Note: Descriptions are shown in the official language in which they were submitted.
s~
This inventlon relates to oral compositions
containing an anticalcul~s agent~
Calculus is a har~, mineralized formation which
forms on the teeth. Regular brushing prevents a rapid
; 5 build-up of these deposits, but even regular brushing is
not sufficien-t 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 ma-trix of the dental plaque
and become sufficiently closely packed together for the
`aggregates to become resistant to deforma~lon. There is
no complete agreement on the route by which calcium and
orthophosphate ultimately become the c:rystalline material
- oalled hydroxyapatite (~AP). It is generally agreed,
however, that at higher satura-tions, that is, above the
critical saturation limit, the precursor to crystalline
.
;~ hydroxyapatite is an amorphous or microcrystalline calcium
~` phosphate. "Amorphous calcium phosphate" although related
~ , .
~ to hydroxyapatite differs from it in atomic structure,
., 0
particle morpholo~y, and~stoichiometry. The X-ray diffraction
pattern of amorphous calcium phosphate shows broad peaks
typical of amorphous materials, which lack the long-range
atomic order characteristic of all crystalline materials,
including hydroxyapatite. It is apparent therefore that
agents which effectively interfere with crystalline growth
of hydroxyapatite will be effective as anticalculus agents.
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A suggested mech~mism by which the anticalculus agents of
this invention inhibit calculus formation probably involves
an increase of the activation energy barrier thus inhibiting
the transformation of precursor amorphous calcium phosphate
to hydroxyapati~e.
` Studies have shown that there is a good correlation
between the ability of a compound to preven~ hydroxyapatite
crystalline growth in vitro and its ability to prevent
:`
~ calcification in vivo.
.-.
;~ 10 Cationic nitrogen-containing antibacterlal materials
are well known in the art. See, for instance the section on
"Quaternary Ammonium and Related Compounds" in ~he articLe on
"Antiseptics and Disinfectants" in Kirk-Othmer Encyclopedia
: .:
`~ of Chemical Tec}mology, second edition ~Vol. 2, pp. 632-635).
Cationic materials which possess antib3cterial activity
~i.e. are germicides) are used against bacteria and have
been used in oral compositions to co~mter pIaque 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 di-isobutylphenoxy-
ethoxyethyl dimethyl benzyl ammonium chloride. In an oral
preparation this material is highly effective in promoting
oral hygiene by reducing formation of dental plaque and
*Trademark - 3 -
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calculus, which is generally accompanied by a. reduction in
caries :~o~mation and periodontal diseaseæ~ Other cationic
antibacterial agents o~ this type are those mentioned, -for
instance, in U.S. Patent Nos. 2,984~639, 3,3259402, 3,431,208
and 3,703~583 and British Patent ~o. 1,319,396.
;~- Other antiba.cterial anti-plaque ~uate rnary ammonium
compounds lnclude those in which one or two of the sub-
stituents on the quaternary nitrogen has a carbon chaln
length (typically alkyl group~ of some
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~ ~o 20, ty~ically 10 to 18, carbon atoms while the
remainillg substituellts have a lower number of carbon
atollls (typically alkyl or benzyl group), such as 1 to 7
caLbon atoms, typically methyl or ethyl groups. Dodecyl
trimetllyl ammonium bromide, dodecyl dimethyl ~2-
- phenoxyethyl) ammonium bromide, benzyl dimethyl st.earyl
ammollium chloride, cetyl pyridinium chloride and
,
~lu.lterni7.e~1 5-amino-1,3-bis (2-ethyl-hexyl)-5-methyl
;
hexa hydro~)yrimidine are exemplary of other typical
l~ clu;lterllary allllnollium 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 the substituted guanidines e.g.
lS chlorhexidine and the corresponding compound,
alexidine, havin~ 2-ethylhexyl groups instead of
`~ chlorophenyl groups and other bis-biguanides such as
those described in German patent application No. P
~; 2,332,383 published ~anuary 10, 1974, which sets forth
the ~ollowing formula:
1~ NEI N~l NH N~ R '
A- tX) z-N C-NH-C-NH (C1~2) n-NH-~-NH-C- N- (X ' ) zl A'
in whicl- A and A' signify as the case may be either (1) a
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 1-3C atoms, z and
; z' are as the case
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may be eithec zero or 1, R and R' as the case may be may
répresent either hydrogenr an alkyl radical with 1 to
about 12C-atollls or an aralkyl radical with 7 to about
12C-atoms, n is a whole number of 2 to inclusively 12
ancl the polymethylene chain (CH2) 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-
chloroben7yl)-N5-(2,4-dichlorobenzyl) biguanide; p-
chlorobenzyl biguanide, 4 chlorobenzhydryl guanylurea;
N-3-lauroxypropyl-N -p-chlorobenzyl biguanide; 5,6-
dichloro-2-guanidobenzimidazole; and N-p-chlorophenyl-
N -laurylbiguanide.
