Note: Descriptions are shown in the official language in which they were submitted.
1 ~ ~ 7 ~ ~ Z J&J 1027
ZINC SALTS O~ SULFONATED POLY (ARYLENE ETHER SULFONE)
POLYMERS AS HIGHLY SUBSTANTI~E DENTAL PLAQUE BARRIERS
Technical Field
This invention relates to oral hygiene compositions and
methods using such compositions to prevent attachment of
bacteria to teeth. More particularly, it relates to zinc
salts of certain sulfonated polysulfone polymers that have
been found useful in inhibiting the agglutination of oral
microbes on teeth.
Background Art
.
The prevention of the deposition of dental plaque on teeth
is a highly desired result. Dental plaque results when
cariogenic bacteria aggregate in colonies on the surface
of teeth and form a tenacious deposit thereon. The
presence of plaque on teeth is believed to be a precursor
to development of gingivitis, dental caries and
periodontal disease.
While many attempts have been made to control the effects
of cariogenic bacteria and the dental plaque they produce,
for example, fluoride, flossing, brushing, etc.,
treatments, these are typically directed to either
counteracting the secondary effects of plaque on the teeth
and gums, or to the removal of plaque that is already
formed on and adhering to the teeth and surrounding
tissue. Sueh treatments are not, however, entirely
successful, and must be supplemented with periodic
treatment by dental professionals. To date, there is no
commercially feasible home treatment method for
preventing the formation of plaque or its adhesion to
teeth.
A number of hydrophilic sulfonic acid and sulfonic acid
salt derivatives of certain poly (arylene ether sulfone)
7~
polymers have been synthesized and found to inhibit the
deposition of dental plaq~e onto human teeth. These
hydrophilic polymeric sulfonates have good film forming
characteristics and, accordingly, are applied to teeth
from various dentifrice formulations, mouth rinses, or
other oral hygiene procedures. The salts of the
sulfonated p~lymers are highly anionic in nature and
substantially soluble in water or water/organic solvent
vehicles, primarily because of the relatively high degree
of sulfonation achieved during preparation of these
derivatives. While the mechanism of action of the
hydrophilic polymeric films in retarding plaque deposition
is not known with absolute certainty, it is presumed that
the films of anionically-charged polymers deposited on
teeth effect a mutual repulsion between the negatively
charged polymer film and the negatively charged
microorganisms in oral fluids responsible for plaque
generation. For example r when powdered human dental
enamel is dispersed in the aqueous media containing salts
of the polymeric sulfonates, a substantially negative
surface charge is imparted to the enamel particles, as
determined by zeta potential measurements.
The sulfonated poly tarylene ether sulfone) polymers are
especially effective as components of dentifrices and
other oral hygiene preparations in reducing dental plaque
deposition on teeth. These hydrophilic, polymeric,
anionic sulfonates are prepared by aromatic sulfonation of
poly (arylene ether sulfone) polymers, followed by
3~ conversion of the polymeric sulfonic acid derivatives to
metal salts and ammonium or amine-salts. The metal and
ammonium salts are preferred over the free sulfonic acid
forms of the polymers because of their higher water
solubility and lower degree of acidity, thereby favoring
their use in oral hygiene formulations as agents for
reducing dental plaque deposition.
~3Z
The Invention
In accordance with the present invention, it has now been
found that the zinc salts of the foregoing sulfonated
poly(arylene ether sulfone) polymers exhibit surprisingly
superior substantivity to human dental enamel, as
determined, e.g., by zeta potential measurements, after
repeated washings with water) to that exhibited by other
salts. Accordingly, the present invention provides highly
substantive oral hygiene preparations for reducing dental
plaque deposition on teeth comprising a zinc salt of a
sulfonated poly(arylene ether sulfone) polymer, as more
fully defined hereinafter, in a pharmaceutically
acceptable oral hygiene delivery system compatible
therewith.
