Note: Descriptions are shown in the official language in which they were submitted.
1'~6~83~
2301-1300
AN'I'IPLAQUE/ANTIGINGIVITIS COMPOSITION
'I`his invention relates to non~antibacterial agents and oral
compositions useful for promoting human oral hygiene, and to a method
for treatin~, controlling or inllibiting both plaque and gingivitis,
~hich latter is characterized by such symptoms as inflammation, bleeding,
recession, and/ors~elling of the gums. Types of gingivitis include
afunctional gingivitis, gingivitis marginal and cotton-roll gingivitis.
Gingivitis leads to periodontitis.
'I'he gums are seriously harmed by deposits of dental plaque,
a combination of minerals and bacteria ~ound in the mouth. Tlle bacteria
associated with plaque can secrete enzymes and endotoxins which can
irritate the gums and cause an inflammatory gingivitis. As the gums
become increasingly irritated by this process they have a tendency to
bleed, lose their toughness and resiliency, and separate Erom the teeth,
leaving periodontal pockets in which debris, secretions, more bacteria
and toxlns further accumulate. It is aLso possible for food to accumulate
in thcs~ pockets, the*eby providing nourishment Eor increased growth
o~ bact~3ria and production o endotoxins and destructive enzymes.
'Actinomyces viscosus, a gram positive rod, has been identified
as implicated in the etiology of gingivitis loeche et al "Bacteriology
of human experimental gingivitis: effects of plaque and gingivitis sores,"
Infection and Immunity 21, 830-839 (1978). This organism attaches to
tooth surfaces to form the dental plaque.
A multitude of materials have been prev~ously proposed and
employed for controlling plaque and gingivitis, but none have been
entirely satisfactory. For example, some of such materials have been
found to be unstabl~ in the presence o the anionic surface active age-nts
generally present in conventional oral preparations~ A number of such
materials such as the cationic quaternary ammonium agents exert an anti-
ha,cterial function ~'hich undesirahly tends to disrupt or destroy the
normal microflora of the mouth and/or the digestive system,
- 1 -
-2- ~26~837 62301-1300
U.s. 3,l~ C3 issucd ~cbru~ry ~5, l~ to Lco Sl~ ovsky
Dnd assignce in comlnon with thc inst~nt apl~lication proposcs, ~Inong a
number of other watcr soluble polyelec-trolytes, the use of polyvinyl
phosphonic ~cid (Vl'A polymer) or salts thercof for complexing cDlciuln
and inhibiting oral cnlculus, but the sole in vivo test described therein
involvcd thc supllying of drinking water containing a hydrolyzed copolymer
of ethylene and ~alcic ~nhydride for ad libitum drinkin~ by rats for a
period of five days. ~lis test is in the nature of a stoichiometric
complcxation of calcium and is unrelated to the threshhold effect
occurring in actllal or~l use involving trentlnent of dental surFaces l to
3 times substantially dDily for at least 2 weeks or lifetime. When
subjected to such an actual use test, polyvinyl phosphonic acid failed
to significantly inhibit oral calculus.
U.S. 4,342,~57 issued August 3, 1982 to Abdul Gaffar,
discloses and claims antigingivitis compositions containing a vinyl
phosphonic acid/vinyl pliosphonyl fluoride copolymer, but a number of
scientisl:s, authorities and/or jurisdictions object to administration
of fluorinatcd mnterials to humans.
The present invention is based on the discovery that VPA
polymer and its salts interfere with or inhibit the attachment of
~ctinomyces viscosus to saliva coated hydroxyapatite (~P) beads. This
is a rclialle indication that the agent ~ould interfere with the attach-
ment of the organis~ to tooth surfaces, should reduce plaque, and hence
reduce or inllibit gingivitis. Such antigingivitis activity has in fact
been corroborated by an in vivo test on ~eagles as more fully discussed
below.
