.
me amount of the fluorine-providing compound iB
dependent to some extent upon the type of compound, its ~olubillty,
and the type of oral preparation, but it must be a nontoxic amount.
In a solid oral preparation, such as a toothpaste or toothpowder, an
amount of such compound whieh releases a maximum of about 1% by
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1095414
weight of the preparation is considered satisfactory Any
s~itable minimum amount of such compound may be used, but it is
pre~erable to employ sufficlent compound to release from about
0.005% to 1%, and preferably about 0.1~ o~ fluoride ion. Typically,
in the cases of alkali metal fluorides and atannous fluoride,
this component is preaent 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 7~ When present in mixture the ratio of sodium
monofluorophosphate to sodium fluoride is deslrably abo~t 1:1 to
3:1, based on fluorine provided by each,
In a liquid oral preparation such as a mouthwash, the
fluorine-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
fluoride ion.
Various other materials may be incorporated in the oral
preparations of this invention. Examples are whitening agents,
preservatives, silicones, chlorophyll compounds, and ammoniated
materia} such as urea, diammonium phosphate, and mixtures thereof.
These ad~uvants, where present, are incorporated in the prepara-
tions in amounts which do not substantially adversely ~ffect the
properties and characteristics desired.
Any suitable flavoring or sweet~ning material may also
be employed. Examples of suitable flavoring constituents are
flavoring oilsg e.g., oils of spearmint, peppermint, wintergreen
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1095Ai4
sa~safra3, clove, sage, eucalyptus, mar~oram, cinnamon, lemon,
and orange, and methyl sallcylate Suitable sweetenlng agents
include sucrose, lactose, maltose, sorbltol, sodium cycla~ate,
perillartine, and sodium saccharin. Suitably, flavor and
sweetening agents may together comprise from 0.01~ to 5~ or
more of the preparation.
In prepar$ng the oral compositions of this invention
in an oral vehicle whioh typically includes water, lt iB hlghly
desirable if not essential to add the phosphono additive after
the other ingredients (except perhaps some of the water) are
mixed or co~tacted with each other to avoid a tendency towards
formation of a precipitate, etc.
F~r instance, a mouthrinse or mouthwash may be prepared
by mixing ethanol and water with flavorlng oil, nonlonlc surfactant,
humectant, cationic antibacterial antiplaque agent, such as
benzethonium chloride, cet~l pyridlnlum chloride or chlorhexidine,
sweetener and color and then adding the stain reducing agent
compound and additional water a~ desired.
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, anti-
bacterial agent, such as benzethonium chloride, cetyl pyridinium
chloride or chlorhexidine, and additional water, followed by
addition of the ~tain reducing agent. If sodium carboxym~hyl
cellulose is employed as the gelling ~gent the procedure of either
U.S. Patent 3,842,168 or U.S. Patent 3,843,779, modified by the
inclusion of the ~uaternary aminoalkylene phosphonic compound,
ls followed.
-19-
lO9S414
In the practlce of thl~ inventlon an oral composltlon
according to the lnventlon such as a mouthwash or toothpaste
containing cationic or long chain amine antibacterial antlplaque
agent in amount effectlve to promote oral hygiene and the stain
reducing agent in amount effective to reduce staining Or dental
surfaces otherwise resulting from the presence of the antl-
bacterial antiplaque agent 18 applied regularly to dental enamel,
preferably from about 5 times per week to about 3 times dally,
at a pH of about 4.5 to 9, generally about 5.5 to about 8,
preferably about 6 to 8.
The followlng speclfic examples are further lllustratlve
of the na~uro of the present invention; but lt 18 understood that
the lnventlon 18 not limited thereto. The compositions are prepared
in the usual manner and all amounts and proportions referred to
herein and in the appended claims are by welght unles~ otherwise
indlcated.