The zinc salts of the sulfonated poly(arylene ether
sulfone) polymers that are the active ingredients of the
oral hygiene compositions of this invention have repeating
units selected from the group consisting of structure
(A), ( Ar iSO2-Ar2-O t
~A)
and structure (B),
( Arl-S02-Ar2-0-Ar3-0-t--
(B3
wherein Arl and Ar2 are each selected from
~ ~ ~SD~
(
o3 e)~
11~7;~
--4--
provided further that Ar2 also can comprise one or
more spacing units selected from -Ar4-S02-Ar4-
and -Ar4-S02-Ar4-S02-Ar4-, each
Ar4 in said spacing units being separately selected
from
5S
(S~ Jc ,~
~ ~n~ ~ (SO~c
Ar3 is selected from Ar4 and
(~1 (5~)~
where Y is selected from lower alkylene having 1-5 carbon
atoms, lower alkylidine having 2-S carbon atoms,
~ II_C~3
~53~)~ ~ (50~)e (~43~
0, S, and S02; subscript c being an integer selected
from 0, l, and 2; the quotient, obtained by dividing the
total number of sulfonate groups (i.e. the sum of the cls
within each of repeating units (A) and (B) by the number
of aromatic groups in said repeating unit, being (on the
average) at least about 0.2; and M is 1~2 Zn.
~7;~
While the molecular weight of the polymers used in the
compositions of the present invention is not considered to
be a critical factor, they generally hsve a weight average
molecular weight within the broad range of from about
5,000 to about 200,000. A preferred molecular weight
range is from about 20,000 to about 50,000.
The polymers utilized for conversion to sulfonate
derivatives are available either commercially or
synthesized by known procedures found in the literature.
Representative examples of commercial poly (arylene ether
sulfone) polymers which can be sulfonated to the
hydrophilic, anionic sulfonates include the following:
(a) Udel~ Polysulfone, type P1700 or medical grade MGll,
available from Union Carbide Corp. in a molecular weight
of about 35,000, and having the following repeating unit
structure:
~ ~ ~ ~ ~ O
tb) Victrex~ Polyethersulfone, grades lOOP, 200P, 300P,
from ICI America, Inc.:
~ ~
(c) Radel0 Polysulfone from Union Carbide Corp., and
thought to have the following repeating unit structure:
3~
--6--
~O~S~O~ '
The generalized structures for other poly (arylene ether
sulfone) polymers that can be sulfonated to form the
sulfonated polymers of this invention are represented as
formulas (I) and (II), and their method of synthesis is
indicated in equations (1) and (2) below:
~Ar5-so2~ ( A2 5-S02-A~6-0-Ju~7-~
~II )
(l~ X-~5-502-Ar6-OM ~ ~Ar5 82 A~6 ~
(2) Y-~ -502-Ar -X + )~'O-~.r -0~' ~
5 2 As6 o-Ar7-o~ + 2M'X
wherein X is a halogen; M' is a univalent metal such as
sodium or potassium;
Ar5 and Ar6 are each selected from
.
35 ~ ~.J ~
7~2
provided further that Ar6 also can comprise one or
more spacing units selected from -Arg-502-Ar8-
and -Arg-S02-Arg-S02-Arg-, each
Ar8 is said spacing units being separately selected
from
10 ~,
Ar7 is selected from AR8 and
~673~;~
where Y is selected from lower alkylene having 1-5 carbon
atoms, lower alkylidine having 2-5 carbon ato~ns,
~ I ~
~1~>
O, S, and SO2.