~ccordinl~ to th~ present invcntion, there is now provided
un anti-~ingiVitiS nrld nnti-pla(lueornl composition for inhibiting dental
plaquc and ~ln~ivitis comprising a dentally acccptable oral vehicle and
an effcctive pl~luc~ Dnd ~inF~ivitis-inllibiting amount of polyvinyl
pllospl~onic ncid or ;ln orally ;Icceptnblc salt thcreof, wherein said
: polyvinyl phosphonic acid has a number average molecular
weight of about 6,000 to about 8,000.
~3
-3- 62301-1300
126(}837
The invention also includes a method of inhibiting
human dental plaque and gingivitis comprising applying to the
human oral cavity a composition containing a dentally acceptable
oral vehicle and an e-f~ective plaque- and gingivitis- inhibiting
amount of polyviny] phosphonic acid or an orally acceptable salt
thereof.
The VPA polymer used in this invention should prefer-
ably have a number average molecular weight (obtained ~rom
viscosity or l:ight scattering measurements) of about 6,000 to
about 8,000, and may be prepared in known manner by polymerizing
vinyl phosphonyl dichloride under substantially anhydrous con-
ditions in the prcsence of a free radical catalyst, and then
mixing the resulting polymer with water to hydrolytically
convert the vinyl phosphonyl dichloride units in the polymer
to VPA units. The resulting polymer is in free acid form and
may desirably ~e converted to salt :form by treatment with any
orally acceptable cation - providing base such as alkali metal
(e.g. sodium or potassium), ammonium, Cl 1~ mono-, cli- and tri-
substituted atnmonium, ~e.g. alkanol substituted ammonium, such
as mono-, di- and tri-ethanolammonium, organic amines, etc.
~6(?~37
62301-1300
It will be understood that the mono- and di- forms of the
polymer are the equivalent of the free acid form and that the
term "water soluble" applicable to all such forms is inclusive
o~ readily water dispersible forms thereof in the usual use
concentrat iOllS .
It will also be understood that the VPA polymer may
also contain minor proportions, i.e. less than 50 wt.%,
preferably less than about 10 wt. %~ more preferably less than
about 5 wt. % most preferably less than about 2 wt. %, of units
derived from ol;her non-fluorinated ethylenically unsaturated
monomers which~ in type and amount, are nontoxic and do not
interfere with the desired water soluble and antigingivitis
activities of the polymer. Other such monomers may, Eor
example, include olefins such as ethylene, propylene,
isoprop~lene, butylene and isobutylene, vinyl lower alkyl
ethers such as vinyl methyl, ethyl and isobutyl ethers, alpha,
beta unsaturated carboxylic acids and their lower alkyl and
substituted lower alkyl esters such as acrylic, methacrylic,
aconitic, maleic and fumaric acids and their methyl, ethyl,
isobutyl and dimethylaminoethyl esters, allyl alcohol and
acetate, vinyl and vinylidene halides, vinyl lower alkanoic
acid esters such as vinyl acetate and butyrate, acrylamide and
methacrylamide and N-lower alkyl and N, N-dilower alkyl
~ substituted derivatives thereof, and the like.
; The concentration of the VPA polymeric antigingivitis
agent in oral comlpositions can range widely, typically upwards
of about 0.01% by weight with no uE)per 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
~6~1~37
62301-1300
course of usage could be accidentally ingested preEerably
contain concentrations in the lower portions of the foregoing
ranges.
In certain highly preferred forms of the invention,
the oral composition may be substantially liquid such as
mouthwash or rinse. Such preparations generally contain a
humectant and the vehicle is typically a water-alcohol mixture.
Generally, the ratio of water to alcohol is in the range o~
from about 1:1 to about 20:1 preEerably from 3:1 to 20:1 and
most preferably about 17:3, by weight. The total amount of
water-alcohol mixture in this type of preparation is typically
in the range of from about 70 to about 99.9% by weight of the
preparation. The pH of such liquid and other preparations of
the invention is generally in the range of from about ~.5 to
about ~ and typically from about 5.5 to 8Ø The pH is
preferably in the range of from about 6 to about 8Ø It is
noteworthy that the compositions of the invention may be
applie~ oral]y at a lower pH without substantially decalcifying
dental enamel.
