Note: Descriptions are shown in the official language in which they were submitted.
- `` ~
This application is rela~ed to United States Patent
4,080,441.
This invention relates to oral compositions containing
an anticalculus agent.
Calculus is a hard, mineralized formation which forms
on the teeth. Regular brushing prevents a rapid build-up of
these deposits, but even regular brushing 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 phos-
phates begin to be deposited in the pellicle and extracellularmatrix of the dental pla~ue and become sufficiently closely
packed together for the aggregates to become resistant to defor-
mation. I'here 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 microcrystalline calcium phosphate. "Amor-
phous calcium phosphate" although related to hydroxyapatite
differs Erom it in atomic structure, particle morphology, and
stoichiometry. The X-ray diffraction pattern of amorphous cal-
cium phosphate shows broad peaks typical of amorphous materials,
which lack the long-range atomic order characteristic of all
crystalline materials, including hydroxyapatite. A suggested
mechanism by which the nontoxic anticalculus agents of this in-
vention inhibit calculus formation probably involves such agents
functioning to bind the amino groups in the matrix system in the
oral cavity at physiological pH and temperatures and also cross-
links the protein.
, ,,,~
,,,.,,~
~ 2 -
~
A suk;stantial number of different types of compounds
and compositions have been developed for use as antibacterial,
and antiplaque and anticalculus agents in oral compositions, in-
cluding for example such cationic materials as the bis-biguanide
compounds and quaternary ammonium compounds, e.g. ben~ethonium
chloride and cetyl pyridinium chloride, disclosed in United
States 4,080,4~1. These cationic materials however tend to stain
the teeth with continued use.
It is an object of this invention to provide an improved
anticalculus oral composition which will have relatively little
or no tendency to stain the teeth.
A further object of the invention is to provide an oral
composition which inhibits the transformation of amorphous cal-
cium phosphate to hydroxyapatite crystal structure normally
associated with calculus.
Another object o~ this invention is the provision of an
improved method for inhibiting the formation of calculus.
Other objects and advantages will appear as the descrip-
tion proceeds.
The invention provides a substantially anhydrous oral
composition devoid of stain-inducing antibacterial antiplaque
agents and comprising an orally acceptable vehicle and in an
effective amount as an anticalculus agent at least one bis(o-
carbox~ phenyl) ester of a C2 8 aliphatic dicarboxylic acid.
The antlcalculus agents of this invention may be
represented, in their free acid form, by the formula:
OOC ~C~3n C~O
COOH HOOC
J~ ~
~,~,,,.,~
~ - - ~
wherein preferably the R's are independently H or Cl 4 alkyl,
pre~erably H, and n is an integer of O to 6, pre~erably 2, the
preferred anticalculus agent accordingly being bis(o-carboxyphenyl)
succinate (BOCS). The -~CRR~-ngroup may however be a single bond
when n is O as in the bisesters o~ oxalic acid, or may be any Cl_6
alkylene or alkenylene group, i.e. straight or branched saturated or
unsaturated, O or S chain interrupted, Cl 4 alkoxy substituted, or
the like. When -the ~ CRR group is part of an ethylenic group, one
or both R's may be ~ero, i.e. replaced by a valence bond. The
bis(o-carboxyphenyl) esters of the following aliphatic dicarboxylic
acids are only illus-trati~e of the anticaiculus agents of this
inrention:
oxalic (ethanedioic)
malonic (propanedioic)
succinic ~butanedioic)
glutaric (pentanedioic)
adipic (hexanedioic)
pimelic (heptanedioic)
suberic (octanedioic)
maleic (1,2-ethylenedicarboxylic HOOCCH:CH-COOH)
itaconic (methylenesuccinic HOOCC(:CH2)CH2-COOH)
isosuccinic (2-methylpropanedioic)
muconic (2,1l-hexadienedioic HOOCCH: CHCH: CH-COOH )
dihydromuconic (HooccH2cH2cx:cHcooH)
dihydroitaconic (methylsuccinic)
3-ethylhexanedioic
~urther, one or both phenyl moieties in this agent may
be nuclearly substituted with one or more Cl_~ alkyl or alkoxy
groups such as methyl or isobutoxy, or halo such as chloro, bromo,
iodo or fluoro.
Suitable methods for preparing these anticalculus agents
are disclosed in the a~orementioned U.S. 4,080,441. Another improved
method for such preparation is described in Example A below.