The long chain tertiary amines also possess
2~ antibacterial and antiplaque activity. Such
an~ibacterial agents include 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 of from 2 to 50 ethenoxy
groups per molecule) and sal~s thereof with acids and
compounds of the structure:
/(CH2CH20)zH (CH2CH20)XH
I
R-N-CH2CH2N
\ (CH2CH20)yH
where R is a fatty alkyl group containing 12 to 18
carbon atoms and x, y and 2 total 3 or higher, as well as
salts thereof. Generally, cationic agents are preferred
for their antiplaque ef~ectiveness.
` .
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~lh~ ~n~ibact~Li~l antiplaque compound is
preferably one which has an antibacterial activity such
~h~l~ its phel)ol co-e~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.~.C.) of benzethonium chloride is given by the
manut`acturer as 410, for S. aureus. The cationic
antibacterial agent will generally be a monomeric (or
~, ~ o~
-~ possibly dimeric) materia~ ~olec~lar weight well below
2,000, such as less than about 1,000 It is, however,
within the broader scope o~ the invention to employ a
polymeric cationic antibacterial agent. The c:ationic
antibacterial is pref~rably supplied in the form of an
orally acceptable salt thereof, such as the chloride,
bromide, sulfate, alkyl sulfonate such as methyl
sul~onate and ethyl sulfonate, phenylsulfonate, such as
I
; . p-methylphenyl sulfonate, nitrate, acetate, gluconate,
etc.
The nitrOgen-CQntaining cationic antibacterial
agents and long chain tertiary amine antibacterial
agents effectively promote oral hygiene, particularly by
removing plaque. However, their use has been observed
to lead to staining of dental sur~aces 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 ~HAP) which includes Ca~2 and PO4 3 ions.
~ In the absence of dental plaque additional Ca+2 and PO4 3,
- particularly from saliva, can be deposited on the
enamel and such deposits can include color ~odies which
ultimately stain the tooth enamel 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 environ-
ment and the denatured protein can then act as a nucleating agent which is
deposited on and stains or discolors tooth enamel.
P~eviously employed additives which reduced dental staining by
cationic antibacterial antiplaque agents also generally reduced the activity
- of antibacterial antiplaque agents such as bis-biguanido compounds, as by
forming a precipitate with such agents.
; 10 In accordance with certain of its aspects, this invention relates
to an oral composition comprising an orally acceptable vehicle containing
approximately by weight GoOl% to 10% of a 2-phosphono-butane-1,2,4-
tricarboxylic acid (PBTA) compound of the formula
':~. O CH2-COOH
HO ¦¦ ¦
(I~ \ P-C - COOH
HO ¦ R
R-CH- ff H-COOH
~ wherein R is hydrogen, lower alkyl or carboxyl, and R is hydrogen or methyl,
or an orally acceptable salt thereof, preferably water soluble, such as with
~ an alkali metal (e.g. sodium and potassium), ammonium, Cl-C18 mono-, di- and
; tri-substituted ammonium (e.g. alkanol substituted such as mono-, di- and
tri-ethanolammonium) cation, and 0 to 15% of at least one normally staining
nitrogen-containing antibacterial antiplaque agent based on the free base
form of said agent.
Compounds of the above formula, and methods Eor their production
are disclosed in United States Patent Nos. 3,886,204 and 3,886,205. The
preferred PBTA compound for use in the present invention is the unsubstituted
compound of the above formula (I) in which R and p~l are each hydrogen. When
R is lower alkyl, it preferably contains 1 to 4 carbon atoms, especially
methyl.