Such liquid oral preparations may also contain a
surface active agent and/or a fluorine-providing compound.
In certain other desirable forms of this invention,
the oral composition may be substantially solid or pasty in
character, such as toothpowder, a dental tablet, a toothpaste
or dental cream. The vehicle of such solid or pasty oral
preparations cont:ains polishing material. Examples of
polishing matericlls are water-inso:luble sodium metaphosphate,
potassium metaphosphate, tricalcium phosphate, calcium
pyrophosphate, magnesium orthophosphate, trimagnesium
phosphate, calcium carbonate, alumina, hydrated alumina,
aluminum silicate, zirconium silicates, silica bentonite, and
12~;~83~
62301-1300
mixtures thereof. Preferred polishiny materials include
crystalline silica havin~ particle sizes of up to 5 microns a
mean particle size of up to 1.1 microns, and a surface area of
up to 50,000 cm2/gm., silica gel, complex amorphous alkali
metal aluminosilicate, hydrated alumina, dicalcium phosphate.
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 0.037~, at 110C., and which has a
speciEic 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 particularly desirable.
When visually clear gels are employed, a polishing
agent of colloidal silica, such as those sold under the
trademark S~LOID as Syloid 72 and Syloid 7~ or under the
trademark SANTOCEL as Santocel 100 and alkali metal
aluminosilicate complexes are particularly useful, since they
have reEractive 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 "insoluble" polishing materials
are anionic in character and also include small amounts of
soluble materials. Thus, insoluble sodium metaphosphate may be
formed in any suitable manner, as illustrated by Thorpe's
Dictionary of Applied Chemistry, Volume 9, fourth Edition, pp.
510-511. The for~ls of insoluble soclium metaphosphate known as
Madrell's salt and Kurrol's salt are further examples of
suitable materials. These metaphosphate salts exhibit a minute
solubility in water, and therefore are commonly referred to as
insoluble metaphosphates. There is present therein a minor
amount of soluble phosphate material as impurities, usually a
1~6~:)837
62301-1300
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 oE insoluble metaphosphate,
may be reduced by washing wi-th water if desired. The insoluble
alkali metal metaphosphate is typically employed in powder form
of a particle size such that no more than about 1% of the
material is larger than 37 microns.
The polishing material is generally present in
amounts ranging from about 10 to about 99~ by w~ight of the
oral preparatlon. Preferably, it is present in amounts ranging
from about 10 to about 75% in toothpaste, and from about 70 to
about 99% in toothpowder.
In the preparation of toothpowders, it is usually
sufficient to admix mechanically, e.g., by milling, the various
solid ingredients in appropriate quantities and particle sizes.
In pasty oral preparations the above-defined
combination of the antigingivitis agent and polishing material
should be compatible with the other components of the
preparation. Thus, in a toothpaste, the liquid vehicle may
comprise water and humectant typically in an amount ranging
from about 10 to about 90~ by weight of the preparation.
Glycerine, sorbitol, or polyethylene glycol may also be present
as humectants or binders. Particularly advantageous liquid
ingredients are polyethylene glycol and polypropylene glycol.
Also advantageous are liquid mixtures of water, glycerine and
sorbitol.
In clear gels where the refractive index is an
important consideration, about 3-30% by weight of water, 0 to
about 80~ by weight of glycerine, and about 20-28~ by weight of
sorbitol is preferably employed. A gelling agent, such as
natural or synthetic gums or gumlike materials, typically Irish
12bi0837
62301-1300
moss, sodium carboxymethylcellulose, methyl cellulose,
hydroxyethyl cellulose, gum tragacanth, polyvinylpyrrolidone,
starch, and preferably hydroxypropyl methyl cellulose and the
Carbopols* (e.g. 934,9~0 and 941), etcetera is usually present
in toothpaste in an amount of up to about 10% by weight,
preferably in the range of from about 0.5 to about 5%. In a
toothpaste or gel, the liquids and solids are proportioned to
form a creamy or gelled mass which is extrudable from a
pressurized container or from a collapsible, e.g., aluminum or
lead, tube.
