Note: Descriptions are shown in the official language in which they were submitted.
WO 95/07684 2 1 ~ 1 5 3 0 PCT/US9~/10227
1
PYROPHOSPHATE DIESTERS FOR TARTAR CONTROL
BACKGRO~ND OF THE rNVENTION
The present invention relates to compositions comprising one or more
phosphate derivatives, and carrier materials wherein the compositions are in a form
suitable for oral or topical administration. These compositions preferably contain a
10 safe and effective amount of one or more active materials such as those whichprovide nutritional, therapeutic, antimicrobial, pharmaceutical medicinal, and/or
aesthetic benefit, and those commonly used in health care products.
A wide variety of flavor, coolant and sweetener agents are used in consumer
and health care products today. Aesthetic qualities of these compositions such as
15 taste, smell, mouthfeel, and after-taste are important concerns for consumer
acceptability. Products with poor flavor, a bad after-taste or other negative
aesthetics may limit consumer acceptability initially or over an extended period of
time, thereby limiting consumer usage and compliance with treatment regimens.
An additional aspect of consumer acceptability and compliance is the
20 consumer's perception of efficacy. Consumer satisfaction with a product is likely to
be increased if some type of sensory signal exists to remind the consumer that the
product is working after ingestion, administration or expectoration.
It has been discovered that phosphate derivatives comprising flavor, coolant,
and/or sweetener components may be incorporated into oral or topical compositions
25 to deliver pleasing aesthetics and high consumer acceptability. It has also been
discovered that these compositions for oral or topical administration may be
formulated to include a safe and effective amount of one or more actives. These
compositions may provide sustained coolant, flavor and/or sweetener activity,
depending on the particular derivative being used. These phosphate derivatives may
30 also serve to improve the aesthetics of the compositions and provide a sensory signal
to the user.
It has also been discovered that a specific type of phosphate derivative, 1,2-
disubstituted-dihydrogen pyrophosphate and salts thereof, can be used in oral
compositions to achieve several possible benefits: tartar control, improved taste
35 (cooling and/or flavoring) and/or an antimicrobial effect (see section herein entitled
"Pyrophosphate Diesters in Oral Compositions" and Example V on).
W O 95/07684 PCT~US9~110227
5~ 0 2 ~
All percentages and ratios used herein are by weight, and all measurements
are made at 25C, unless otherwise specified.
SU~ARY OF THE INVENTIQN
The present invention relates to a tartar control oral composition, comprising,
S by weight of the composition:
(a) from about 0.001% to about 20% of one or more compounds of the
formula;
R ~ ¦ \ R'
/\X / ' X' /
X"
R~/ n
where R and R' are independently selected from the group consisting of a
coolant component, a sweetener component, an antimicrobial agent and a
flavorant component; and where R or R' is hydrogen,
each R" is independently selected from the group consisting of R and R", an
adherent group, M+, M++, C+, and hydrogen;
X, X', and X" are independently selected from the group consisting of
oxygen, nitrogen, and sulfur;
n is an integer greater than or equal to l;
M+ and M++ are physiologically relevant metal cations; and
C+ is an organic cation; and
(b) from about 80% to about 99.999% of a carrier material;
and wherein further the composition is in a form suitable for oral
iqdministration.
DETAILED DESCRIPTION OF THE rNVENTION
The subject invention relates to a composition comprising one or more
phosphate derivatives, and carrier materials wherein the compositions are in a form
woss/076&~4 2 1 7 1 5 30 PCT~S94/10227
3
suitable for oral or topical administration. These compositions also preferably
contain a safe and effective amount of one or more actives.
The term "active" as used herein means an agent which provides an effect
greater than an excipient such as agents providing nutritional, therapeutic, medicinal,
antimicrobial, and/or aesthetic benefit, and those commonly used in health care
products.
The phrase "suitable for oral or topical administration" as used herein means
any formulation that is suitable for the convenient administration of the composition
whereby the composition is intentionally swallowed, chewed, ingested, retained in the
oral cavity for any period oftime, placed in contact with internal mucous membranes
of the body, such as those of the nose, mouth, or throat whether by direct or indirect
application or inhalation to the nasal passages, or applied to the surfaces of the skin
for therapeutic reasons or reasons other than for cosmetic benefit.