Polymers of structure (I) can be synthesized by the
general procedure ~summarized in equation (1) above)
described by T. E. Attwood, et al., in Polymer, Volume 18,
pages 354-374 (1977). Polymers of structure (II) are
prepared by reaction of bis(haloaryl) sulfones with
univalent metal salts of aromatic diols, such as the
reaction taught by R. N. Johnson, et. al., J. Polymer
Science, Part A-l, Volume 5, pp 2375-2398 (1967). Poly
(arylene ether sulfone) polymers suitable for conversion
to sulfonated derivatives for use in the compositions and
method of the present invention can be synthesized by
varying the nature of the aromatic group, orientation of
the linkages on the aromatic ring, and spacing of the
sulfone (SO2), ether (O) and other connecting groups
in accordance with the foregoing definitions of the
aromatic polymeric structures (I) and (II).
The sulfonation of poly (arylene ether sulfone) polymers,
such as Udel~ Polysulfone, to water insoluble sulfonated
polymers with low degrees of sulfonation, that are suit-
able as membranes for water desalination, have been
described in the literature and patent publications such
as A. Noshay and L. M. Robeson, J. Applied Polymer
Science, 20, 1885-1903 (1976); C. L. Brousse, et. al.,
~i73~;~
g
Desalination, 18, 137-153 (1976); and U.S. Patents
Nos. 3,709,841 (issued January 9, 1973), 3,855,122 (issued
December 17, 1974), and 3,875,096 (issued April 1, 1975).
The sulfonated polysulfones reported in this literature
differ from the polymeric materials employed in the
compositions of the present invention in that they are
substantially water insoluble, due to the relatively low
degree of sulfonation, and therefore cannot be utilized in
the aqueous media required for oral hygiene applications.
As will be described hereinafter, the poly(arylene ether
sulfone) zinc sulfonates of the present invention are
substantially soluble in water or mixed solvents
comprising water and an organic solvent miscible therewith
(generally at least 1% w/w) and hydrophilic as a
consequence of their higher degree of sulfonation. As
discussed in greater detail hereinafter the degree of
sulfonation ~D.S.) also has a significant effect on the
extent of dental plaque deposition. D.S. as used herein
is the average number of sulfonate or sulfonic acid groups
per repeating unit of the polymeric structure.
Preferred sulfonation agents for preparing the sulfonatèd
polymeric barriers of this invention are anhydrous sulfur
trioxide, triethyl phosphate (TEP) complexes of sulfur
trioxide, and chlorosulfonic acid. Sulfonations can be
effected in solvents such as methylene chloride,
1,2-dichloroethane, and chloroform. Temperature control
of the sulfonation reaction with sulfur trioxide and its
complexes with TEP is not very critical. Acceptable
results are obtained over a -20C to +40C range.
Sulfonations are generally effected at ambient room
temperatures, since the sulfonation exotherm is very mild
and rarely results in temperature increases beyond 3SC.
Typical impurities in the sulfonated polymer are small
amounts of unreacted polymer, excess sulfonation agent (as
1~73f~Z
--10--
sulfuric acid), and residual triethyl phosphate which are
occluded in the solid polymer. Substantial purification
is effected by slurrying the polymeric sulfonic acid
derivatives in non-solvents therefor, such as the
halocarbons. The preferred process for purification of
the sulfonated polymers (both free acids and salts),
particularly highly water soluble types, is by dialysis
of their aqueous solutions in membrane tubes or hollow
fiber dialyzing units having a molecular weight cut-off
well below the molecular weight of the polymer. Dialysis
removes all of the low molecular weight impurities,
triethyl phosphate, and inorganic salts. ~igh purity
polymers are isolated as solids by freeze-drying or spray
drying the dialyzed polymer solution.
The zinc salts of the sulfonated polymers are conveniently
prepared by addition of at least stoichiometric quantities
of a zinc oxide, carbonate, acetate, chloride, nitrate, or
sulfate to the agueous or alcoholic solutions or
dispersions of the sulfonic acid derivative. In an
alternate procedure, zinc salts can be prepared by an
ion-exchange reaction between the zinc ion and an alkali
metal sulfonate derivative of the polymer.