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:~ The concentration ~ the PBTA compound (or salt) in the
oral composition~ can range widely, typically upward ~rom about
O.01~ by weight, with no upper limit on the amount that can be
utilized except as dlctated by cost or incompatibility with the
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vehicle. Generally, concentrations of ab~ut 0.01~ to about
10~ and preferably about .1% to 6% by weight are utilized
Oral compo~itions which in the ordinary course of usage
could be accldentally inge~ted pre~erabl~ contain lower
- 5 concentrations of the P~TA compound Thus~, a mo~thwash in
accordande with this invention preferably contains less
than about 2 weight ~ o~ the PBTA compound, preferably about
0.1 - 1.5 wt. ~. Other dentifrice compo~itions, topical
solutions and prophylactic pastes~ the latter to be administer-
IO ed profesgionally~ can preferably contain about 0.1 to 3
weight % o~ the PBTA compound.
The PBT~ compounds of this invention are anti-
nucleating agents, oral composition~ of this invention con-
taining them are effective in reducing formation of dental
. .
calculus without unduly decalcifyin~ the dental enamel3 and
in contrast to the above descrlbed nltrogen-contalning anti-
bacterial, antip~aque agents, such PBTA compounds and
- ~ compositions have little or no tendency to stain the teeth,
in addition to e~fectively inhibiting gingivitis.
It is a further advantage of this lnvention th&t
these anti-nucleating antlcalculus PBTA compounds unexpect-
edly inhibit, l e. prevent or remove, the staining of dental
enamel caused by the above-described nitrog~n-contalning
antiplaque, antibacterial agent~ without preclpit&ting or
substantially adversely a~ectlng their antibacterial and
antiplaque activity. Not all anti-nucleatirig agents are
effective t~ prevent ~tainlng by such antibacterial agents.
Victamide (also known as Victamine C) which is a condensa-
tion product of ammonia with phosphoruspentoxide, actually
; ~ 30 increase~ staining even ln the absence of such antibacterial
' agents.
.
~8-
When pre~ent, these normally staining antibacter-
i~l antiplaque agents are typically employed in normally
effective amountsg e.g., such that the ora]. product contAins
between about 0.001 and 15~ by weight thereof. Preferably
: 5 for desired levels o~ antiplaque efrect, t~le ~inished oral
.
product contains about 0.01 to about 5%, and most preferably
~.~ ab~ut 0.25 to 1.0% by weight of the antibacteria.l antlp~que
.~ . agent, re.ferring to lts free base form. Most de~irably the
; PBTA compound is present in a molar exce~s relative to the
: 10amount of antlbacter~al antiplaque agent (based on it~ ~ree
., .
:~ base form) in order to best minimize~ inhibit or prevent
staining.
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ln certain highly preferred forms of the invention
the oral composition may be substan~ially liquid in character,
-~ such as a mouthwash or rinse. In such a preparation the
~ vehicle is typically a water-alcohol mixture desirably
. .
including a humectan-t as described below. Generally, the
ratio of water to alcohol i6 in the range of ~rom about 1l1
to a~out 20~1, pre~erably about 311 to lOsl and most preferably
about 411 to about 5-1, by weight. The to-tal amount o~ water-
.:
alcohol mixture in this type o~ preparation is typically
~.
in the range of from about 70% to about 99.9% by weight of
the preparation. The pH of such liquid and other preparations
~` of the inverltion i5 generally in the range o~ from ~bout 4.5
.
to about 9 and typically ~rom about 5.5 to 8, The pH is
prererably in the range of from about 6 t~ about 8,0, It
is noteworthy that the composi-tions of the invention may
. .,
~ be applied orally at a pH below 5 without substan-tially
`~ decalcifying dental enamel. The pH can be controlled with
acid (e.g. citric acid or benzoic acid) or base (e.g.
sodium hydroxide) or buffered (as with phosphate buffers).
Such ~liquid oral preparations may also oontain a surface
active agent and/or a fluorine-providing compound.
In certain other desirable forms of this invention,
the oral composition may be substantially solid or pasty in
character, such as toothpowder, a dental tablet, a toothpaste
or dental cream. The vehicle of such solid or pasty oral
preparations generally contains polishing material. Examples
of polishing materials are water-insoluble sodium metaphosphate,
potassium metaphosphate, -tricalcium phosphate, dihydrated
calcium phosphate, anhydrous dicalcium phosphate, calcium
pyrophosphate, magnesium orthophosphate. trimagnesium
, ~ -
~s~
Phospha.te, calclum carbonate~ alumina~ hydrated alumina,
:` aluminum silicateg zirconium silicate, silica, bentoniteg
.. and mixtures thereof~ Preferred polishing materials include
silica gel or colloidal silica~ complex amorphous alkali
~ 5 metal aluminosilicate and hydrated al~ina.