The phrase "a safe and e~ective amount", as used herein, means a sufficient
amount of material to provide the desired benefit without undue adverse side effects
(such as toxicity, irritation or allergic response) commensurate with a reasonable
benefit/risk ratio when used in the manner of this invention. The specific safe and
effective amount will vary with such factors as the particular condition that is being
treated, the severity of the condition, the duration of the treatment, the physical
condition of the patient, the nature of concurrent therapy (if any), and the specific
formulation and optional components employed.
The components for use in the present compositions and the preferred
amounts to be utilized are described in detail hereinafter.
Phosphate Derivatives:
The present invention compositions contain one or more phosphate
derivatives. These compounds may be formulated by phosphorylating a least one
coolant, sweetener or flavorant component. These compounds also include linking at
least one coolant, sweetener or flavorant component to an adherent component via a
phosphate bridge. In addition, pyrophosphate and triphosphate groupings may be
substituted for the phosphate group. Coolant, flavorant, or adherent components
may also be linked to phosphorous via two functional groups or attachment sites.Furthermore, the phosphate derivatives described above may be bound via coulombic
interaction with charged compounds or materials, including polymers.
The present compositions may deliver the desired coolant, flavorant and/or
sweetener qualities through the action of the phosphate derivative itself. The
compositions potentially provide a sustained effect through the release of the coolant,
WO 95/0768~ PCT/US9~1/10227
4
flavorant and/or sweetener component from the molecule after cleavage by
phosphatase enzymes.
The term "coolant component" as used herein refers to coolant compounds
having a hydroxy, amino, or thiol functionality which is capable of forming an ester,
S amido, or thioester linkage with a phosphorus(V) atom. Preferred coolant
components are selected from the group consisting of l-menthol, d-menthol, 3-1-
menthoxypropane-1,2-diol ("TK-I0"), menthone glycerol acetal ("MGA"), and 1-
menthyl lactate.
The term "flavorant component" as used herein refers to flavorant compounds
10 having a hydroxy, amino, or thiol functionality which is capable of forming either an
ester, amido, or thioester linkage with a phosphorus(V) atom. Preferred flavorant
compounds are selected from the group consisting of methyl salicylate, eugenol,
vanillin, thymol, cinnamaldehyde glycerol acetal ("CGA"), and linalool.
The term "sweetener component" as used herein refers to sweetener
15 compounds having a hydroxy, amino, or thiol functionality which is capable offorming either an ester, amido, or thioester linkage with a phosphorus(V) atom.
Preferred sweetener components are saccharin, mannitol, sorbitol, glucose, sucrose,
fructose, and neohesperidin dihydrochalcone.
The term "adherent component" as used herein refers to either monomers,
20 oligomers, or polymers having hydroxy, amino, or thiol functionalities which are
capable of forming either ester amido, or thioester linkages with phosphorus(V)
atoms. The monomers, oligomers, or polymers may also possess additional hydroxy,amino, or thiol groups which may either remain unsubstituted or be linked via ester
amido, or thioester linkages to a phosphorus(V) atom which is also attached to a25 coolant, flavor, or active portion. P-eferred compounds are selected from the group
consisting of C12-C18 diacyl glycerol, partially hydrolyzed vinyl acetate/ethylene
copolymer, cellulose, chitin, glucose, glucosamine, silica gel, glycerol, and methyl
vinyl ether-maleic acid.
The terms "M+" and "M++" as used herein refer to physiologically relevant
30 metal cations. The phrase "physiologically relevant metal cations" as used herein
refers to metal cations that are significant to the organic or bodily processes of a
human or lower animal. Preferred "M+" cations are sodium and potassium.
Plert:lled "M++" cations are calcium, zinc, and magnesium.
The term "C+" as used herein refers to an "organic" cation. An "organic"
35 cation as used herein refers to cations that contain positively charged nitrogen,
phosphorous, oxygen, or sulfur atoms. Such cations may contain more than one
positively-charged site and in the case of oligomers or polymers containing nitrogen,
2 1 7 1 530
WO 95/076;8'~ PCTIUS9~/10227
~ 5
phosphorous, oxygen, or sulfur atoms, many positively-charged centers may exit.
Preferred "organic" cations include ammonium, protonated amines such as
protonated glucosamine, and partially or fully protonated amine-containing polymers
such as protonated chitosan.