It will be understood that the ~ree acid form of these
anticalculus agente may be converted to and employed in their
equivalent salt form by treatment with any base containing an
orally acceptable cation such as alkali metal (e.g. sodium~
potassium), alkaline earth metal (e.g. calcium, magnesium), me'al,
ammonium, mono-di-or tri- Cl_lg alkyl or alkanol- aubstituted
ammonium or organic amine (e.g. methyl, ethyl, hydroxyethyl
substituents).
The anticalculus agents of this invention are anti-
nucleating agents, oral compositions of this invention containingthem are effective in reducing formation of dental calculus without
unduly decalcifying the dental enamel, and in contrast to the above-
mentioned cationic an~tibacterial, antiplaque and anticalculus agents,
such agents and compositions have little or no tendency to stain
the teeth, and can further be found to e~fectively reduce or inhibit
gingivitis.
The concentration of these an-ticalculus agentsin oral
compositions can range widely, typically upward from about 0.01%
by weight, with no upper limit on the amount -that can be utilized
except as dictated by cos-t or incompatibility with the vehicle.
Generally, concentrations from about 0.01% to about 10%, preferably
about 0.05% to about 8.o%~ and more prefera~ly about 0.1% to about
4% by weight are utilized. Oral compositions which in the ordinary
course of usage could be accidentally ingested preferably contain concentra-
tions in the lower portions of the foregoing ranges.
Although these anticalculus agents vary in water solubility depend-
ing upon their molecular weight, identity and proportions of salt-forming
cations, etc, they are sufficiently soluble in aqueous media, e.g. in the
oral cavity, in the low concentrations employed herein to be termed water
soluble to that extent. It has however been unexpectedly found that oral
compositions containing such agents in an aqueous medium undergo significant
hydrolysis or other deterioration in storage. In accordance with a further
aspect of this invention, it is preferred to provide oral compositions which
are substantially anhydrous, e.g. containing 0 to less than about 0.2 moles
of water per mole of the anticalculus agent.
When the oral compositions of this invention are in liquid, paste
or cream form, as in mouthwashes and rinses, toothpastes and dental creams,
a water-miscible (preferably water soluble) organic normally liquid orally
acceptable vehicle is preferably employed. Typically, such vehicles include
water soluble C2 ~ monohydric and polyhydric alkanes and Cl 4 alkyl ethers
thereof such as ethanol, ethyiene glycol, methyl, ethyl and butyl ethers
thereof (methyl, ethyl and butyl Cellusolve*), propylene glycol, tetra-
methylene glycol, and glycerin, and water soluble poly (ethylene glycols)such as diethylene glycol, methyl, ethyl, diethyl and butyl ethers thereof
(methyl, ethyl, diethyl and butyl Carbitol*), triethylene glycol, low mole-
cular weight polyethylene glycols, e.g. 400, 600, and mixtures thereof etc.
* Trade Mark
Polyhydric compounds in the aforementioned group, especially
propylene glycol, glycerin, and the low molecular weight poly-
ethylene glycols, generally function also as humectants which are
desirable components of the oral compositions of this invention.
Other types of such water miscible liquid vehicles
which may be employed are the polar aprotic solvents such as
dimethyl ~ormamide and sulfoxide, N-methyl pyrrolidone, sulfolane,
tetramethyl sulfone, acetorlitrile, and preferably et~ylene and
propylene carbonate.
Essentially water-immiscible organic liquid vehicles may
also be employed representative of which are hydrocarbon, fatty acid
and fatty acid ester oils such as mineral oil, tetradecane, pentane,
caproic, acid~ oe~anthylic acid 7 methyl caproate and laurate,
ethylene glycol dicaprylate and the like.
Mixtures of the same types and/or of different types of
liquid vehicles as described above may of course be employed.
The proportion of the aforementioned liquid vehicle
employed in these oral compositions will obviously depend for the
mos-t part upon the desired degree of fluidity or viscosity and will
be readily determinable in routine manner in any particular instance.
Typically, liquid compositions such as mouthwashes and rinses contain
about 70% to about 99.9%, and toothpastes and dental creams contain
about 10% to about 80%, by weight of such liquid vehicle, about 10%
to about l00% of which may be a humectant. ~ormally solid humectants
such as sorbitol may also be included.