: Alumina, particularly the hydrated alumina sold by
Alcoa as C333, which has an alumina content of 64.9~ by weight,
a silica content of o.oo8~, a ferric oxide content o~ 0.003~,
and a moisture content o~ 0 37%, at 110C., and which has a
specific gravity of 2 ~2 and a particle slæe such tha.t 100
: of the particles are 1~9s than 50 microns and 84% o~ the
particles are less than 20 microns, is very erfective.
When visually clea.r antlcalculus gels are employed,
a polishing agent of colloidal siIica, ~uch e~s those sold
under the trademark SYLOID as Syloid 72 and Syloid 74 or under
the trademark SANTOCEL as Santocel 100 and alkali metal alumino-
silicate c~mplexes 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. For similar reasons~ alkali
metal aluminosilicate complexes are particularly useful as
polishing agents in visually clear gels contalning the PBTA
compound in comblnation with the described nitrogen-containing
antibacterial antiplaque agents~
Many o~ the so-called "water-insoluble" polishing
: materials are anionic in character and also include small
amounts of soluble material. Thus, insoluble sodium meta-
phosphate may be formed in any sultable manner, as illustrat-
ed by Thorpe's ~lctionary of A~lied Chemistry, Volume 9,
4th Edition, pp. 510 - 511. The forms of insoluble
~ r~
~15~
;odium metaphosphate kno~l ~s Madrell~s sal-t an~ 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
metaphosphatcs. There is present therein a minor amount
of soluble phosphate material as impurities, usually a
- ~ew percent such as up to 4yO by weight. The amount ofsoluble phosphate material, whic~ is believed to include
a soluble sodium trimetaphosphate in the case of insoluble
~etaphosljhate~ may be reduced by washing with wa-ter if
desired. The insoluble al}cali metal metapho~phate .is
typicc~lly employed in powder form of a particle~size such
that no more than about 1% of the material is larger than
about 37 microns.
The polishing material is general].y present in
amounts ranFin~ from about lO~ to about 99% by weight of
the oral preparation. Preferably, it is present in amounts
ranging from about lO~ to about 7~ in toothpaste, and from
about 70~0 to about 99% in toothpowder.
In the preparation of toothpowders, i-t is usually
sufficient -to admix mechanically, e.g., by milling, the
various solid ingredients in appropriate quantities and
particle sizes.
In pasty oral preparations thc PBTA compound should
be compatible with the other components of the preparation,
Thus, in a too-thpastej the liquid vehicle may comprise water
and humectant typically in an amoun-t ranging fram about
10% to about 90% by weight of the preparation. Glycerine,
propylene glycol, sorbitol, or polyethylene glycol 400 may
also be present as humectants or binders. Particularly
advantageous liquid in~redients comprise mixtures of water,
glycerine and sorbitol.
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In clear gel~ where the refractive index ls ~n
important consideration, about 3-30% by we.ight of water,
O 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 mater-
ials, typically Irish~moss~ sodium carboxymethylcellulose,
methylcellulose~ hydroxyethylcellulose~ hydroxypropylmethyl-
cel1ulose, the Carbopols(e g., 934, 9~0 and 941), gum
tragacanth, polyvinylpyrrolidone or starch or mixtures there-
of or the like is usually pres~nt in toothpaste ln an ~nountup to about 10% by weight, pre-~erably in the range of ~:r.om
about 0.5~ to aOout 5%. In a toothpaste or gel3 the liquids
and solids are proportioned to ~orm a creamy or gelled mass
which is extrudable from a pressurized container or ~rom a
collapsible, e.g., aluminum or lead, tube
The solid or pasty ora.l preparation whlch typically
has a pH measured on a 20~ slurry o~ about 4.5 to 9, generally
about 5.5 to about 8 and pre.~erably about 6 to about 8.o,
may also contain a surface active agent and/or a ~luorine-
providing compound.
It will be understood that, as is conventiona.l,
: the oral preparatlons are to be sold or otherwise distrubuted
in suitable labelled packages. Thus a ~ar o~ mouthrinse
will have a label describing it, in substance~ as a mouth-
rinse or mouthwash and having dlrections .~or its use; and
a toothpaste will usually be in a collapsible tube, typically
aluminu~, lined lead or plastic, or other squeeze dispenser
for metering out the contents, having a label describing it,
in substance, as a toothpaste or dental cream.