The phosphate derivatives of this invention are represented by the following
formula: =
R / ¦¦ R'
/~X/ IP X'/
X"
I o ~ J
In the above formula,
R is selected from the group consisting of a coolant component, a sweetener
component, and a flavorant component;
R' and R" are independently selected from the group consisting of R, an
adherent component, M+, M+~, C+, and hydrogen;
X, X', and X" are independently selected from the group consisting of
oxygen, nitrogen, and sulfur; and
n is an integer from 1 to 3.
In addition, R' may equal R", preferably wherein R' and R" are selected from
the group consisting of calcium, zinc, manganese, and magnesium.
Preferred phosphate derivatives have the formula:
W O 95/07684 PCTrUS9~/10227
2~7~53~ o
R ~ \ R'
/\X / ' X'
X"
R~ / n
In the above formula:
R is selected from the group consisting of l-menthol, d-menthol, TK-I0,
S MGA, I-menthyl lactate, methyl salicylate, saccharin, mannitol, sorbitol, glucose,
sucrose, fructose, neohesperidin dihydrochalcone, eugenol, vanillin, thymol, CGA~
and linalool;
R' and R" are independently selected from the group consisting of R, C12-
C18 diacyl glycerol, partially hydrolyzed vinyl acetate-ethylene copolymer, cellulose,
10 chitin, glucosamine, silica gel, glycerol, lower alkyl vinyl ether maleic acids, sodium,
potassium, calcium, zinc, magnesium, ammonium, protonated amines, partially or
fully protonated amine-containing polymers, and hydrogen,
X, X', and X" are independently selected from the group consisting of
oxygen, nitrogen, and sulfur; and
n is and integer from l to 3.
In addition, R' may equal R", preferably wherein R' and R" are independently
selected from the group consisting of calcium, zinc, manganese, and magnesium.
Most preferred phosphate derivatives are menthyl monophosphate, eugenyl
monophosphate, thymyl monophosphate, menthyl diphosphate, bis menthyl
20 pyrophosphate, and menthyl triphosphate. "Menthol" and "menthyl" herein refer to d
or l (most pre~l ed) or racemic mixtures of d and l.
The phosphate derivatives are used in the present invention at levels of from
about 0.001% to about 25%, preferably from about 0.01% to about 15%, by weight
of the composition.
25 Carrier M~teri~ls:
In formulating the compositions of this invention the phosphate derivative
will be incorporated into a carrier which may be completely inert or which may be or
contain other active ingredients. The term "carrier materials", as used herein, means
one or more compatible substances suitable for administration to a human or lower
30 animal. The term "compatible", as used herein means that the components of the
W095/07684 2 1 7 ~ 530 PCTJUSg4/10227
7
compositions are capable of being commingled with phosphate derivatives, actives,
and with each other, in a manner such that there is no interaction which would
substantially reduce the efficacy of the present compositions under ordinary usesituations. Carrier materials must also be of sufflciently high purity and sufficiently
5 low toxicity to render them suitable for administration to the human or lower animal
being treated.
A wide variety of carriers will be suitable depending upon the end use of the
compositions. The phosphate derivatives can be incorporated into a range of
compositions generally divided into oral and topical compositions, both terms being
10 meant in their broadest possible sense. Oral compositions include not only foodstuffs
and beverages taken into the mouth and swallowed, but also other orally ingestedcompositions taken into the mouth for reasons other than for sustenance. Such
compositions include (but are not limited to) solid oral dosage forms such as tablets,
tablet coatings, caplets, hydrogels, and liquid oral dosage forms such as syrups,
15 emulsions and suspensions. Oral compositions also include those compositions
which are taken into the mouth but are not necessarily swallowed, e.g. chewing gum.
Topical compositions include compositions applied to, or which in normal
usage come in contact with, the internal membranes of the body such as those of the
nose, mouth, or throat, whether by direct or indirect application. Such compositions
20 include (but are not limited to) nasal sprays, dentifrices, oral rinses, lozenges, foams,
gels, and throat sprays. Topical compositions may also be compositions applied to
the external surfaces of the body for therapeutic reasons or reasons other than for
cosmetic benefit. Such compositions include ointments, lotions, gels, and creams.
Preferred compositions of the present invention are health care compositions such as
25 dentifrices, oral rinses, liquid oral dosage forms and nasal sprays.
The present compositions preferably comprise from about 0.1% to about
99%, and preferably from about 1% to about 99%, by weight of the composition.
