Note: Descriptions are shown in the official language in which they were submitted.
iL1~`~i35i~ ~
mi8 invention relates to oral composition~ containing
an anticalculus agent.
C&lculus is a hard, mineralized formation which forms on
the teeth. Regular brushing prevent~ a rapid build-up of these
deposlts, but even regular brushlng 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 microcrystQlline calcium phosphate.
"Amorphous calcium phosphate" although related to hydroxyapatite
differs ~rom it in atomic structure, particle morphology, and
stoichiometry. me X-ray diffraction pattern of amorphous calcium
phosphate shows broad peaks typic~l of a~orphous materials, wh~ch
lack the long-range atomic order characteristic of all crystalline
materisls, including hydroxyapatite. It is apparent therefore that
agents which efPectively interfere with crystalline grcwth of
hydroxyapatite will be e~fective as anticalculus agents. A
suggested mechanism by which the anticalculus agents of this inven-
tion inhibit calculus for~ation probably involves an increase of
the activation energy barrier thus inhibiting the transformation
of precursor ~morphous calcium phosphate to hydroxyapatite.
Studie~ have shown that there is a good correlation
between the ability of a compound to prevent hydroxyapatite crystal
line growth in vitro and its ability to prevent calcification in vivo.
-2-
~a~s3s~ 1
A substantial number of different types of compounds and
compositions have been developed for use as antibacterial, and ~nti-
plaque and anticalculus agents in oral compositions, including for
example such cationic materials as the bisbiguanide compounds and
quaternary ammonium compounds, e.g. benzet~onium chloride and cetyl
pyridinium chloride, disclosed in U.S. 4,110,429. These cationic
materials h~wever tend to stain the teeth with continued use. Further,
they exert an antibacterial function which undesirably tends to dis-
rupt or destroy the normal micro~lora of the mouth and/or the
digestive system. Other such materials have been found to be un-
stable in the presence of anionic surface active agents often present
in conventional oral compositions.
It is a ~bject of this invention to provide an oral anti-
calculus composition which will not be subject to one or more of the
above deficiencies.
It is another object of this invention to provide an
improved anticalculus oral composition which will have relatively
little or no tendency to stain the teeth.
A fu-rther ob~ect of the invention is to provide an oral
composition whlch inhibits the transformation of a~orphous calcium
phosphate to hydroxyapatite crystal structure normally associated
with calculusO
Another object of this invention is the provision of an
improvea method for inhibiting the ~ormation of calculus and/or
staining of teeth by N-containing cationic antibacterial antiplaque
agent~.
A still further object of the invention is the provision of
an oral composition containing a nitrogen - containing cationic anti-
bacterial antiplaque age m , which composition has a reduced tendency
3 to stain the teeth.
Other ob~jects and advantages will appear as the description
proceeds.
In accordance with certain o~ its aspects, this invention relates
to an oral composition co~prising an oralLy acceptable vehicle con-
~L~753S8
taining in an effective amount at least one cationic nitrogen-
containing antibacterial antiplaque agent hased on its free
base form and an effective stain-inhibiting amount of a
copolymer consisting essentially of ~A~ n units having the
molecular configuration of unlts derived from glutamic acid,
(s) m units having the molecular configuration of units
derived from alanine, and (C) p units having the molecular
configuration of units derived from tyrosine, the ratio of
(n + m) : p ranging from about 5:1 to about 9.5:1 and the ratio
of m:n ranging from 0:1 to about 0.6:1, the molecular weight of
the copolymer ranging from about 5,000 to about 150,000.
The aforementioned copolymers may be prepared in
well known manner, as for example by the procedure disclosed
in Chase and Williams "Immunochemistry", Vol. 2, pp 168, 169
(1978) Academic Press. In general, the copolymers are prepared
by random copolymerization of the N~carboxyanhydrides of
glutamic acid, tyrosine and alanine in the required molar
proportions in the form of a mixture in an organic solvent such
as dioxane, benzene, dimethyl formamide or N-methyl pyrrolidone
and in the presence of an initiator such as an organic amine
(e.g. triethylamine) or sodium methoxide.