The ln vitro test procedure we have employed for testing
plaque barrier activity begins with growth of plaque in
small jars containing sterilized trypticase media that has
been supplemented with sucrose. Typically, ten jars are
individually inoculated with 0.5 ml of unpooled freshly
collected human plaque from 10 subjects. In a control
series, a presterilized glass slide or an extracted human
tooth is inserted into each jar. In the test series, the
tooth or glass slide is pretreated with a 1% solution of
the test compound (dissolved in water or other vehicle),
allowed to dry in order to deposit a thin film of the
compound on the surface, and the glass slide or tooth
1~ Ei73~2
placed in the growth media. The jars are incubated under
anaerobic conditions for two days at 37C. The tooth or
glass slide is removed, air dried, and stained with 0.15%
FD&C #3 red dye solution to reveal the accumulated plaque
deposits. The tooth or glass slide is scored for plaque
density on a 0 to S scale. Plaque barrier activity is
reported as the % of average plaque reduction, as compared
to appropriate controls for ten subjects.
A preferred ln ~itro test procedure utilized to establish
the degree of substantivity of the zinc salts of the
sulfonated poly(arylene ether sulfones) is ~ased on
measurement of the zeta potential of powdered human dental
enamel which has been contacted with an aqueous solution
of the polymeric zinc sulfonate compound. This
microelectrophoresis technique involves measurement of
adsorption isotherms by determining the zeta potential of
dental enamel in the presence of increasing concentrations
of the polymeric zinc sulfonate, all solutions being made
in 0.0200 M sodium chloride. When Udel~ Polysulfone zinc
sulfonate of D.S. 1.8 was so tested, the resultant
adsorption isotherms indicated that the surface potential
of the tooth enamel particles became increasingly negative
with increasing concentration of the zinc salt. A plateau
value of about -40mV was reached and indicated that the
surface of the enamel was saturated with the polymeric
anion~ In the absence of any of the polymeric zinc salt,
the zeta potential of dental enamel was about -lOmV.
These experimental techniques established that the
polymeric anion is indeed adsorbed on the enamel surface.
In desorption studies designed to measure the degree of
substantivity of the polymeric zinc sulfonate compound,
powdered enamel was contacted for a short time with a 0.1
weight/volume solution of the zinc salt and then, after
measurement of the initial charge on the enamel particle,
was washed successively with large volumes of 0.0200 M
1~73~2
-12-
sodium chlorlde and the zeta potential measured after each
wash. The zeta potential after the first wash was 40mV
and remained relatively constant after a total of five
consecutive washes. This data indicated that the zinc
S salt of the polymer was physically bound to the surface of
the enamel and surprisingly resistant to desorption on
multiple washings. In contrast, the corresponding sodium
salt of the ~del~ Polysulfone sulfonic acid, D.S. 1.8,
desorbed rapidly from an initial value of about -50mV to
about -15mV after only one or two washings with 0.020 M
sodium chloride.
The degree of sulfonation of the poly ~arylene ether
sulfone) pol~mer has a significant effect on the reduction
of plaque deposition, and it is found that a certain
minimal D.S. is required for development of adequate
plaque barrier activity. The D.S. can be varied at will
by adjusting the conditions of the sulfonation reaction,
such as the molar ratio of sulfonating agent to polymer.
The nature of the aromatic polymer repeating unit governs
the maximum D.S. which can be achieved. Linking groups,
such as ether, sulfone, and various organic radicals (see
e.g. the definition of Y set forth above) attached to the
aromatic rings in the polymer chain structure can have
either a deactivating or activating effect on aromatic
sulfonation. Electronic and steric effects determine the
position of sulfonation as well as ease of sulfonation.
These mechanistic considerations have been reviewed in
general organics texts, such as that by R. T. Morrison and
R. N. Boyd, "Organic Chemistry," Third Edition, Allyn and
sacon, Inc., Boston, 1973. In the poly (arylene ether
sulfone) polymers, the ether linkages activate sulfonation
in the available ortho-positions of the adjoining aromatic
rings; in contrast, the sulfone group will deactivate the
aromatic rings to which it is bonded with respect to
aromatic sulfonation.