Suitable carrier materials herein, depending on intended end use, are selected from
the group consisting of solvents, suspending agents, solubilizing agents, diluents,
30 surfactants, buffers, lubricants, thickeners, emulsifiers, flavoring agents, colorants,
humectants, sweeteners, co-solvents, binders, disintegrating agents, flow-inducing
agents, coolants, wetting agents, antioxidants, stabilizers, and tableting agents.
Dentifrices
Dentifrice compositions may be of the liquid, paste, powder or gel type.
35 These compositions will usually comprise a finely divided abrasive or polishing
material, e.g. precipitated chalk, silica, magnesium silicate, calcium
polymetaphosphate, aluminum hydroxide or other similar materials well known in the
WO 95/07684 PCT/US9~/10227
30 ~ ~
art. Abrasive materials are more fully described in U.S. Patent 3,070,510, Cooley et
al., December 25, 1962, which is incorporated herein by reference. TooLnpaste
compositions additionally contain a surfactant or foaming agent. Suitable surfactants
are those which are reasonably stable and foam throughout a wide pH range,
S including non-soap anionic, nonionic, cationic, zwitterionic and amphoteric organic
synthetic detergents. These surfactants are disclosed by Gieske et al. in U.S. Patent
4,051,234, issued September 27, 1977, also incorporated herein by reference.
Optional ingredients in dentifrice compositions include flavoring agents,
colorants, buffers, lubricants, thickeners, emulsifiers or plasticizers, and humectants.
Dentifrice carrier materials typically comprise from about 50% to about 94%, andpreferably from about 60% to about 80%, by weight of the dentifrice compositions.
Oral Rinses
Oral rinses usually comprise an aqueous, alcoholic, or aqueous-alcoholic
solution of an antiseptic which is often colored or flavored for palatability. Optional
ingredients include humectants, surfactants, sweeteners, emulsifying agents, fluoride
ion sources, tartar control, and anti-plaque agents. Oral rinse products may also be
formed by dissolving a powder or tablet containing stannous gluconate in water just
prior to use.
Conventional oral rinse compositions generally comprise from about 0% to
60% ethyl alcohol, 0% to 20% of a humectant, 0% to 2% emulsifying agents, 0% to
0.5% sweetening agents, 0% to 0.3% flavoring agents and the balance water.
Liquid Oral Dosa~e Forms
Liquid oral dosage forms include aqueous and nonaqueous solutions,
emulsions, pseudo emulsions~ suspensions, and solutions and/or suspensions
reconstituted from non-effervescent granules. These dosage forms also contain
suitable solvents, emulsifying agents, buffering agents, suspending agents, diluents,
natural and artificial sweeteners, coloring agents, and flavoring agents. Antioxldants
such as butylated hydroxy anisole or butylated hydroxy toluene, and preservatives
such as methyl or propyl paraben or sodium benzoate may also be included. Specific
examples of carriers and excipients that may be used to formulate oral dosage forrns,
are described by Roberts in U.S. Patent 3~903~297, issued September 2, 1975, which
is incorporated herein by reference.
Since many of the actives are generally used in the form of a water-soluble
salt, they can be readily incorporated into conventional aqueous-based formulations.
Water-insoluble or poorly soluble actives, generally in base form, may also be
incorporated into aqueous-based orally acceptable carriers such as dispersions,
suspensions, oil-in-water emulsions and the like by means of suitable dispersing,
wo gs/076g~ 2 1 7 1 5 3 0 PCT/US9~/10227
suspending or emulsifying agents, respectively, which are readily apparent to those
skilled in the art of formulations.
In preparing the liquid oral dosage forms, the active components are
incorporated into an aqueous-based orally acceptable carrier consistent with
conventional practices An "aqueous-based orally acceptable carrier" is one wherein
the entire or predominant solvent content is water. Typical carriers include simple
aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions
such as the oil-in-water type. The most p,efel,ed carrier is a suspension or solution
of the phosphate derivative and active in an aqueous vehicle containing a suitable
suspending or solubilizing agent. Suitable suspending agents include celluloses, carboxymethyl cellulose and its salts, guar gum and the like. Suitable solubilizing
agents include sucrose solutions, ethanol, and surfactants such as polyoxyethylene
derivatives of fatty acid partial esters of sorbitol anhydrides (e.g., Polysorbate 80).
Suspension systems, suspension and solubilizing agents, and methods for their use
are described in M. Pernarowski, "Solutions, Emulsions and Suspensions"
Remington's Pharmaceutical Sciences (A. Osol, editor, 15th Edition, 1975), which is
incorporated herein by reference. While the amount of water in the compositions of
this invention can vary over quite a wide range depending upon the total weight and
volume of the essential ingredients and other optional ingredients, the total water
content will generally range from about 20% to about 75%, and preferably from
about 20% to about 40%, by weight of the composition.