The (A) units in the copolymer may be depicted as
having the structural formula:
~. _ _
(A) _ - HN - CX - CH2CH2 - CO-
COOH n
n being a numerical value representing the number of (A) units
I of glutamic acid in the copolymer.
~A 4 -
~53~8
The (B) units in the copolymer may be depicted as
having the structural formula:
t N CH - CO
CH3 m
:. :
~::
::
~ ~ - 4a -
7S358
m being a numerical value representing the number of (1) units of alanine in
the copolymer.
The ~C) units in the copolymer may be depicted as having the struc-
tural formula:
(C) - ~ - CH - CO - _
CH2
OH P
p being a numerical value representing the number of (C) units of tyrosine
in the copolymer.
As defined above, the ratio of (n ~ m) : p ranges from about 5 : 1
to about 9.5 : 1, the ratio of m : n ranges up to about 0.6 : 1 and the
values of m, n and p are such that the copolymer has a molecular weight of
about 5,000 to about 150,000, preferably about 17,000 to about 100,000.
Especially preferred copolymers are a two component copolymer con-
taining glutamic (A) units and tyrosine (B) units in a ratio of about 9 : 1
and having a molecular weight of about 17,000 to about 21,000, and a three
component copolymer containing glutamic (A) units, alanine (B) units and
tyrosine (C) units in a ratio of about 6 : 3 : 1 and having a molecular
weight of about 80,000 to about 100,000.
It will be ~mderstood that the free acid form of the copolymers
employed herein may be converted to, and employed, in their equivalent salt
form by treatment with any base containing an orally acceptabl~ cation such
as alkali metal (e.g. sodium or potassium), ammonium, Cl 18 mono-, di- or tri-
-substituted ammonium (e.g. alkanol substituted such as mono-, di- or tri-
-ethanolammonium), organic amines, etc. It will also be understood that when
referring to these copolymers as being water soluble such copolymers should
be water soluble or readily water dispersible in the concentrations employed
in conventional oral compositions such as mouthwashes, toothpastes and the
like.
~1~7535~
The copolymers employed in accordance with this invention are
peculiarly advantageous oral anticalculus agents. Bearing in mind that
human saliva contains natural inhibitors of calcium and phosphate precipita-
tion including glutamic acid and tyrosine, the instant copolymers are rela-
tively safe to use even if ingested since they are readily hydrolyzed in the
stomach by chymotyprin, a proteolytic enzyme known to hydrolyze tyrosine.
In contrast, other non-hydrolyzable anticalculus agents when absorbed in the
G.I. tract could cause changes in the bone. These copolymers are addition-
ally advantageous in being substantive to oral surfaces.
; 10 The concentration of these copolymer anticalculus agents in oral
compositions can range widely, typically upwards of about 0.01% by weight
with no upper limit except as dictated by cost or incompatibility with the
vehicle. Generally, concentrations of about 0.01% to about 10.0%, preferably
about 0.1% to about 8.0%, more preferably about 0.5% to about 5.0% by weight
are utilized. Oral compositions which in the ordinary course of usage could
be accidentally ingested preferably contain concentrations in the lower por-
tions of the foregoing ranges.
Cationic nitrogen-containing 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, second 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 anti-plaque quaternary
; ammonium compounds is benzethonium 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 accom-
panied by a reduction in caries formation and periodontal diseases. Other
117S3S8
cationic antibacterial agents of this type are those mentioned, for instance,
in U. S. Patent Nos. 2,984,639, 3,325,402, 3,431,208 and 3,703,583 and
British Patent No. 1,319,396.
Other antibacterial antiplaque quaternary ammonium compounds in-
clude those in which one or two of the substituents on the quaternary
nitrogen has a carbon chain length (typically alkyl group) of some
~7S358
8 to 20, typically 10 to 18, carbon atoms while the
remaining substituents have a lower number o~ carbon
atoms (typically alkyl or benzyl group), such as 1 to 7
carbon atoms, typically methyl or ethyl groups. Dodecyl
trimethyl ammonium bromide, dodecyl dimethyl ~2-
phenoxyethyl) ammonium bromide, benzyl dimethyl stearyl
ammonium chloride, cetyl pyridinium chloride and
quaternized 5-amino-1,3-bis (2-ethyl-hexyl)-5-methyl
hexa hydropyrimidine are exemplary of other typical
quaternary ammonium antibacterial agents.