EXAMPLES 1-3
The following mouthwash iB prepared and tested:
Parts
Flavored alcohol 15
Pluronlc*F-108 (polyalkene
oxide block polymer) 3
Glycerlne 10
Benzethonlum chloriae (BC) 0.075
Sodium saccharin 0.03
QMATMP x
Water Q.S. to 100
pH 7.0 (ad~usted wlth 5 N sodlum hydroxlde)
Trade~nark
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1095414
All compo~itlone are clear wlthout vislble evldence
of precipltation. me QMATMP (N-methyl aminotri (methylene-
phosphonic acld)), and about 10 parts of the water, are added
to the other prevlously mixed ingredients.
The in vitro staining characteristics of the compositlon
are te6ted as follows in this and other~examples: Stain Test -
250 mgs. bovine albumin (crystallized three times) are added to
2 grams of hydroxyapatite (HAP) powder (Biogel) which serves as
a substrate for a stain while the proteins simulate dental pelllcle
and provide an "amine source." me mouthrinse is added to the
mixture followed by a 7.5% of differed buffered acetaldehyde
which serves as a carbonyl 60urce. 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 differen~e meter. Color levels are determined
on a Gardner Color Difference Meter~before and after the test
composition i~ applied to the colored material.
The following TABLE I shows the antlstain results when
the inalcated amounts (x) of QMATMP are employed in the above
mouthwash formulation.
TABLE I - ANTISTAIN
Parts (x) Reflectance
Example QMATMP Reilectance Difference
1 0 41.0 0
2 0.1 56.o 15.0
3 0.2 58.o 17.0
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~09S4~4
The above result~ plalnly establlsh that these
quaternary aminoalkylene pho~phonic acld compounds, as exempllfied
~y QMATMP, substantlally and significantly reduce dental staining
ordinarily caused by BC. These tests are condueted wlth the pH
adJusted to about 7.0, the pH pr~or to ad~ustment ranging from
about 4 to 4.8. Fo~mulations ad~usted to pH ranging from about
5 to 8 yleld ~lmilar results.
EXAMPLES ~-7
Substltution of equivalent amounts of the following
phosphono-containlng compounds for the QMATMP employed in Examples
2 and 3 yields formulatlons also producing unexpected reductions
in dental stalning:
Example Quaternary amlnoalkylene phosphonate
4 N-ethyl amlnotrl (methylene phosphonlc acld)
N-lsobutyl amlnotrl (methylene phosphonlc acld)
6 N-ethyl aminotrl (ethylene phosphonic acid)
7 N-methyl amlnotrl (butylene phosphonlc acid)
EXAMPLES 8-14
Substltutlon of equlvalent amounts of the followlng
antlbacterlal antlplaaue agents ~or the BC employed ln Examples
2-7 ylelds formulatlons also produclng unexpected reductlons ln
dental staining:
Example Antlbacterlal AntiPlaaue Agent
8 chlorhexidine diacetate
9 chlorhexidlne dlgluconate ~;
alexldlne dihydrochlorlde
ll dodecyl trlmethyl ammonium bromlde
12 benzyl dlmethyl stearyl ammonlum chlorlde
13 cetyl pyridinlum chloride
14 C12-18 alkyl N-CH2CH2N--CH2CH20H
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lO9S~14
It ls further notable that the antlplaque actlvity of
the above-exemplified rormulations containlng the lndlcated
quaternary amlnoalkylene phosphonic compounds are substantially
equal to corresponding ~ormulations omltting such compounds.
EXAMPLES 1S, 16
The ~ollowing ~ormulationR exemplify toothpastes with
antlplaque activity and reduced ~tainlng.
Example
16
.