The solid or pasty oral preparation which typically
has a pH measured on a 20~ slurry of about 4.5 to 9, generally
about 5.5 to about 8 and preferably about 6 to about 8.0 may
also contain a surface active agent and/or a fluorine-providing
compound.
It will be understood that, as is conventional, the
oral preparations are to be sold or otherwise distributed in
suitable labelled packages. Thus a jar of mouthrinse will have
a label describing it, in substance, as a mouthrinse or
mouthwash ancl having directions for its use; and a toothpaste
will usually be in a collapsible tube, typically aluminum or
lined lead, or other squeeze dispenser for metering out the
contents, having a label describing it, in substance, as a
toothpaste or dental cream.
The oral compositions of this invention may contain a
non-soap synthetLc 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 foaming properties.
U.S. Patent No. 4,041,149 discloses such suitable anionic
surfactants in column 4, lines 31-38, and such suitable
* Trade mark 8
126~837
62301-1300
nonionic surfactants in column 8, lines 30-68 and column 9,
lines 1-12.
In certain forms of thls invention a fluorine-
providing compound is present in the oral preparation. These
compounds may be slightly soluble in wa-ter 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 components of the oral preparation. Among
these materials are inorganic 1uoride 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
fluoricle, zinc fluoride, a tin fluoride such as stannic
fluoricle or stannous chlorofluoride, barium Eluoride, sodium
fluorsilicate, ammonium fluorosilicate, sodium fluorozirconate,
sodium monofluorophosphate, aluminum mono- and di-
fluorophosphate, and fluorinated sodium calcium pyrophosphate.
Alkali metal and tin fluorides, such as sodium and stannous
fluorides, sodium monofluorophosphate and mixtures thereof, are
preferred.
The amount of the fluorine-providing compound is
dependant to some extent upon the type of compound, its
solubility and the type of oral preparation, but it must be a
nontoxic amount. In a solid oral preparation, such as
toothpaste or toothpowder, an amount of such compound which
releases a maximum of about 1% by weight of the preparation is
considered satisfactory. Any suitable minimum amount of such
compound may be used~ but it is preferable to employ sufficient
compound to release about 0.005 to 1%, and preferably about
0.1% of fluoride ion. Typically, in the cases of alkali metal
fluorides and stannous fluoride, this component is present in
~;~60~37
62301-1300
an amount up to about 2~ by weight, based on the weight of the
preparatlon, and preferably in the range of about 0.05 to 1~.
In the case of sodium mono-~luorophosphate, the compound may be
present in an amount up to 7.6% by weight, more typically about
0.76%.
In a liquid oral preparation such as a mouthwash, the
fluorine-providing compound is typically present in an amount
sufficient to release up to about 0.13%, preferably about
0.0013 to 0.1% and most preferably about 0.0013% by weight, of
~luoride.
VarLous other materials may be incorporated in the
oral preparations of this invention, subject to the above.
Examples are whitening agents, preservatives, silicones,
chlorophyll compounds, and ammoniated material such as urea,
diammonium phosphate , and mixtures thereof. These adjuvants,
where present, are incorporated in the preparations in amounts
which c~o not substantially adversely afEect the properties and
charact:eristLcs desired.
Any suitable flavouring or sweet:ening material may
also be employed, also subject to the above. Examples of
suitable flavouring constituents are flavouring oils, e.g.,
oils of spearmint, peppermint, wintergreen, sassafras, clove,
sage, eucalyptus, marjoram, cinnamon, lemon and orange, and
methyl salicylate. Suitable sweetening agents include sucrose,
lactose, maltose, sorbitol, sodium cyclamate, perillartine, APM
~aspartylphenylalanine, methyl ester) and saccharin. Suitably,
flavour and sweetening agents may together comprise from about
0.1 to 5% or more of the preparatic,n.