Other types of cationic antibacterial agents
which are desirably incorporated in oral compositions to
promote oral hygiene by reducing plaque formation ar`e
the amidines such as the substituted guanidines e.g.
chlorhexidine and the corresponding compound,
alexidine, having 2-ethylhexyl groups instead o~
chlorophenyl groups and other bis-biguanides such as
those described in German patent application No. P
2,332,383 published January 10, 1974, which sets forth
;
20 ~ the followlng formula:
R NH NH NH NH R '
A-~X)z~N~C~NH~C~NH(C~l2)n~NH~~~NH~C- N-(X')zlA'
.
in which A and A' signify as the case may be either (1) a
~25 phenyl radical, which as substituent 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 12C-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 I-3C atolns, z and
z' arc as the case
~7535 53
may be either zero or 1, ~ and R' as the case may be may
represent elther hydrogen, an alkyl radical with 1 to
about 12C-atoms or an aralkyl radical with 7 to about
12C-atoms, n is a whole number of 2 to inclusively 12
and the polymethylene chain (C~2~ can be interrupted by
up to 5 ether, thioether, phenyl-~r naphthyl groups;
these are available as pharmaceutically suitable salts.
Additional substituted guanidines are: N'-(4-
chlorobenzyl)-N5-(2,4-dichloroben7yl) 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 cationic aliphatic tertiary ~nes also pos~e6s
~antibacterial and antiplaque activity. Such
,~ antibacterial agents include tertiary amines having one
Eatty alkyl group (typically 12 to 18 carbon atoms) and
2 poly(oxyethylene) groups attached to the nitrogen
. (typically containing a total of from 2 to 50 ethenoxy
~25~ ~groups per molecule) and salts thereof with acids and
compounds of the structure:.
~'" 'J /(CH2CH2O)zH /(CH2CH2O)xH
R-N-CH2CH2N
(CH2CH2O)yH
where 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
~or their anl:ipl.aque e~ectivencs-..
-
r~
IL75358
'l'he antibactelial antiplaque compound is
preferably one which has an antibacterial activity such
that its phenol co-efficient 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 molecular weight well below
~10 2,000, such as less than about 1,000. It is, however,
within the broader scope of the invention to employ a
polymeric catlonic antibacterial agent. The cationic
antibacterial is preferably supplied in the form of an
orally acceptable salt thereof, such as the chloride,
lS bromide, sulfate, alkyl sulfonate such as methyl
`sulfonate and ethyl sulfonate, phenylsulfonatet such as
p-methylphenyl sulfonate, nitrate, acetate, gluconate,
; etc.
~ The nitrogen-containing cationic antibacterial
agents (in^cluding the tertiary amine) antibacterial
; ~ agents effectively promote oral hygiene, particularly b~
removing plaque~ However, their use has been observed
to lead to staining of dental surfaces or discoloration.
The reason for the formation of such dental
stain has not been clearly established. However, human
dental enamel contains a high proportion (about 95%) of
hydroxyapatite (HAPj which includes CA~2 and PO4 3 ions.
In the absence of dental plaque ad~itional Ca~2 and PO4 3
particularly from saliva, can be deposited on the
enamel and such deposits can include color bodies which
-10-
~53S~3
ultimately stain the tooth enamel as a calcified depogit thereon.
It ca~ e that as the cationic (including the tertiary amine) ant~-
bacterial agents remove plaque they also denature protein from saliva
in the oral environment and the denatured protein c~n then act QS a
nucleating agent which is deposited on and stains or discolors tooth
enamel.
Previously employed additives which reduced dental staining
by cationic antibacterial antiplaque agents also generally reduced the
activity o~ antibacterial antiplaque agents such as bis-biguanido
compounds, as by forming a precipitate with such agents.