Hydrated Alumlna 30 (parts 30
Glycerlne 16 16
Sorbitol (70%) 6 6
Pluronic F-108 3 3
Hydroxyethyl cellulose 1.2 1.2
Benzethonium chloride 0.5
Chlorhexidlne digluconate
(20%) ___ 4.725
QMATMP 2 2
Sodium saccharln 0.17 OCl7
Flavor o.8 o.8
Water Q.S. to lOO Q.S. to lOO
EXAMPLES 17-23
A basic mouthwash formulation ls prepared and tested
as ~ollows:
Mouthwash Formulatlon Parts
Flavored alcohol 15
Pluronic*Fl08 (polyalkene oxlde
block pclymer) 3
Glycerine lO
Benzethonium chloride (BC) 0.~5
Trademark
--23-
~09S41~4
Sodlum saccharin 0.03
Pyrrolldone-5~5-dlphosphonic
acld (PYDP) x
Water q.s. to 100
pH 7.0 (adJusted with 5N NaOH)
Appearance, st~bility clear
me PYDP, &nd about 10 parts of the water, are added
to the other pre*iously mixed ingredients.
The following Table I shows the in vitro antls~aln results
when the indicated amounts (x) of PYDP are employed in the above
Mouthwash Formulation.
TABLE I - ANTISTAIN
Phosphono Parts Re~lectance
Example~ompound (x)Reflectance Dlfference
17 - O 40.0 0
18 PYDP 0.1 52.0 12.0
19 PYDP 0.2 55.0 15.0
PYDP 0.3 5. 10.0
21 PYDP 0.4 54.0 14.0
22 PYDP 0.5 52.0 12.0
23 PYDP 1.0 51.0 11.0
The above results plainly establish that the pyrrolidone
diphosphonic acid additives of the present invention, as exemplified
by PYDP substantially reduce dental staining ordinarily produced
by BC. These tests are conducted with the pH of the formulation
aa~usted to about 7.0, the pH prlor to ad~ustment ranglng from
about 3.5 to 4.6. Formulations ad~usted to pH ranging from about
5 to 8 yield simllar results.
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109S4~4
EXAMPLES 24-30
Substitution of equivalent amounts of the following
pho~phono-containing compounds for the PYDP employed ln Examples
2-7 yield formulations also producing unexpected reductions ln
dental staining:
Example Phosphono Compound
24 N-methyl pyrrolidone-5,i5*diphosphonic acid
N-ethyl pyrrolidone-5, 5~dipho~phonic acid
26 N-butyl pyrrolidone-5, 5-diphosphonic acld
27 N-(2-hydroxyethyl~ pyrrolldone-5, 5-
diphosphonic acld
28 3-butyl pyrrolldone-5, 5-diphosphonic acld
29 3,4-tetramethyl pyrrolldone-5, 5-
diphosphonic acid
4, 4-diethyl pyrrolidone-5, 5-dipho~phonic
EXAMPLES 31-36
~ ub~titutlon of equlvalent amounts Or the followlng
antlbacterial antlplaque agents for the BC employod ln Examples 18-30
yield formulations also producing unexpected reduction~ in dental
staining:
Example Antibacterial AntiplQque Agent
31 chlorhexidine diacetate
32 chlorhexldlne digluconate
33 dodecyl trimethyl ammonium bromide
34 cetyl pyridinium chloride
~H2CH30H ~CH2CH20H
C12-18 alkYl--~-CH2CH2N~ CH2CH20H
36 alexidine dihydrochloride
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lO9S~14
EXAMPLE0 37-38
The ~ollowing formulations exempllfy toothpaste~
with antiplaque activity and reduced stalnlng:
Example
37 38
Hydrated alumina 30 parts 30
Glycerlne 16 16
Sorbltol (70~) 6 6
Pluronic F-108 3 3
Hydroxyethyl cellulo~e 1.2 1.2 :~
Benzethonlum chlorlde 0.5 --
Chlorhexldlne dlgluconato 4.725
P DP 2 ' 2
Sodlum saccharln 0.17 0.17
Flavcr o.8 o.8
Water q~ tO 100 100
EXAMPLES 39-45
A mouthwàsh formulatlon 1~ preparod and tested
as ~ollows:
Parts
Flavored al~ohol 15
Pluronic F-108 (polyalkene
oxlde block power) 3
~lycerlne 10
Beinzethonium chloride (BC) 0,075
Sodium saccharln o,o3
IDANMPA x
Water Q.S. to 100
pH 7.0 ~adJu~ted wlth 5 N ~odium hydrox~de)
.