In the practice of this invention an oral composition
according to this invention such as a mouthwash or toothpaste
containing the antigingivitis agent in an orally acceptable
3L;26~1~37
62301-1300
vehicle may be prepared by unifying the components in
conventional manner, and applied to the gingiva and teeth
regularly, substantially daily, e.g. from about 1 to 3 times
daily or every second or third day, etc., at a pH of about ~.5
to about 9, generally about 5.5 to about 8.5, preferably about
6 to about 8, preferably for at least two weeks up to eight
weeks or more or lifetime.
In the case of chewing gum and other products, the
VPA active ingredients can b~ incorporated in any suit~ble
manner during the usual manufacture of the product. For
example, they can be incorporated in a warm gum base with
stirring to distribute the same uniformly therein. They can
also be added to the exterior or outer surfaces oE a gum base
in order to coat the base. The usual gum bases can be used,
representative materials being jelutone, rubber latex, vinylite
resins, etc., in addition to other usual materials such as
plasticizers or soteners, sugar or other suitable
carbohydrates such as glucose, sorbitol, etc.
The following examples are further illustrative of
the nature of this invention but it is understood that the
invention is not limited thereto. All amounts and proportions
referred to herein and in the appended claims are by weight,
and temperatures are in degrees C unless otherwise indicated.
The VPA polymer employed in these examples was in the form of
disodium salt.
lZ6~837
62301-1300
EXAMPLE I
Adsorption of Sodium Polvvinyl PhosDhonate to Dental Enamel:
The adsorption of the polymer to enamel surfaces was
measured in vitro. Human extracted, non-carious and non-filled
molar teeth were cleaned by pumicing. They were then polished
with a rubber cup and polishing agent. They were mounted onto
a rubber stopper via a nichrome wire which was tied through a
hole in the roots. A sodium salt of polymer solutions at pH
7.0 were disp~nsed ln polyethylene tubes. The teeth were
submerged in the solution at 37C. for 1 hour under a
continuous agitation. Special care was taken to avoid the
contact of solution wi-th roots of the teeth. After one hour
incubation, the teeth were removed and the solutions were
analyzed for the amount of polymer left in the solution. The
adsorption was calculated by a diEerence between amount
initially added minus the amount left after exposing to teeth.
The concentration of the polymer in the solution was
assessed by turbidimetric measurements using 5M CaC12 solution
at pH 4.5. 1 cc. of CaC12 was added to 1 cc. of the polymer
solution. The turbidity of resull:ing colloidal suspension at
500 nanometer proved to be proportional to the polymer
concentration ranging from 1 to 8 mgs/ml. A calibration curve
was carried out with the known amount of the polymer.
TABLE 1
Results:
Conc. of POly-Amt. Left After Tooth Amt. Adsorbed to
Na2VPA (mg/ml) Immersion (mg/ml) Teeth tmg/ml)
2 0.4 1.6
3 0.7 2.3
4 1.1 2.9
1.6 3.4
6 2.4 3.6
7 3.3 3.7
The data indicated a significant adsorption of the VPA polymer
to enamel surfaces, 12
. .
126~837
62301-1300
EXAMPLE II
Effect of Polymer on the Adsorption of Actinomvces Viscosus T14
on Saliva Coated Hydroxyapatite (HAP) Beads:
80 mgs. of HAP beads were pre-coated with human
saliva (blood type A) for 12 hours. The beads were washed and
pre-treated with the solution of the polymer at pH 7.0 for 5
minutes. The treated beads were washed with a buffer
consisting of 0.05 M KCl lmM P04, lmM CaCl2 and 0.1 mM MgCl2 at
pH 6Ø This buffer simulates saliva inorganic constituents.