7~Z
--13--
The degree of sulfonation (D.S.l of the poly(arylene ether
sulfone) derivative can be determined by any of several
methods: (a) NMR analysis, (b) elemental analysis for
sulfur to carbon ratio, or (c) direct titration of the
sulfonic acid with standard sodium hydroxide. The NMR
method is perhaps the more exact procedure, since it is
not prone to interference by other impurities, such as
with the acidimetric or elemental analyses.
The acidimetric procedure for D.S. determination involves
titration of an accurately weighed two gram sample
(+0.1 mg) of the sulfonic acid polymer, dissolved in about
ten volumes of water, alcohol, or other solvents, with
standardized sodium hydroxide to the potentiometric
endpoint. The acidity, A, of the samples is expressed in
milliequivalents/gram (meq/g). Using the acidity value,
A., and the formula weight, R, of the unsulfonated repeat
unit in the polymer, the D.S. is calculated from the
following equations:
(ml. of titrant) (NormalitY)
A = sample weight, in grams
D.S. = 1010 -- 80A
A related concept to D.S. which is sometimes more useful
in correlating polymer structure with plaque barrier
activity is the average number of sulfonate or sulfonic
acid groups per aromatic group in the repeating unit. This
is simply the D.S. tas determined by the aforementioned
procedures) divided by the number of aromatic groups in
the repeating unit, i.e., D.S./Ar. For example, ~del~
Polysulfone zinc sulfonate of D.S. 2.0 can be expressed as
1167;3~
-14-
exhibiting a D.S./Ar of 0.5, since there are four aromatic
groups within each repeating unit.
Generally, sulfonated poly (arylene ether sulfone)
polymers of high pla~ue barrier activity are obtained only
when the average number of sulfonate groups per aromatic
group (D.S./AR) within the polymer is at least about 0.2.
Aside from being insoluble in water, the non-sulfonated
polymeric intermediates exhibit no plaque barrier
activity. Effective pla~ue barrier activity (plaque
reduction of at least above 40%) is seen only when the
hydrophilic properties of the polymer are increased by
introduct on of either sulfonic acid or sulfonate salt
functional groups.
Example 1
Udel0 P~lysu1fone Sulfonic Acid, D.S. 1.8
A 12 liter resin flask was fitted with a mechanical
stirrer, thermometer, two addition funnels, and a nitrogen
inlet adapter. The flask was charged with 3000
ml. methylene chloride which was dried over molecular
sieves. Into one of the addition funnels was charged a
solution of 664 g (1.50 moles) Udel~ Polysulfone (type
P1700, medical grade, MG 11; Union Carbide) in 3000
ml. dry methylene chloride. Into the other addition
funnel was charged the sulfonation agent, prepared by
controlled addition of 360g (4.50 moles) anhydrous liquid
sulfur trioxide to a cooled solution of 205g (1.125 moles)
triethyl phosphate dissolved in 3000 ml. dry methylene
chloride.
While stirring the methylene chloride solvent in the resin
flask, the solutions of the polymer and sulfonation agent
were added simultaneously over one to two hours at the
ambient temperature, varying from 23 to 32C. After the
additions were completed, the resultant suspension of
11~;73~Z
-15-
white solids was stirred another one to two hours at the
ambient temperature. The product was vacuum-filtered on a
glass-fritted funnel, washed three times with 4 liters of
methylene chloride by mechanical slurry and filtered each
time. A final slurry wash in anhydrous diethyl ether
whi~ened the product. After air drying at room
temperature the yield of the sulfonic acid derivative of
~del~ Polysulfone was 1043 grams. The degree of
sulfonation (D.S.), determined by acidimetric titration or
NMR analysis, was 1.8.