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-12-
1~ S~S:l
- ~rganic surf'ace-ac-tive a~ents are used in the
composi-tions of the present invention to achieve increased
prophylactic action, assist in achieving thorough and
complete dispersion of the PBTA ' agent -throughout
the oral cavity, and render the instant compositions more
cosmetically acceptable. The organic surface-ac-tive ma-terial
is preferably anionic, nonionic or ampholytic in nature, and
it is preferred to employ as the surface active agent a
de-tersive material which imparts to the composition detersive
and foaming properties. Suitable examples of anionic
surf.~ctants are water-soluble salts of higher. fatty acid
mono~lyceride monosulfates, such as the sodium salt of the
monosulfated monoglyceride of hydrogenated coconut oil
fatty acids, higher alkyl sulfates, such as sodium lauryl
~ 15 sulfate, alkyl aryl sulfonates, such as sod.ium dodecyl
benzene sulfonate, higher alkyl sulfoace-ta-tes, higher fatty
`~ acid esters of` 1,2 dihydroxy propane sulfonate, and the
substantially saturated higher aliphatic acyl amides of
lo'wer aliphatic amino carboxylic acid compounds, such as
: 20 those having 12 to 16 carbons in the f'at-ty acid, alkyl, or
acyl radicals, and the like. Examples of the last mentioned
amides are N-lauroyl sarcosine, and the sodium, potassium,
and ethanolamine salts of N-lauroyl, N-myris-toyl, or N-palmitoyl
sarcosine which should be substantially ~ree from soap or
'~ 25 similar higher fatty acid material. The use of these
s~-~rcosinate compounds in dentif'rice compositions of the
present invention is particularly advantageous since these
materials exhibit a prolonged and marked effect in the
inhibi-tion of acid formation in the oral cavity due to
carbohydrate breakdown in addition to exerting some reduction
in thc solubility of tooth enamel in acid solutions.
~ -13-
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~xample~, of water--soluble nonionic surfactants are
condensat,iorl products o~ ethyl~ne oxide wl th variou~ reactiv~
hydrog~n-containin~ compounds reactive therewith having long
hydrophobic chains (e,~, alipha-tic chains of about 12 to 20
S carbon a-toms), which condensation products ("ethoxamers")
contain hydrophilic polyoxyethylene moieties, such as
condensation products of poly (ethylene oxide) with fatty
acids, fat-ty alcohols, Xatty amides~ polyhydric alcohols
(e.g. sorbi-tan monos-~arate)and polypropyleneoxide (i,e,
- ~ 10 Pluronic ma-terials).
~ In certain forms of this invention a fluorine- '
providing compound is present in the oral preparation, I
These compounds may be slightly soluble in water or may
be fully water-soluble, They are characterized by their ~,
abili-ty to release fluoride ions in water and by substantial
freedom from reaction with other compounds of -the oral
prepara-tion~ Amon~ these materials are inorganic fluoride
salts, such as soluble alkali metal~ alkaline earth me-tal
and heavy metal salts, for example, sodium fluoride, I
potassium fluoride, ammonium fluoride, a
copper fluoride such as cuprous fluoride, zinc fluoride,
a tin fluoride such as stannic fluoride or stannous chloro-
fluoride, barium fluoride, sodium fluorsilicate, ammonium
fluorosilicate, sodium fluorozirconate, sodium monofluoro-
phosphate, aluminum mono~ and di fluorophosphate, and
fluorinated sodium calcium pyrophosphate, Alkali metal
and tin fluorides, such as sodium and stannous fluorides,
sodium monofluorophosphate and mixtures thereof, are
preferred,
3Q 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, bu-t it must
Tf~de /i1ar,K
-14-
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bc a non-toxic amo-lnt. In a solid oral preparation, such
as toothpa~te or toot}lpowder, an amount of such compound
which releases a maximum of abou-t l~o by weight of the
preparation is considered sa-tisfactory. Any suitable
minimum c~nount of such compound may be used, but it is
prt~fer.lbly to cmF)loy sufficient compound -to release about
0.005~ to 1~" and prefcrably about O.l~o of fluoride ion.