For the adsorption studies the mixture (1.0 ml)
contained 5 x 107 3H thymidine labelled bacteria (Actinomvces
viscosus), 30 mg saliva coated beads (S HAP) and the buffer.
The mixture was continuously shaken at room temperature for 2
hours. The beads were allowed to settle for one minute and the
supernatant which contained unadsorbed cells was removed. The
radioactivity was measured via liquid scintillation counts.
Portions of known H3 labelled cells were counted in a similar
manner so that counts per minute may be related to bacterial
cell member. Control bacterial suspensions were incubated with
S-HAP beads.
TABLE 11
Results:
Effects of Pre-Treatina Saliva Coated HAP Beads With PolYvin
Phos~honate on Adsor~tion of Bacteria
A. Viscosus LY7
S-HAP Cells Adsorbed (X 107)
Treatment Per 20 mq S-HAP~ Relative to Buffer
Buffered KCl 3.88 + 0.04 100
1% Na2VPA 1.23 + 0.05 32
Polymer
0.1% Na2VPA 3.54 ~ 0.16 91
Polymer
0.01% Na2 VPA 3.55 + 0.09 92
13
J~26~83~
62301-1300
The results show that a pre-treatment of S-~AP with 1~
polyvinyl phosphonate was significantly effective in inhibiting
bacterial attachment.
EXAMPLE III
This study in 20 beagle dogs evaluated the effect of
a placebo and a rinse containing 1~ sodium salt of polyvinyl
phosphonic acid on plaque/gingivitis for 4 weeks. The dogs
were given complete prophylaxis to remove salt and hard dental
deposits. A disclosing solution was used to insure the
complete removal of dental deposits. The beagles were kept on
a soft diet for,4 weeks. Group I (10 dogs) were then treated
with the placebo rinse, while Group II was treated with the
rinse containing the polymer. The treatment was done l/day/5
days per week by applying 5-6 cc. of the rinse on all
dentition. The study was double blind. Neither the evaluator
nor the~ people involved ln the treatments knew the assignments
of rinses in the respective groups. The plaque and gingivitis
was as~;essed via Loe and Silness index (Ac,ta Odontolo~ica
Scandinavica, 21:551-555 t1963)).
TABLE III
Results:
Plaque Index/ Gingival Index
Mouth Tooth - 4 wks % 4 Wks Post
Rinse N Group Post Treatment Change Treatment Change
Placebo 10 I 0.99 + 0.23 --- 0.91 + 0.10 ---
1% Na 10 II 0.68 + 0.23 -31 0.73 + 0.29 -20
VPA Poly-
mer
Compared to the placebo rinse, the polyvinyl phosphonate rinse
significantly recluced plaque/gingivitis for four weeks.
126Q83~
62301-1300
The ~Eollowing examples of oral (mouthwash and
toothpaste) formulations are further illustrative of this
invention.
EXAMPLE IV
Wt. Percent
Glycerin 10.0
Ethanol 10.0
Pluronic* Fl08* 3.8
Na Saccharin 0.03
Polyvinyl phosphonate 1.0
Flavour 0.22
Water to make lO0.00
* BAS F-Wyandotte block polymer nonionic surfactant
containing about 20 wt.% polyoxypropylene chain of
about 3251) M.W. and about 80 wt.% polyoxyethylene.
- 14A -
* Trade;mark
:, . .. .
126(~837
EX~MPLE V
Wt, Perccnt
Clycerin 25.0
Carboxymet~iyl Ce11ulose 1.3
Sodium Benzoate 0.5
Na Saccharin 0.2
Silica 30.0
Sodium Lauryl Su:Lfate l.S
Polyvinyl Phosphonate . 3.0
Water to make 100.0
This invention has been disclosed with respect to
preferred embodiments and it will be understood that modifications
~nd variations thereof obvious to those skilled in the art ate to
be included within the spirit and purview of this application and
the scope of the appended claims.
q
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