It is a further advantage of this invention that the above-
deæcribed copolymers are antinucleating agents~hich unexpectedly inhibit,
i.e., prevent or remove, the staining of dental enamel caused by such
cationic (including the tertiary amine) antibacterial agents without
precipitating or substantially adversely affeoting their antibacterial
and antiplaque activity. In themselves (even in the ab~ence of such
antibacterial agents), these copolymer additives are effective to
reduce formation of dental calculus without unduly decalcifying dental
enamel9 in addition to effectively inhibiting gingivitus. However, not
all anti-~ucleating agents are effective to prevent staining by such
antibacterial agents. Victamide (also known as Victamine C) which is
a condensation product of ammonia with phosphoruspentoxide, actually
increases staining even in the absence of such antibacterial agents.
;
~L~7S3~i8
Cationic nitrogen-containing antibacterial antiplaque
agents optionally employed in the practice of this invention
are described above. When such agents are present they are
typically employed in amounts such that the oral product contains
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 5~0, and most preferably
about 0.25 to l.O~o by weight of the antibacterial antiplaque
agent, referring to its free base form.
In certain highly preferred forms of the invention the
oral compositlon may be substantially liquid in character, such
as a mouthwash or rinse. In such a preparation the vehicle is
typically a water-alcohol mixture deæirably including a humectant
as described below. Generally, the ratio of water to alcohol is
~ ln the~range of ~ro~ 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.
t
The total amount of water-alcohol mixture in this type of pre-
paration 18 typically in the range of from about 7 ~0 to about 99.9~0
; by weight of the preparatlon. The pH of such liquid and other; ~20 ~ ~ preparations Or the invention i: generally in the range of from
about 4~.5~to about 9 and typically from about 5.5 to 8. The pH
is pre~erably in the range of from about 6 to about 8.o. It is
,
noteworthy that the compositions of the invention may be applied
orally~a~ a lawer pH without substantially decalcifyine dental
25e~a~el. The pH ca~ be controlled with acid (e.g.
~: .
~ -12-
S35~51
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 com-
position 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 meta-
phosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous
dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, tri-
magnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminum
silica~e, zirconium silicate, silica, bentonite, and mixtures thereof. Pre-
ferred polishing materials include Dical (Calcium dihydrogen phosphate),
colloidal silica, silica gel, 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 llO 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.
~ hen 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
- 13 -
~.
117S3~3
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 there-
fore 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 mate-
rial 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 appro-
priate quantities and particle sizes.
In pas~y oral preparations the copolymer 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 humec-
tants. Particularly advantageous liquid ingredients comprise mixtures of
water, glycerine and sorbitol.
- 14 -
7S3S~il
ln clc.lr gcls whc~c thc rerractivc indcx is an
iml)or1;arlt consideration, about 3-30y' by weight of water, O
to about ~0~0 by wei~ht of glycerines and about 20-80% by ~
weight o~ sorbitol is preferably employed. A gelling agent,
such as natural or synthetic ~ums or gum-like materials,
typically lrish moss, sodium carboxymethylcellulose, methyl
cellulose, or hydroxyethyl cellulose a may be employed.
Other gelling ager.ts which may be employed include gum
tragacanth, polyvinylpyrrolidone and starch. They are usually
present in toothpaste in an amount up to abou-t 10% by weight,
preferably in the range of from about 0.5~ to about 5%. The
prefe~rred gelling agents are methyl cellulose and hydroxyethyl
cel1ulose. In a toothpaste or ~el, the liquids and sol;ds
arc I)roportioned to ~orm a creamy or gelled mass which is
extrudable i`rom a pressurized container or from a collapsible 3
c.g., nluminum or lead, tube.
The solid or pasty oral preparation which typically
has a pH measured on a 205' slurry of about 4.5 to 9,
generally about ~,5 to about 8 and preferably about 6
2~ 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 subF,tance, as a toothpaste or dental cream.