Although water itself may make up the entire carrier, typical oral formulations
also contain a co-solvent including but not limited to alcohol, propylene glycol,
glycerin, sorbitol solution, and the like, to assist solubilization and incorporation of
water-insoluble ingredients, flavoring oils and the like into the composition. In
general, the compositions preferably contain from about 5 to about 25
volume/volume percent of the co-solvent, most preferably from about 10 to about 20
volume/volume percent of the co-solvent.
Nasal Sprays
Carriers suitable for nasal administration provide a product which is delivered
to the nasal passages. Such carriers may be for example, aqueous or aerosol and are
more fully described in Remington's Pharmaceutical Sciences (17th Edition, 1985),
which is incorporated herein by reference. Such product forms include (but are not
limited to) nasal solutions for use as drops or as sprays, nasal suspensions, nasal
ointments, nasal gels, or other vehicles suitable for nasal administration.
Preferred nasal dosage forms are solutions, suspensions, and gels, which
normally contain sodium chloride in a major amount of water (preferably purified
WO 95/07681 PCT/US9~/10227
a ,0
water). Other ingredients including but not limited to: pH adjusters such as sodium
hydroxide; emulsifiers or dispersing agents; buffering agents such as sodium
bicarbonate; preservatives such as benzyl alcohol, parabens, benzalkonium chloride,
chlorhexidine gluconate and disodium EDTA; agents for regulating isotonicity such
S as sodium chloride, boric acid, potassium phosphate and propylene glycol; wetting
agents; thickening agents such as methylcellulose, zanthan gum, carboxymethyl
cellulose, and carbomer; humectants such as sorbitol, propylene glycol, sorbitol, and
glycerol; surfactants such as polyoxyethylene derivatives of fatty acid partial esters
of sorbitol anhydrides; and mixtures thereof, may also be present.
Solid Oral Dosage Forms
The present composition may also be in a solid oral dosag~ form. Tablets can
be compressed, triturated, freeze dried, sugar-coated, film-coated or multiple
co,,,pl essed. The tablees may contain suitable binders, lubricants, diluents,
disintegrating agents, coloring agents, flavoring agents, preservatives and flow-
inducing agents. In general, carrier materials suitable for the preparation of unit
dosage forms for oral administration are well-known in the art. Their selection will
depend on secondary considerations like taste, cost, and shelf stability, which are not
critical for the purposes of the present invention, and can be made without difficulty
by a person skilled in the art. Techniques and compositions for making solid oral
dosage forms are described in Marshall, "Solid Oral Dosage Forms", Modern
Pharmaceutics, volume 7, (Banker and Rhodes, editors), 359-427 (1979),
incorporated herein by reference Techniques and compositions for making tablets,capsules, and pills are describe~ In Remington's Pharmaceutical Sciences (ArthurOsol, editor), 1553-1593 (1980), incorporated herein by reference.
Lozen~es and Chewin~ Gums
Other embodiments of the subject invention include lozenges and chewing
gums. Lozenge compositions comprise a lozenge carrier (i.e. a candy base). Candybases are disclosed in U. S. Patent 4,472,373, Ryan, issued September 18, 1984, and
in U.S. Patent 4,083,955, Grabenstetter et al., issued April 11, 1978. Chewing gum
compositions comprise a chewing gum carrier such as those which are disclosed inthese same patents, both of which are incorporated herein by reference. Chewing
gum carriers may comprise, for example, a gum base, flavoring agents, and
sweetening agents.
Other Carriers
The invention compositions may be formulated with a wide variety of carrier
materials in addition to those already disclosed. Some examples of substances which
can serve as carrier materials are sugars such as lactose, glucose, and sucrose;
21~153~
Wo 95/07684 PCT/US9~/10227
Il
starches such as cornstarch and potato starch; cellulose and its derivatives such as
sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered
tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; dicalcium phosphate;
calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil,
corn oil, and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol,
mannitol, and polyethylene glycol; agar; alginic acid; as well as other non-toxic
compatible substances used in consumer or health care
formulations.