Example 2
Udel~ Polysulfone Sodium Sulfonate, D.S. 1.8
A stirred solution of 1030 grams of the sulfonic acid
derivative, prepared according to Example 1, in 5150
ml. 95% ethanol, was stirred vigorously during slow
addition of 2N sodium hydroxide (in ethanol) to the
neutralization endpoint (pH 8-9). The suspension of the
sodium sulfonate derivative was stirred another hour,
suction filtered, washed with 95% ethanol on the funnel
and subsequently by mechanical slurry in 2000 ml. 95%
ethanol. The solids were air dried at room temperature to
remove most of the solvent before final drying in a forced
air oven at 60C. to near constant weight. The yield of
the sodium sulfonate derivative, D.S. 1.8, of Udel~
Polysulfone was 1041 grams.
Example 3
Udel~ Pol sulfone Zinc Sulfonate, D.S. 1.8
Y.
A stirred suspension of 133.0 9 Udel~ Polysulfone sodium
sulfonate derivative, D.S. 1.8, prepared as in Example 2,
in 1200 ml. water was heated to dissolve the polymer,
cooled to room temperature, and the solution centrifuged
to remove about 4% of highly insoluble solids. An aliquot
of the total centrifugate containing about 26.3 g sodium
sulfonate sclids was diluted to about 500 ml. with water.
1~7~B2
-16-
A solution of 10.5 g zinc chloride in 20 ml. water was
added and the resultant hazy solution, pH 6.2, dialyzed in
a membrane tube ~6000 - 8000 m~lecular weight cut-off)
surrounded with distilled water for two days. Removal of
the water from the dialyzed polymer solution, pH 6,5, by
freeze drying gave 25.4 g of purified Udel~ Polysulfone
zinc sulfonate, D.S. 1.8, as fluffy white solids.
In an alternate procedure, the solution of the sodium
- 10 sulfonate derivative in water is prepared and centrifuged
after addition of the zinc chloride to give a clarified
solution of the zinc sulfonate derivative. Further
purification is effected, particularly on a larger scale,
by continuous dialysis through a Tri-Ex-l Hollow Fiber
Dialyzer (Extracorporeal Medical Specialties, }nc.) using
two passes through the dialy%er at a polymer solution flow
rate of 100-200 ml/minute and countercurrent distilled
water flow rate of about 500-600 ml/minute. The dialyzed
polymer solution is freeze dried to afford the purified
polymeric zinc salt.
The polymeric zinc salt was quite hygroscopic and absorbed
considerable water (35-40% weight gain) when exposed to
relative humidities of both 42 and 75~ for about 24 hours.
To stabilize the water content of a bulk supply of polymer
for clinical studies, the zinc sulfonate obtained via
freeze drying was deliberately exposed to laboratory
ambient conditions (at a temperature in the range of about
20-25C. and relative humidities that ranged between about
40 and 70%) to allow for maximum moisture uptake for
several days to substantially constant weight. Using this
procedure, an 8 kg. lot of zinc salt was eguilibrated to a
water content of 21.5% by weight, as determined by
thermogravimetric analysis.
11673~Z
-17-
The assay values for this lot of polymeric zinc salt are
shown in Table 1 and, when corrected for the water
content, agreed very well with the theoretical values for
the anhydrous zinc salt having a D.S. of 1.8.