-15-
"
:~iL17S3~
The oral compositions of this invention may contain a non-soap syn-
thetic sufficiently water soluble organic anionic or nonionic surfactant in
concentrations generally ranging from about 0.05 to about 10, preferably
about 0.5 to about 5, weight percent, to promote wetting, detersive and foam-
ing properties. U. S. Patent No. 4,041,149 discloses such suitable anionic
surfactants in col. 4, lines 31-38, and such suitable nonionic surfactants
in col. 8, lines 30-68 and col. 9, lines 1-12.
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 mate-
rials are inorganic fluoride salts, such as soluble alkali metal, alkaline
earth metal and heavy metal salts, for example, sodium fluoride, potassium
fluoride, ammonium fluoride, Ca 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 fluorosili-
cate, 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 mono-
~ fluorophosphate 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 pre-
paration, but it must
- 16 -
131753S~3
be a nontoxic amount. In a ~olid oral prep~ration, ~uch as tooth-
paste or toothpowder, an amount o~ such compound which releases a
maximum of about 1~ by weight o~ the preparation iB con~idered
satisfactory. Any suitable minimum about of such compound ~ay be
used, but it is preferably to employ ~uf~icient compcund to release
about 0.005% to 1~, and pre~erably about 0.1% o~ fluoride ion.
Typically, in the cases oP alkali metal ~luorides and stannou~
fluoride, this component is present in an amount up to about 2%
by weight, ba~ed on the weight of the preparation, and preferably
ln the range Or about 0.05% to 1~. In the case of sodium mono-
~luorophosphate, the compound may be present in an a~ount up to
7.6% by weight, more typically about o.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 ionO
Various other materials may be incorporated in the oral preparations
o~ this invention such as whitening agents, preservatives; silicones,
chlorophyll compounds, other anticalculus Qgents, antibacterial
antiplaque agents, and/or ammoniated ~Qterial such as urea,
dia~monium pho~phate, and mixtures thereof. These adjuvants, where
present, are incorporated in the preparations in a~ounts which do
',
not substQntially adversely affect the properties and char~cteristics
desired.
In preparing the oral ccmpositions of this invention
comprising the above-defined combination of antibacterial ~gent
and additive in an oral vehicle which typically includes water, it
is highly preferred if not essential to add the additive after the
other ingreaients (except perhaps some of the water) ~re mixed or
contacted ~ith each other to avoid a tendency ~or ~aid agent to be
precipitat~d.
~l~S358
Any suitable flavoring or sweetening material may al80
be e~ployed. Exa~ples of suitable ~lavoring or sweetening material
may also be employed. Example9 of suitable flavoring con~tituenks
are ~lavoring olls, e.g., oils of spearmint, peppermint, wintergreen,
6assafras, clove, sage, eucalyptus, major~m, cinnamon, lemon, and
orange, and ~ethyl salicylate. Suitable sweetening agents include
sucrose, lactose, fructose, maltose, sorbitol,xylltol~ sodium
cyclamate, perillartine, APM (aspartyl phenyl alanine, ~ethyl ester),
saccharin and the like. Suitably, ~lavor and sweetening ~gents may
together comprise from about 0.01~ to 5~ or more of the preparation.
In the practice of this invention an oral composition
according to t~is invention such as a mouthwash or toothpaste
containing the defined copolymer in an a~oNnt effective to inhibit
calculus on dental sur~aces is applied regularly to dental enamel,
preferably ~rom about 5 times per week to about 3 ti~es dally, at a
pH of about 4.5 to about 9, generally about 5.5 to about 8, prefer-
ably about 6 to 8.
The ~ollowing 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 ~re by weight unless
otherw~se indicated.
Ex~m~le
Inhibition oX Crystal Groith of HAP
This is evaluated by a pH Stat method. 1.0 ~1 of an
aqueous solution of IX10 4M to lX10 ~ of the antic~lculus 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 at~osphere of nitrogen. To thifi i3 added 1 ml. of O.IM
CaC12 and the pH ad~usted to 7.4+~ 0.05 with NaOH (final conc. of Ca~+
and P043 =4X10 ~ ) Consumption of O.lN NaOH is recorded automatically
by ~ pH Stat (Radiometer). In thiQ te~t~ the formation o~ HAP occurs
in 2 distinct phase~. First rapid base consumption (1-4 min.3 then
diminishes unt~l 15-20 mlnutes when second rapid uptake take~ place.