*
Trademark
-26-
10 9 S4 1 4
All composltions are clear wlthout vlslble evldenco Or
preclpitatlon. The IDANMPA, and about 10 parts Or the water,
aro sddod to the other prevlously mixed lngredlents. Color levels
aro dotormlned in vitro on a Gardner Color Dlrreren~e Meter before
and artor the test composltlon 1~ applled to the colored materlal.
Tho ~ollowlng Table I shows the antlstsln results when the
lndlcated amounts (x) of IDANMPA are omployod ln tho above
mouthwaah ~ormulation.
TABLE I - ANTISTAIN
P*rts (x) Re~loctance
Exam~leID~NMPA Re~lectance Dlf~èrence
39 0 40.0 0
~0.1 52.0 12.~
41 ~ 0.2 56.o 16.0
42 0.3 57.0 17,0
43 0.4 51.0 11.0
44 0.5 58.o lô.0
1.0 57.0 17.0
The above results plainly ostabllsh that tho N-methyleno
phosphonate addltives Or the prosent lnvontlon, as oxompllrled
by IDANMPA, substantially reduce dental staining ordlnarlly
producod by BC. Those tests are donducted with the pH adJ~stod
to about 7.0, the pH prior to addustmont ranglng rrom about 3.5
to 4.8. Formulations ad~ustod to pH ranglng rrom about 5 to 8
yiold similar results.
EXAMPLES 46-48
,
Substltutlon of equlvalent amounts o~ the rollowing
phosphono-containing compounds for tho IDANMPA omployod ln
Examplos 2-7 yleld ~ormulations al80 producing unoxpocted
reduction~ in dental staining.
-a7
lO9S414
Example N-methylene pho~phonate '~
46 N-carboxymethyl-amino-di-methylene
phosphonlc ac:ld
47 N-hydroxyethyl-amino-di-methylene
phosphonic acid
48 N,N-di~ydroxyethyl-amino-met,~ylene
phosphonlc acid
AMPLES 49-55
Substitution of equivalent amounts of the following
antibacterial antlplaque agents for tho BC employed in Examples
40-48 yleld formulatlons also produclng unexpected reductlons
in dental stalnlng:
Example Antlbacterial Antlp~aque Agent
49 chlorhexldine dlacetate
chlorhexldine dlgluconate
51 alexldlne dlhydrochlorlde
52 dodecyl trimethyl ammon~um bromlde
53 benz,yl dimethyl stsaryl ammonlum chloride
54 cetyl pyrldlnlum chlorlde
~H2CH20H ~CH2CH20H
C12_18 alkYl-~-CH2CH2N CH2CH20H
It 18 further notable that the antlplaque activlty
o~ the above-exemplified formulations contai~ing the lndlcated
pho~phono-containing addltlves compounds are substantlally
equal to corrssponding formulatlons omltting such compounds.
EXAMPLES 56-57
Example
56 57
Hydratsd Alumlna 3o(pa~t8) 3o
Glycsrlne 16 16
Sorbltol ~70%) 6 6
Pluronic F-108 3 3
Tradem~rk
-2~-
109S414
Hydroxyethyl cellulose 1.2 1.2
Benzethonium chlorlde 0.5
Chlorhexidine digluconate 4.725
IDANMPA 2 2
Sodium saccharln 0.17 0.17
Flavor o.8 o.8 ~3
Water ~.S. to 100 Q.S. to 100
EXAMPLES 58-64
Tne following mouthwash formulatlon 1B prepared and
tested: `~
Mouthwash Formulation Parts
Flavored alcohol 15
Pluronic*F 108 (polyalkene oxlde 3
block polymer)
Gl~cerlne 10
Benzethonium chloride (BC) 0~075
Sodlum saccharin o.o3
Phosphonoacetic acid (PAA) x
Water Q.S. to 100
pH 7.0 (ad~usted with 5N NaOH~
Appearance, stabllity Clear
The PAA, and about 10 parts of the water, are added to the other
previously mlxed ingredlents.