TABLE 1
Analytical Data on Udel Polysulfone Zinc Sulfonate,
D.S. 1.8
Found Theory For
Assay "As Isn nAnhydrous Basisl' D.S. 1.8
Carbon, ~ 39.83 50.73 50.38
Hydrogen, ~3.71 3.1g 3.16
Sulfur, % 11.0 14.1 13.95
Zinc, % 7.0 8.9 9.14
Water, % 21.5 0 0
Chloride, %0.094 0.12 0
Sodium, ~ 0.36 0.46 0
Phosphate (as 0.27 0.34 0
Triethyl Phosphate)
Sulfate, %,Not found - 0
as Na2S04
Absorptivity26.78 34.11
at 272 nm
D.S. via NMR1.8 1.8 1.8
pH, 1% in water 6.9 - -
Example 4
Udel~ Polysulfone Zinc Sulfonate, D. S. 1.8, Via
Ion-Exchange of The Sulfonic Acid Derivative
A solution of 5.0 g of the Udel~ Polysulfone sulfonic acid
derivative (16.6 milliequivalents of acidity) in 100
ml. water was prepared a~d, after addition of 2.25 g (33.0
meq.) zinc chloride, was allowed to stand at room
1~1 673~3Z
-18-
temperature overnight to allow ion-exchange to proceed.
The solution was clarified by filtration on an 0.8 micron
membrane filter and the filtrate dialyzed in a dialysis
membrane tube (M.W. 12,000 cutoff) in water. The
hydrochloric acid by-product formed in the ion-exchange
reaction was removed to the exten~ of 94% within one hour
of dialysis, as determined by titration of the surrounding
water (pB2.7) with sodium hydroxide. The dialysis was
allowed to proceed several days, and the purified polymer
solution stripped free of water under reduced pressure to
give 3.7 g of the hygroscopic zinc sulfonate derivative of
Udel~ Polysulfone. Analysis: Zinc, 7.08%; Sodium,
0.026%; Absorptivity at 274 nm, 31.9; sulfate and triethyl
phosphate were not detectable.
The plaque barrier oral compositions of this invention may
comprise any conventional pharmaceutically acceptable oral
hygiene formulation that contains (and is compatible with)
an effective amount of a plaque barrier agent as defined
herein. Such formulations include, for example,
mouthwashes, rinses, irrigating solutions, nonabrasive gel
dentifrices, denture cleansers, coated dental floss and
interdental stimulator coatings, chewing gums, lozenges,
breath fresheners, foams and sprays.
The plaque barrier agents may be present in these
formulations in effective concentrations generally in the
range of from about 0.05 weight percent to as much as 30
weight percent or the limit of compatibility with the
vehicle. However, no advantage will be derived from
concentrations in excess of about 20 weight percent. A
preferred concentration range for the plaque barrier
agents in the formulations of the invention is from about
0.5 to about 10 weight percent. A more preferred range is
from about ~ to about 8 percent by weight, about 5% being
the presently most preferred concentration in a
nonabrasive gel vehicle.
--19--
The pH of these plaque barrier preparations should be
between pH 5.0 and 10.0, preferably between pH 5.0 and
8.0, more preferably between about pH 6.0 and 7.5. Lower
pH than 5.0 is undesirable because of the possible
enhancement of enamel demineralization.
Suitable conventional pharmaceutically acceptable vehicles
that can be employed with the plaque barrier agents to
prepare the barrier compositions of this invention may
comprise water, ethanol; such humectants as polypropylene
glycol, glycerol and sorbitol; such gelling agents as
cellulose derivatives, for example, Methocel,*
carboxymethylcellulose (CMC TMF) and Klucel*HF,
polyoxypropylene/polyoxyethylene block copolymers, for
example, Pluronic*F-127, PLURONIC F-108, PLURONI~P-103,
PLURONIC P-104, PLURONIC P-105, and PLURO~IC P-123,
colloidial magnesium aluminosilicate complexes such as
Veegum* and mucoprotein thickening agents such as Carbopol*
934; gel stabilizers such as the silicon dioxides, for
example, Cab-O-Sil*M5 and polyvinylprolidone; sweeteners
such as sodium saccharin; preservatives such as citric
acid, sodium benzoate, cetylpyridinium chloride, potassium
sorbate, methyl and ethyl parabens; detergents such as
sodium lauryl sulfate, sodium cocomonoglyceride sulfonate,
sodium Iauryl sarcosinate and polyoxyethylene isohexadecyl
ether (Arlasolve*200) and approved colors and flavors.