A delay in the time o~ second rapid consu~ption or a total absence
1~535i~
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 tested by the foregoing procedure, the following
results are obtained.
Table I
Anticalculus Agent Time ~Min.) for Delay (MinO) for
(conc.) _ HAP Formation HAP Formation
~a) Water (Control) 21.0 --
(b) Copolymer 9/1 (20 p.p.m.) 30.0 g.o
(c) " (21 p.p.m.) 40.0 19.0
(d) " ~27 p.p.m.) 87.0 66.0
~e) " ~32 p.p.m.) 117.0 96.0
~f) Copolymer 6/3/1 (40 p.p.m.) 31.0 10.0
~g) Copolymer 7/3 ~40 p.p.m.) 21.0 0
(h) Copolymer 1/1 (1 x 10 4) 21.0
(i) Copolymer 3/7 (40 p.p.m.) 21.0 0
(j) Copolymer G/L/T (32 p.p.m.) 21.0
(k) Glu/Tyr 1/1 (2 x 10 4) 18.0 0
~1) Glu/Ala/Tyr 1/1/1 ~32 p.p.m.) 21.0 0
~m) Tyr ~32 p.p.m.) 18.0 0
The copolymers tested as above indicated were prepared by copoly-
merization of alpha-amino acid anhydride mixtures by the procedure described
in "Immunochemistry" supra. Copolymer 9/1, illustrative of the invention, was
prepared from a 9:1 molar mixture of glutamic acid and tyrosine, and was
determined by centrifugation to have a molecular weight of about 19,300.
Copolymer 6/3/1, also illustrative of the invention, was prepared from a
6:3:1 molar mixture of glutamic acid, alanine and tyrosine, and was deter-
mined to have a molecular weight of about 90,800. The remaining copolymers
are comparative. Thus, copolymers 7/3, 1/1 and 3/7 were prepared from mix-
tures containing proportions of glutamic acid: tyrosine outside those re-
- 19 -
~L7S3S15
quired herein, i.e. in molar ratios of 7:3, 1:1 and 3:7. Copolymer G/L/T
was prepared from a 1:1:1 molar mixture of glutamic acid, lysine and tyrosine.
The agents tested in (k), (1) and (m) were monomers or monomer mixtures in-
cluding glutamic acid, tyrosine and/or alanine, the mixtures containing
equal molar proportions of monomer components.
The results shown in TABLE I plainly show the effective inhibition
by the copolymers of this invention, in (b), (c), (d), (e), and (f), of cry-
stal growth of HAP in vitro, and that the inhibition is not due to complexa-
tion or chelation of calcium since sub-stoichiometric ratios of copolymer:
calcium were employed. The failure of comparative agents (g) thru (m) to
inhibit HAP formation emphasi~es the criticality of the instant copolymers,
with respect to components and ratios of such components therein, for achiev-
ing the unexpectedly improved HAP inhibition of this invention.
In the following examples illustrative of mouthwash formulations
according to the invention, Pluronic F108 is a polyoxyalkylene block polymer.
Example
2 3 4 5
:
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 Saccharin0.03 0.03 0.03 0.03
Copolymer 6/3/1 0.1 0.2 0.5 1.0
Water q.s. to 100 100 100 100
~ :
*Trade Mark - 20 -
75358 ,~
I~.xa~l e G
'roothpaste ~ormulation
l~t. Percellt
Glycerin 25.0
Carboxymethylcellulose 1.3
Sodium benzoate ~ 5
Na Saccharin 0.2
Sil1ca 30 ~
Sodium lauryl sulfate 1.5
Flavor 1.0
Copolymer 9/1 3 0
Water to make lO0
-
.