The following ~ABLE I shows the in vltro antlstaln
resul~s when the indicated amou~ts (x) of PAA are employed ln
the above mouthwash formulatlon.
Trademark
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'1095414
TABLE I - ANTIST~IN
Parts (x) Reflectance
E*ample PAA ReflectanceDifference
58 0 39.o o
59 o.l 56.o 117.0
~0 0.2 54.0 15.0
61 0.3 56.o l~.o
62 o.4 53.0 14.0
63 o.5 55.0 16.0
64 l.o 53.0 14.0 ~i
The above results plainly establish that PAA, at all
levels Or x, substantially and signlficantly reduces dental
stainlng ordlnarily produced by BC. mese tests are conducted
with the pH adJusted to about 7.o, the pH prlor to ad~ustment ;
ranglng from about 3.5 to 4.6. Formulations adJusted to pH
ranging from about 5 to 8 yield similar results.
EXAMPLES 65-71
Substitution of equivalent amounts Or the following
antibacterial antiplaque agents for the BC employed in
Examples 2~71yield formulatlons also produclng unexpected
reductions ln dental staining.
Example Antibacterial AntiPlaque A~ent
Chlorhexidine diacetate
66 Chlorhexldlne dlgluconate
67 Alexldlne dihydrochlorlde
68 Dodecyl trlmethyl ammonlum bromide
69 Benzyl dlmethyl stearyl ammonium chlorlde
Cetyl pyrldlnlum chloride .
CH2CH20H ,5aH2CH20H
71 C12-18 alkyl_ ~-cH2cH2~-cH2cH2oH
-3o-
~09S4L4
It iB ~urther notable that the antiplaque activlty of
the above-exemplified formulatlons containlng PAA are substantially
equal to corresponding ~ormulations without the PAA.
The following formulations exemplify toothpastes
with antiplaque activity and reduced staining:
Example
72 73
Hydrated Alumina 30~0 (parts) 30
Glycerine 16 16
Sorbitol (70%) 6 6
Pluronic F-108 3 3
Hydroxyethyl cellulose 1.2 1.2
Benzethonium chloride 0.5 ---
Chlorhexidine digluconate (20%) --- 4.725
Phosphonoaceti~acid 2 2
Sodium saccharin 0.17 0.17
Flavor o.8 o.8
Water Q.S. to 100 Q.S. to 100
Examples 74_99
In the followlng exAmples, a baslc mouthwash
formulation is prepared and tested AB follows:
Mouthwash Formulation '- Parts
Flavored alcohol 15
Pluronic F108 (polyalkene oxide
block polymer) 3
Glycerine 10
Benzethonium chloride (BC) 0.075
Sodium saccharin o.o3
*
Trademark
~095414
Phosphono-contalnlng compound x
Water q.s. to lOO
pH 7 0 (adJusted with 5N NaOH) `!~
Appearance, stabillty clear
The phosphono-contalnlng compound, and about 10 parts
of the water, are added to the other previously mixed
ingredients.
The follow~ng Table I shows the in vitro antistain results
when the indicated amounts (x) of the lndlcated phosphono-
containlng compound are employed in the above MouthWash
Formulation.
TALLE I - ANTISTAIN
PhosphonoParts Reflectance
Example Compound (x) R~flectanceDifference
- 0 40.0 o
76 DPPD* 0.1 45. 5.0
77 " 0.2 49.0 7.o
78 " o.3 53.o 13.0
79 " o.4 60.o 20.0
" -5 53- 13.0
8~ " l.o 56.o 16.~
82 PEDA** O.l 4~.o 3.0
83 " 0.2 54.o 14.0
84 " 0.3 58.o 18.0
" o.4 52.o 12.0
86 " 0.5 54.o 14.0
8~ " o.6 60.0 20.0
88 " 1.0 51.0 11.0
*l,l-diphosphonopropane-2,3-dlcarboxylic acid.