Coolant materials may also be included as carrier materials in the invention
compositions. Preferred coolants in the present compositions are the paramenthane
carboxyamide agents such as N-ethyl-p-menthane-3-carboxamide (known
commercially as "WS-3"), and 3-1-menthoxypropane-1,2-diol (known commercially
as "TK-10"), and mixtures thereof. These coolants are described in PCT Patent
Application Publication WO 92-17164, to Upson et al., published October 15, 1992.
TK-10 is also described in U.S. Patent 4,459,425 to Amano et al., issued July 10,
1984; and WS-3 and the paramenthane carboxyamide agents are also described in
U.S. Patent 4,136,163 to Watson et al., issued January 23, 1979. The disclosures of
all three of these patent publications are incorporated by reference herein in their
entirety.
When desired or necessary, suitable binders, lubricants, and disintegrating
agents can also be incorporated in the compositions. Suitable binders include starch,
gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia
sodium alginate, carboxymethylcellulose, microcrystalline cellulose, polyethylene
glycol and waxes. Lubricants may include, for example, starch, methylcellulose,
agar, bentonite, guar gum, etc. Wetting agents such as sodium lauryl sulfate, as well
as coloring agents, flavoring agents, sweetening agents, excipients, tableting agents,
stabilizers, antioxidants, and preservatives can also be present.
Active:
The invention compositions may also contain a safe and effective amount of
one or more actives. Some actives that are useful in these compositions include (but
are not limited to) antimicrobial agents such as iodine, sulfonamides, mercurials,
bisbiguanides, or phenolics; antibiotics such as tetracycline, neomycin, kanamycin,
metronidazole, or clindamycin; anti-inflammatory agents such as aspirin,
acetaminophen, naproxen, ibuprofen, flurbiprofen, indomethacin, eugenol, or
hydrocortisone; immune-suppressive or stimulatory agents such as methotrexate orlevamasole; dentinal desensitizing agents such as potassium nitrate, strontium
chloride or sodium fluoride; odor masking agents such as peppermint oil or
wo gS/7682 ~ 1 ~ 53~ 12 PCT/US9-1/10227
chlorophyll, immune reagents such as immunoglobulin or antigens; local anesthetic
agents such as lidocaine or benzocaine; nutritional agents such as amino acids,
essential fats, vitamins and minerals; antioxidants such as thymol, alphatocopherol
and butylated hydroxy toluene; lipopolysaccharide complexing agents such as
polymyxin; quaternary ammonium compounds such as benzalkonium chloride and
cetyl pyridinium chloride; aromatics such as camphor, eucalyptus oil, and aldehyde
derivatives such as benzaldehyde; denture adhesives such as lower alkyl vinyl ether-
maleic acid or anhydride copolymers and their salts; coolants having therapeuticefficacy such as menthol; or peroxides such as urea peroxide. It is recognized that in
certain forms of therapy, combinations of these agents in the same delivery system
may be useful in order to obtain an optimal effect. Thus, for example, an
antimicrobial and an anti-inflammatory agent may be combined in a single delivery
system to provide combined effectiveness. Preferred actives are nutritional,
therapeutic, medicinal, pharmaceutical, and those commonly used in health care
products.
Preferred formulations for the present invention compositions which comprise
one or more actives are dental care prepal~lions such as dentifrices and oral rinses,
and cough/cold preparations in liquid oral dosage forms. Actives commonly utilized
in cough/cold preparations include but are not limited to decongestants such as
pseudoephedrine hydrochloride, phenylpropanolamine HCI, pseudoephrine
hydrochloride and ephedrine hydrochloride; antitussives such as dextromethorphan,
chlophedianol, carbetapentane, noscapine, codeine, hydrocodone, hydromorphone;
analgesics such as acetaminophen and ibuprofen; expectorants or mucolytics such as
glyceryl guaiacolate, guaiacolate, terpin hydrate, ammonium chloride, N-
acetylcysteine and ambroxol; antihistamines such as chlorpheniramine maleate,
æatadine, doxylamine succinate, brompheniramine maleate and diphenhydramine
hydrochloride; and non-sedating antihistamines such as astemizole, acrivastine,
ketotifen, and terfenadine. These components as well as others are described in the
following U.S. Patent 4,619,934 to Sunshine et al., issued October 28, 1986, andU.S. Patent 4,783,465 to Sunshine et al., issued November 8, 1988 which are
incorporated herein by reference. Also useful are bronchodilators such as
theophylline and albutsrol; and stimulants such as caffeine.