The oral compositions o~ this invention typically have,
in aqueous medium, e.g. in the oral cavity or in the form o~ a 20%
aqueous slurry or solution, a pH oI' about 3.5 to about 8, pre~erably
--7--
about 4 to about 7, more pre-ferably about 4 to 6. Such pH can be controlled
by inclusion of the re~uired amounts of acidic substances such as citric or
benzoic acid, basic substances such as sodium hydroxide, and/or buffering
agents such as sodium citrate, benzoate, bicarbonate or carbonate, disodium
hydrogen phosphate, sodium dihydrogen phosphate, or mixtures thereof.
The vehicle i.n solid or pasty compositions such as toothpowders,
tablets, toothpastes and dental creams generally contains polishing material.
Examples of polishing materials are water-insoluble sodium metaphosphate
(IMP), potassium metaphosphate, tricalcium phosphate, anhydrous, mono-
hydrated and dihydrated calcium and dicalcium phosphate, calcium pyrophos-
phate, magnesium orthophosphate, trimagnesium phosphate, magnesium and cal-
cium carbonate and sulfate, alumina, hydrated alumina, aluminum silicate,
alkali metal and alkaline earth metal aluminosilicates, zirconium silicate,
silica, bentonite, and mixtures thereof. Preferred polishing materials in-
clude crystalline and colloidal silica, silica gel, complex amorphous alkali
metal aluminosilicate, hydrated alumina and IMP.
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 moi.sture content of 0.37%, at ll0 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 ef:Eective.
When visually clear gels are employed, a polishing agent of col-
loidal silica, such as those sold under the trademark SYLOID as Syloid 72,
74 or 244 or under the trademark SANTOCEL as Santocel l00
* Trade Mark
--8--
and alkali metal aluminosilicate complexes are par-ticularly use~ul,
since they have re~ract:ive indices close to the refractive indices
of gelling agent-liquid systems commonly used in dentifrices.
Many of the so-called "water-insoluble" polishing
material are anionic in character and also include small amounts of
soluble material. Thus, insoluble sodium metaphospha-te may be
formed in any suitable manner, as illustrated by Thorpe's Dictionary
of Applied Chemistry, ~lolume ~ 9 4th Edition, pp. 510-511. The forms
of insoluble sodium me-taphosphate known as Madrell's salt and Kurrol's
salt are further examples o~ suitable materials. These metaphosphate
salts exhibit a minute so~ubility in water, and there~ore are
commonly referred to as insoluble metaphosphates. There is present
therein a minor amount of soluble phosphate rnaterial 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 o~ insoluble metaphosphate, may
be reduced by washing with water if desired. The insoluble alkali
metal metaphosphate is typically employed in powder form o~ a
particle size such that no more than abou-t 1% of the material is
larger than about 37 microns.
The polishing material is generally present in amounts
ranging from about 20% to about ~% by weight of the oral prepar~tion.
Preferably, it is present in amoun-ts ranging from 20% to about 75%
in toothpaste, and from about 70% to about ~% in toothpowder.
In the preparation of toothpowders, it is usually
sufficient to admix mechanically, e.g., by milling, the various
solld ingredients in appropriate quantities and par-ticle sizes.
In a too-thpaste, cream or gel, the liquids and solids
typically are suitably proportioned to form a creamy or gelled mass
which is extrudable from a pressurized container or from a
collapsible tube. Thickening -to the proper desired viscosity
or ~lowability is typically facilitated or achieved by lnclusion
of a binding, t~ic~ening or gelling agent such as natural or
synthetic gums or gum-like materials, typically Irish moss,
Pluronics , sodium carbox~methylcellulose and carboxyethylcellu-
lose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, hydroxybu~yl methyl-
*
cellulose t Laponite CP or SP (synthetic hectorite clay of
Laporte Industries Ltd.), viscarin, gelatin, glucose, sucrose,Carbopols (e.g. 934,940,941), gum karaya, gum arabic, gum
tragacanth, polyvinylpyrrolidone, polyvinyl alcohol and starch.
They are usually present, singly or plurally, in an amount up to
about 10~ by weight, preferably in the range of from about 0.5
to about 5%. The preferred gelling agents are Pluronics and
hydroxypropyl cellulose. Pluronics such as F108 and F127 are
polyoxypropylene polyoxyethylene block polymers which simul-
taneously function as nonionic surfactants.
The oral compositions of this invention may contain a
non-soap synthetic sufficiently water soluble organic anionic or
nonionic surfactant in concentrations generally ranging ~rom
about 0.05 ~ about 10, preferably about 0.5 to about 5, weight
percent, to promote wetting, detersive and foaming properties.