**l-phosphonoethane-1,2-dlcarboxylic acid.
The above results plalnly establlsh that the phosphono-
alkane polycarboxylic acid additives of the present lnventlon,
_32- -;
. . .
lO9SA~4
as exempllfied by DPPD and PE~A, substantially reduce dental
stalning ordinarily produced by BC. These tests are conducted
with the pH of the formulation ad~usted to about 7.0, the pH
prior to ad~u~tment ranging ~rom about 3.5 to 5Ø Formulations
ad~usted to pH ranging from about 5 to 8 yleld similar results.'
Sub6tltution of equlvalent amounts of the ~llowing
phosphono-containing compounds for those employed in xamples
75-88 yield formulations also producing unexpected reductions
in dental staining:
xample Phosphono-eontaining Compound
89 2-phosp~onopropane-2,3-dicarboxyllc acid
2-phosphonobutane-2,3-dicarboxylic acid
91 1,1-diphosphonobutane-2,3-dicarboxyllc acid
92 1-phosphonopropane-1,2,3~tricarboxylic acid
93 2-phosphonobutane-2,3,4-trlcarboxylic acid
Substitutlon of equlvalent amounts of the following
antlbacterlal antlplaque agents for the BC employed ln Examples
75-93 yield formulations also producing unexpected reductlons in
dental staining:
Example Antibacterial Antiplaque Agent
94 chlorhexidine dlacetate
chlorhexidine digluconate
96 dodecyl trimethyl ammonlum bromide
97 cetyl pyridinium chloride
1 2 2 ~ 2
98 cH12_18 alky~ - ~-CH2CH2 ~ CH2CH20H
99 alexidine dlhydrochloride
It is further notable that the in vitro antlplaque
activity of the above-ex~mplified formulations containing the
indicated phosphcho-containing additive compounds are
-33
~095414
sub~tantlally equal to corre~pondlng formulatlons omlttlng
such compound~.
Example 100
In vivo te~ts for antiplaque and antistain activity
are conducted on beagle~ with the mouth~ash formulatlon of
Example 6 containing 0.075 parts of BC and 0.5 parts of DPPD,
the oontrol formulation of Example 1 contalnlng 0.075 parts of
BC and no DPPD, and a placebo devoid of both BC and DPPD. The
beagles are first sub~ected to dental prophylaxis to remove
exlsting soft and hard dental deposlts. A discloslng ~olutlon
is used to insure complete removal. Appllcations are made by
gentle spraying twice a day, 5 days a week ~or 6 weeks. Staln
iB evaluated relatlvely by visual observatlon of the oral
cavity. Plaque 18 evaluated after spraylng the teeth with
dlsclosing solution. me results are as follows:
Staln
Nc. Mean Diiference
of Plaque Mean Compared to
~ogs Score Stain Placebo
Placebo 8 2.4 o.38 0
Control (+BC) 7 1.8 0.53 +39.4%
+BC+DPPD 8 1.8 0.32 _42.3
It is clear from the above results that the
phosphono-contalning additlve compounds of thls inventlon, as
exemplified by DPPD, significantly and substantlally reduce
dental stainlng (by 42.3%) caused by antlbacterial antiplaque
agents as exemplified by the cationic BC, ln fact reduclng
stainlng to le~s than the placebo. These results also show
that such additive compounds do not affect the anti~laqae
activity of the stain-produclng antlbacterlal antiplaque agents.
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1095414
Examples 101-102
The followlng formulations exemplify toothpastes
with antiplaque activity and reduced stalning:
Example
101 (PartB) 102
Hydrated alumina 3~ 3
Glycerine 16 16
Sorbitol*(70%) 6 6
Pluronic*F-108 3 3
Hydroxyethyl celluloBe 1 . 2 1.2
Benzethonium chlorlde0.5
Chlorhexidlne digluconate
(20~) ~ 4.725
DPPD 2 2
Sodium saccharin 0.1~ 0.17
Flavor o.8 o.8
Water q.~:. 100 100
This invention has been described with respect
to preferred embodiments and it will be understood that
modifications and variations ~hereof obvlous 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.
*
Trademark
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