Typica11y, in -the cases of a~kali metal fluorides and
stannous iluoride, this componen-t is present in an amount up
to abou-t 2~ by weif~)lt, based on -the weight of the preparation,
and preferab1y in the range of about 0.05~0 to 1%. In the
cac,e ol~ sodium mono~luorophospha-te, the eompound may be
present in an amoun-t up to 7.65~ by weigh-t, more typlcally
abollt o.7G%.
~; 15 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
abou-t 0.0013% to 0.1% and most preferably about 0,0013% to
0.5~, by weight, of fluoride ion,
Various other materials may be incorporated in
the oral prepara-tions of this invention such as whitening
agents, preservatives, silicones, chlorophyll compounds,
~; otheF anticalculus agents, antibacterial antiplaque agents9
and/or ammonia-ted material such as urea, diammonium phosphate,
and mixtures thereof, These adjuvan-ts, where present, are
incorporated in the preparations in amounts which do not
substantially adversely affect the properties and
characteristics desired.
~ny suitable flavoring or sweetening material
may also be employed. Examples of
'
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1L5~
suitable flavoring constituents are ~lavorlng oils, e.g.,
oil of spearmint, peppermint, wintergreen, sassa~ras~ clove,
sage, eucalyptws, mar~oram, cinnamon, lemon, and orange, and
methyl salicylate. Suitable sweetening agents include
sucrose~ lactose, maltose, sorbitol, xylitol, sodium cycla-
mate, perillartine, APM (aspartyl phenyl alanine, methyl
ester) 3 saccharine and the like. Suitably, ~lavor and
sweetening agents may together comprise ~rom about 0.01% to
5~ or more o~ the preparat~on.
In preparing the oral compositions of this invention,
it 1s preferred but not essential to add the PBTA after the
other ingredients (except perhaps some o~ the water) ars
mixed or contacted with each other to avoid a tendency ~or
the PBTA to be precipitated.
For instance, a mouthrinse or mouthwash may be
prepared by mixing ethanol and water with flavoring oil,
surfactant~ humectant, optional antibacterial antiplaque
agent, such as cetyl pyrid1nium chloride, benzethonlum
chloride or chlorohexidine~ swee~ener~ colo-r and then the
above-de~ined PBTA compound followed by additional water as
desired.
A toothpaste may be prepared by ~orming a gel with
humectant, gum, thickener or gelling agent such as hydroxy-
ethyl cellulose, sweetener and adding thereto polishing
ag0nt3 flavor, optional antibacterial antiplaque agent~
additional water, and then the above-defined PBTA compound.
~f sodium carboxymethylcellulose is employed as the gelling
agent together with a bis-biguanide type antibacterial
.
-16-
.
antiplaque agent~ the procedure of ei-ther.U.S. Patent No.
3,84~168 or U.S. Patent No. 3~843,7793 modi:fied by the
inclusion of the PBTA compound i~ followed.
In the pra,ctice o' this invention an oral composi-
tion according to this invention such as a mouthwash or
toothpaste is applied regularly to dental ena,mel, preferably
from about 1 to about 3 times daily, at a pH of about 4.5
to about 9, generally about 505 to about 8, preferably about
- 6 to 8.
. .
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The follo/in~ exaulpleo are further illu trative
of t;he naturc of the present inventiQn, but it i~ understood
that tlle invention i6 no-t limited thereto. All amounts
and lroportions referred to herein and in the appended
claim~ are by weight unless otherwise indicated. I
1,
ll) This is evaluated by a pH Stat method. 1.0 ml
an nqucou3 solution of lX10 4M to lX10 5M of the anti-
calculus agent being tested and O.l M sodium dihydrogen
phosphate is placed in a reaction flask with 22 to 23 ml.
o~ distilled water with continuous stirring in an atmosphere
Or nitrogen. To this is added 1 ml. o~ O.lM CaCl2 and the
pH adjusted -to 7.4 ~ 0.05 with NaOH (final conc. of Ca and
; Pol~3 =4X10 3~). Consumption of O.lN NaOH is recorded
automa-tically by a pH Stat ~Radiometer), In this test, the
formation of HAP occurs in 2 distinct phases. First rapid
base consumption (1-4 min.) then diminishes until 15-20
minutes when second rapid uptake takes place~ A delay in
the time of second rapid consumption or a total absence of
the second rapid consumption indicates an interference with
the crystal growth of }~P. Agents which interfere with HAP
crystal growth are effective anticalculus agents. When
PBTA is tested by the foregoing procedure, the following
results are obtained.
.