The following specific examples will serve further to
illustrate the plaque barrier compositions of this
invention.
*Trade mark
~3 .
~67~
--20--
EXAMPLE A - Mouthwash Solution
Barrier Agent0.5-2.0 % w/w
Glycerol (humectant~ 6.0
Pluronic F-108 1.0
Sodium saccharin (sweetener) 0.3
~eionized Water q.s.
Flavors 1.0
100.0
EXAMPLE B - Mouthwash Solution
Plaque Barrier Agent 0.5-3.0 % w/w
Ethanol, USP 15~0
Pluronic F-108 (foaming agent) 2.0
Glycerol (humectant)10.0
Sorbitol (humectant)10.0
Sodium saccharin (sweetener) 0.2
Deionized Water q.s.
Flavors 0.2
100. 0
EXAMPLE C - Abrasive Dentrifice Gel
Plaque Barrier Agent2.0-10.0 % w/w
Fumed Silica (abrasive) 55.0
Sodium Lauryl Sulfate ~detergent) 1.5
Glycerol (humectant) 10.0
Carboxymethylcellulo~e (gelling agent) 2.0
Sodium saccharin (sweetener) 0.2
Sorbitol (humectant) 10.0
Flavors 1.0
Deionized Water q.s.
Preservative 0.05
100. 0
X
-21-
EXAMPLE D - Chewing Gum
Plaque Barrier Agent 1.0-11.0~ w/w
Gum Base 21.3
S~gar 48.5-58.5
Corn Syrup (Baume 45)18.2
Flavors 1.0
100. 0
EXAMPLE E - Nonabrasive Gel Dentifrice
Plaque Barrier Agent 0.Q5-30.0% w/w
Sorbistat (preservative) 0.15
Deionized Water q.s.
Silicon Dioxide (gel stabilizer) 1.0
PLURONIC F-127 (gelling agent) 20.0
Sodium Saccharin 0.2
Flavors 1.5
100.O
Example F
20 The following formulation illustrates a presently
preferred nonabrasi~e gel composition containinq a barrier
agent in accordance with the present invention.
Ingredients ~ w/w
Distilled Water q.s.
Sodium Saccharin (sweetener) 0.20
Sodium Benzoate (preservative) 0.30
FD&C Blue ~1 (0.1~aq. soln.) 0.27
D&C Yellow ~10 (0.5% aq. soln.) 0.50
Gelling agent 18.00
Glycerol (Humectant) 20.00
CAB-O-SIL M5 (Silicon Dioxide) 1.00
Plaque Barrier Agent 5.00 tdry basis]
Flavor 0.80
100. 0
,2~ ,_t
8~
--22--
While the details of preparing all of th~ above
formulat-ons are well within the skill of the art, a
suggested procedure for preparing the gel formulation of
this example will be described for completeness.
In a first container the water, sodium saccharin, sodium
benzoate and dyes are mixed. Then the container is put
into an ice bath. When the temperature reaches 6C, the
gellins agent is added and the contents mixed slowly until
the gelling agent is dissolved. Then the solution is
heated to 70C.
Into a second container is added the glycerin. Then the
CAB-O-SIL M5 is sprinkled in with mixing. The~ the plaque
barrier agent is added and mixing contirued to a smooth
paste. The paste is then heated in a water bath with
mixing to a temperature of 70C.
The contents of the first container are added to the
second container and blended together until the batch is
homogenous while maintaining a 70C temperature. Then the
flavoring is added, all mixing is stopped, and the
formulation allowed to settle for approximately one hour.
If necessary to remove air bubbles, overnight
refrigeration may be employed.
While any pharmaceutically acceptable gelling agent that
is compatible with the plaque barrier agent may be
employed, a presently preferred gelling agent is PLURONIC
F-127.
These compositions are preferably employed from one to
three times daily in a routine oral hygiene program to
prevent the attachment of plaque to the teeth.