United States Patent No. 4,041,149 discloses such suitable anio-
nic surfactants in col. 4, lines 31-38 and such suitable non-
ionic surfactants in col. 8, lines 30-68 and col. 9, lines 1-12 n
In certain forms of this invention a fluorine-providing
compound is present in the oral prepara-tion. These compounds may
be slightly soluble in water or may be fully water-soluble. They
* Trade Marks
- 10 -
f/~r,ne C:~"~al~J In~
are characterized by their abili-ty to release fluoridc ions in water
and by substantial freedom ~rom reaction with other compounds of the
oral preparation. Among these materials are inorganic fluoride
salts,, such as soluble alkali me-tal, alkaline earth metal and
heavy metal sal-ts, for example, sodium fluoride, potassium fluoride,
ammonium fluoride, calcium fluoride, a copper ~luoride such as
cuprous fluoride, zinc fluoride, a tin fluoride such as stannic
fluoride or stannous chlorofluoride, barium rluoride 9 sodium
~luorsilicate, ammonium fluorosilicate, sodium fluorozirconate,
sodium monofluorophosphate, aluminum mono-,and di-fluorophosphate,
and fluorinated sodium calcium pyrophospha-te. 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
dependent to some extent upon the type of compound, its solubility,
and the type of oral preparation, but it must be nontoxic amount.
In a thickened or solid oral preparation, such as toothpaste or
toothpowder, an amount of such compound, which releases a maximum of
about 1% by weight o~ 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 pre~erably abou-t 0.1% of fluoride ion. Typically, in
the cases of alkali metal fluorides and stannous fluoride, this
component is present in an amount up to about 2% by weight, based
on -the weight of the preparation, and preferably in the range of
about 0.05% to 1%. In the case of sodium monofluorophosphate, the
compound may be present in an amount up to 7.6% by weight, more
typically about 0.5 to about 1% by weight.
In a li~uid oral preparation such as a mouthwash~ the
~luorine-providlng compound is typical~y present in an amount
su~ficien-t to release up to about 0.()005 to about 0.2%, pre~erably
about 0.001 -to about 0.1~ and more pre~erably about 0.0013% by
weight of f`luoride ion.
Various other materials may be incorporated in the oral
preparations of this invention such as whitening agents~ pre~erYatives
silicones, chlorophyll compounds, o-ther anticalculus agents~ an-ti-
bacterial antiplaque agents, and/or ammoniated material such as
urea, diammonium phosphate, and mixtures thereof. These adjuv~nts 7
where present, are incorpora-ted in the preparations in amounts
which do not substantially adversely a~fect the properties and
characteristics desired.
Any suitable ~lavoring or sweetening material may also
be employed.
Examples o~ suitable ~la~oring constituents
are flavoring oils, e.g., oils of spearmint, peppermint~ wintergreen~
sassa~ras, clove, sage~ eucalyptus, mar~oram, cinnamon, lemon? and
orange3menthol, eugenol, cineol, and methyl salicylate. Suitable
sweetening agents include sucrose, fructose, lactose, maltose~
sorbitol, xylitol, sodium cyclamate, perillartine, APM (aspartyl
phenyl alanine, methyl ester) and saccharine. Suitably 7 ~lavor
and sweetening agents may together comprise ~rom about 0.01% to 5%
or more o~ the preparation.
In preparing the oral compositions o~ this invention,
it is preferred but not essential to add the anticalculus agent
' a~ter the other ingredients ~except perhaps so~e o~ the water~ are
mixed or contacted with each other to avoid a tendency ~or such
agent to be precipitated.
-12-
It will be understood that 7 as is conventional, the
oral preparations are to be sold or otherwise distributed in
suitable labelled packages. Thus a ~ar of mouthrinse will have
a label describing itg in substance, as a mouthrinse or mouthwash
and having directions Por its use; and a toothpaste will usually
be in a collapsible tube, typically aluminum, lined lead or plastic,
or other squeeze dispenser ~or metering out the contents, having a
label describing it, in substance, as a toothpaste or dental cream.
In the practice of this invention an oral composition
according to this invention such as a mouthwash or toothpaste
containing the de~cribed anticalculus agent in an amount effective
to inhibit calculus on den-tal surPaces is applied regularly to
the oral cavity, especially dental enamel, preferably from about 1
to 3 times daily.