~ ~ Table ~ below is illustrative of mouthwash
formulations according to the invention and the
antistaining activity of the instant copolymeradditive
therein. The tooth staining characteristics of the
: : : . :
formulations are evaluated by slurrying hydroxyapatite~20 ~ ~ (Blogel), a~pecific salivary protein, a carbonyl source
(e.g. acetaldehyde), and a pH 7 phosphate buffer, with
and with~ut ~the mouthwash formulations being tested.
; The ;mlxture is~ shaken at 37C. for 18 hours. The
colored HAP powder is separated by filtration, dried and
25~ ~ the color levels (in reflectance units) determined on a
::
~ Gardner color difference meter.
:
.
-21-
:
,J .
S3S~
MOUTHWASH FO~ULATIONS
Placebo Control
Exam~le (7~ 18~ ~9~ ~0
L ~ L _
~thanol lO~ - lO~ lO~ lO~
Glycerine lO lO lO lO
F'lavor 00146 0.146 0.1)-~6 0.14
Saccharin 0.03 0.03 0 03 0.03
Pluronic Fl08 3.0 3.0 3.0 3.0
cpc2 0.1 .~ 0.1
Copolymer 9/13 O.l 0.2
Wa~er, q.s. to lOO lOO lOO lOO
pll (with lN Na~II? 7.0 7.0 7.0 7.0
~eflectance 10.7 41.o 57.7 56.o
~ifference -- ~28.9 -15.9 -11l.2
d ~ v
1. l'oly:~yalkyl~lle block ~olymer (~A~l-Wyall~o~e)
:: 2. Ce~yl pyrir~inium chloride
~ ~3.: Prie~ared by the procedure described in "Immunocilemistry" supra
20: ~for copolymerizing a 9:l molar mixture of glutamic .lCid al1d
:~ : tyrosine, the copolymer being determined by centrilugatio11 to
~have~a molecular weight Or about 1~,300.
The above results plainly establish that the copolymer addi-
tives of the present invention substantially reduce dental s~aining
: ~ ~: : . .,,:
~25 -~ ;ordi~narily~produce~ by cationlc quarternary ammonia antibacterial
;:antiplaque agents as exemplified by CPC.
:Further, in vitro tests establish that the antiplaque activity
of Examples 8 and 9 are substantially equal, indicating that the
~ copolymer additives of this invention do not significantly effect
the antlplaque activity of CPC and the like.
Substitution of equivalent amounts of the followirln; anti- :
l1acterIal ~ntiplslque ag~el1ts for t~lc CP~ el11ployed in l~"~alllple5 3 and
l yield formulations also producing an unexpected re~uction i
dental stainin~.
-22-
75358
X~ltlE~
l~enzetllolliulll cllloride (~,C)
12 chlorllexidine diacetate
. chlorhexidine di~luconate
13 dodecyl trilnethyl ammonium
~romide
C~2CTI2011 ~C~I2( 1I2()~I
1~ . C12 1~3 alkYl-N-C~2C~l2N ~
o 15 alexidine dihydrochloride
The following formulations exemplify toothpastes with anti-
plaque activity and reduced staining.
Example (Parts ?
16 17 18
Hydrated alumina 30 30 30
Glycerine 16 1~ lG
Sorbitol (70~) 6 6
': Pluronic ~l-108 3 3 3
.
Hydroxyethyl cellulose 1.2 1.2 1.2
C 0.5
; : ; Chlorhexidine-digluconate (20~ 40725 --
~: I
CPC :~
~; Copolymer 6/3/1* o.o8 o. 5 1.o
~ Sodlum~saccharin~ 0.17 0.17 0.17
~ ~ Flavor o . 8 o. 8 o. 8
; ~
Water q.s. to 100 100 100
.
:
*Prepared accordin¢ to procedure descri~ed in "Immunvcllemis~l,y"
supra I'or copolymerizin~ a 6:3:1 molar mixture of glutamic acidg
alanine and tyrosine, the resulting copolymer of the invention
~ine determined to have ~ molecular wei~ l, o.~ al~o~ 0,~3
-23-
1~ 7535~ ~ 1
~l'his invention has been described with respect
to preferred embodiments and it will be understood that
modifications and variations ~hereof 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.
I
'` `'
; ,
~ -24-