.
TABLE I
Anticalculus Time for Delay in
Agent (conc)HAP Formation HAP Formation
~` Water (control~15 min. --
PBTA ~4 ppm) 25 min. 10 min.
PBTA ~8 ppm) 75 min. 60 min.
`-~ PBTA (10 ppm)129 min. 114 min.
:~ PBTA (20 ppm)33.8 hrs.
... The above results show that PBTA effectively inhibits crystal
. 10 growth of HAP in vitro and that the inhibition is not due to complexation
or chelation of calcium since sub-stoichiometric ratios of PBTA:calcium
~; are employed.
; In the following examples illustrative of mouthwash formulat~ons
~ according to the invention~ Pluronic F108 is a polyalkylene oxide block
;~ polymer and a Trade Mark.
:. ~ :
Exam~
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
~i Glycerine 10.0 10.0 10.0 10.0
~:: Na Saccharin 0.03 0.03 0.03 0.03
PBTA 0.1 0.2 0.5 1.0
Water q.s. to 100 100 100 100
pH (with NaOH~ 7.4 7,4 7.4 7,4
.. Appearance.Clear. . Clear ~lear... . Clear
,
, . . .
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The following examples are illustrative of anticalculus tooth-
pastes according to the invention:
Example 6
Silica 30
Glycerine 16
Sorbitol ~70%) 6
Pluronic F--108 3
Hydroxyethyl cellulose1.2
PBTA 2
Sodium saccharin 0.17
Flavor 0.8
Water q.s. to 100
Table II below is illustrative of mouthwash formulations according
to the inven~ion and the antistaining activity of the preferred PBT~ additive
therein. The tooth staining characteristics of the formulations are evaluated
by slurrying hydroxyapatite ~Biogel), a specific salivary protein, a carbonyl
source ~e.g. acetaldehyde)l and a pH 7 phosphate buffer, with and without
the mouthwash formulations being tested. The mixture is shaken at 37C. for
18 hours. The colored HAP powder is separated by filtration, dried and the
color levels ~in reflectance units) determined on a Gardner color difference
meter.
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1. Polyal~ylene oxide block polymer
2. Cetyl pyridinium chloride.
The above results plainly establish that the additives of
the present inven~ion, as exemplified by PBTA, substantially reduce
dental staining ordinarily produced by
antibacterial antiplaqu~ agents as exemplified
by CPC. A PBTA concentration of about 1.0% appears to yield
excellent results. Such additives also reduce or inhibit calculus
m gingivitis and do not significantly reduce the antiplaque activity
; 10 of the indicated antiplaque agents.
Substitution of equivalent amounts of the following anti-
- bacterial antiplaque agents for the CPC employed in Examples g -
13 yield formulations also producing an unexpected reduction in
dental staining and calculus.
Example tibacterial Antiplaque Agent
14 benzethonium chloride (BC)
chlorhexidine diacetate
16 chlorhexidine digluconate
17 dodecyl trimethyl ammonium
bromide
2CH2H ~ C~l2CH2OH
C12 18 Alkyl-N-CH2CH2N ~ CH CH OH
19 alexidine dihydrochloride
., ' ''~.
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-21-
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The follo~ing formulations cxemplify toothpastcs with
antiplaquc activity and recluced stainin~ and calculus.
Example (Parts~
~; 20 21 22
I{ydrated alumina 30 30 30
, ,
Polyethylene glycol 600 22 22 22
: Pluronic F-108 3 3 3
~Iydro~ypropyl methyl cellulose 1.2 1.2 1.2
~ ~ BC o.5 __ __
::~ lO Hibitane -~ 4.725 --
. j CPC 0 5
;: I .
PBTA 1~0 1.0 1.0
:~ ,
~ Sodium saccharin 0.17 0.170.17
.~ FIavor 0.8 0.8 0.8
,` y. ~.
~ Water_~_s~ to lO0 ~ 100 100
~-, ,
,` Signi~icant reductions in dental staining, plaque, calculus
~3~ and gingivitis are also obtained according to the present invention
~j when the PBTA in the above e~amples is replaced by any of the
, other PBTA compounds disclosed in United States Patent No. 3~886,20
and 3,886,205.
: This invention has been described with respect to pre-
ferred embodiments and it will be understood that modifications
and variations thereof obvious to those skilled in the art are
to be included within the spirit and purview of this application
and the scope of the appended claims.
.
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