Example A
Preparation of Bis(o-carboxyphenyl)succinate
0.4 moles salicylic acid (55.2 grams)
0.4 moles pyridine (31.2 ml~)
n . 2 moles succinyl chloride (31.0 grams)
The salicylic acid and pyridine are dissolved in 90 ml.
of acetone. To the resulting clear solution, the succinyl chloride
in 90 ml. of acetone is added, with stirring, at a rate to keep
acetone refluxing for half an hour. During this addition, the
desired BOCS product begins to separate and the mixture turns dark -
purple. ~he reaction slurry is stirred for half an hour after all
-the succinyl chloride has been added. Then 200 ml. of water are
added, the acetone evaporated from the slurry in a rotary evaporator
at 35C. and the desired BOCS product collected on a suction Pilter,
washed with water and dried in vacuum at 60C.
-13~
~8~
Yield - 66.5 grams ~93%)
M.P. 177 -177.5C.
Neutral Equivalent 179.9*
Saponification Eq. 186.8*
*calculated for C18H14 8
The following 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 heTein and in the
appended claims are by weight, and temperatures are in C., unless otherwise
indicated.
Example 1
The following formulation is illustrative of a toothpaste in accord-
ance with this invention effective for inhibiting calculus.
Parts by Weight
Propylene glycol 42.0
Hydroxypropyl cellulose 1.0
Polyethylene glycol 60010.0
Sodium saccharin 0.2
2 0.
IMP 28.0
Syloid 244 12.0
Sodium lauryl sulfate
Flavor 1.0
BOCS 3.0
The following formulations, given in parts by weight, are illustra-
tive of mouthwashes in accordance with this invention effective for inhibit-
ing calculus.
-14-
.~JJ
Example
2 3 4
Flavor 0.22 0.22 0.22
Ethanol 15.0 15.0 15.0
Pluronic F108 3.0 3.0 3.0
Glycerine 10.0 10.0 10.0
Sodium saccharin 0.03 0.03 0.03
BOCS 0.05 0.50 1.0
The mouthwash formulations of Examples 2-4 above may be applied to
the oral cavity as is or after dilution with about 2 to 4 times their
volumes of water, i.e. volume ratios of formulation: water of about 1:2 to
about 1:4.
Substitution of equivalent amounts of the following bis ester-
containing compounds for the BOCS employed in the formulations of Examples
2-5 yield formulations also effective for inhibiting dental calculus.
Example Bis Ester-Containing Compound
bis(2-carboxy-4-butoxyphenyl)oxalate
6 bis(2-carboxy-4-propyl-6-chlorophenyl)glutarate
7 bis(2-carboxy-4-methyl-6-bromophenyl)adipate
8 bis(2-carboxy-4-iodo-6-ethoxyphenyl)suberate
9 bis(2-carboxyphenyl)pimelate
bis(2-carboxy-5-methoxyphenyl)malonate
11 bis(2-carboxy-6-butylphenyl)maleate
12 bis(2-carboxyphenyl)itaconate
13 bis(2-carboxy-4-fluorophenyl)muconate
Example 14
In this study on 24 rats, a placebo of water and an 0.1% solution
of BOCS in dimethyl sulfoxide, pH 7.10, as the test anticalculus mouthrinse
are evaluated for effectiveness against formation of calculus for a 30 day
period. Litter matured Osborne-Mendel rats are used. On days 21 and 22 they
-15-
t6~q~
are inoculated intraorally with Strep-mutans and Actinomyces viscous and
feces from caries-active Osborne-Mendel rats, placed on calculogenic diet
580F supplemented with 0.2% P as Na2pO4~ and the placebo and the test mouth-
rinse each applied to molars of a group of 12 such rats twice daily on
Monday to Friday and once daily on Saturday and Sunday for a period oE 30
days. The animals are weighed at the beginning and at the end of the study
to assure that the rats remain in otherwise normal condition. At the end of
the period, calculus formation is assessed according to routine procedures
and the following results are found:
Mean
No. Mean Terminal Calculus
Animals Weight Gain Units*Significance
Placebo (Water) 12 128 grams 17.9
Mouthrinse 12 135 grams 14.8 ~<0.01
(0.1% BOCS)
*20 units at risk
The above results establish that BOCS at 0.1% level when applied
topically is significantly eEfective (at tha +99% level) in reducing
calculus formation.
This invention has been described with respect to preferred embodi-
ments and it will be understood that modifications and variations thereof
obvious to those skilled in the art are to be included wi~hin the spirit and
purview of this application and the scope of the appended claims.
-16-
'~"