Oral forms of cough/cold preparations comprise a safe and effective amount
of one or more active components. Solid oral dosage forms preferably contain from
about 5% to about 95%, more preferably from about 10% to about 95%, and most
preferably from about 25% to about 95%, of the active components. Liquid oral
dosage forms preferably contain from about 1% to about 50%, more preferably from
WO 95/07684 2 1 7 1 5~ ~ PCT/US9~/10227
1~
about 1% to about 25%, and most preferably from about 3% to about 10%, of the
active components.
Dental care preparations typically comprise a soluble fluoride ion source as
one of the actives. The soluble fluoride ion source is used in an amount sufficient to
S provide from about 10 to about 5000 ppm ofthe fluoride ion. Preferred fluorides are
sodium fluoride, stannous fluoride, inidium fluoride, and sodium
monofluorophosphate. Norris et al., U.S. Patent 2,946735, issued July 26, 1960 and
Widder et al., U.S. Patent 3,678,154, issued July 18, 1972, disclose such salts as well
as others. Both patents are incorporated herein by reference in their entirety.
Various polymers and mixtures thereof are also useful in dental care
preparations. These polymers may be synthetic anionic polymeric polycarboxylatesand their complexes and/or carboxyvinyl polymers. Polymers useful in the presentcompositions are disclosed in U.S. Patent 4,906,456 to Gaffer et al., issued March 6,
1990, incorporated herein by reference in its entirety.
Pyrophosphate salts are pharmaceutical actives that may also be included in
dental care preparations. Any of the alkali metal pyrophosphate salts may be used in
either their hydrated or unhydrated forms. Specific salts include tetra alkali metal
pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal monoacid
pyrophospate and mixtures thereof, wherein the alkali metals are preferably sodium
20 or potassium. Pyrophosphate salts are described in more detail in Kirk & Othmer,
Encyclopedia of Chemical Technology, Second Edition, Volume 15, Interscience
Publishers (1968), incorporated herein by reference in its entirety. The amount of
pyrophosphate salt useful is any effective amount and is generally enough to provide
at least 1.0% P2O7-4, preferably from about 1.5% to about 6%, and more preferably
25 from about 3.5% to about 6%, to the compositions. It is to be appreciated that the
level of P2O7-4 is that capable of being provided to the composition (i.e., the
theoretical amount at an appropriate pH) and that other pyrophosphate forms (e.g.,
HP2O7-3) may be present when a final product is established.
Anti-plaque and anti-gingivitis pharmaceutical actives may also be included in
30 the dental preparations. These actives include quaternary ammonium compounds or
bis-biguanides such as chlorhexidine and stannous ion in the form of a combination of
stannous fluoride and stannous gluconate. Oral compositions comprising stannous
ion are described fully in U.S. Patent 5,004,597 to Majeti et al., issued April 2, 1991,
incorporated herein by reference in its entirety. Disinfectant agents like triclosan and
35 antiseptic agents like thymol may also be included in the dental preparations.
Pharmaceutical actives commonly utilized in gastrointestinal products are
those agents which are safe and effective when administered orally for treating
WO 95/0768~ PCT/US9`1/10227
~7~5~0 14
disorders of the upper gastrointestinal tract which result in symptoms of upper
gastrointestinal tract distress. Compositions for relieving gastrointestinal distress
may include antacid agents, acid secretion prevention agents, other pharmaceutical
actives and mixtures thereof.
Antacid agents include aluminum carbonate, aluminum hydroxide, aluminum
phosphate, aluminum hydroxy-carbonate, dihydroxy aluminum sodium carbonate,
aluminum magnesium glycinate, dihydroxy aluminum amino acetate, dihydroxy
aluminum aminoacetic acid, calcium carbonate, c ium phosphate, aluminum
magnesium hydrated sulfates, magnesium aluminate, magnesium alumino silicates,
magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium
oxide, magnesium trisilicate, sucralfate, sodium bicarbonate, and mixtures thereof.
Acid secretion prevention agents include cimetidine, ranitidine, famotidine,
omeprazole, and mixtures thereof. Other useful pharmaceutical actives include
antiflatulent agents such as simethicone and bismuth-containing agents such as,
bismuth subsalicylate, bismuth aluminate, bismuth citrate, bismuth subcitrate, bismuth
nitrate, bismuth subcarbonate, bismuth subgalate, and mixtures thereo The
pharmaceutical actives comprise from about 1% to about 99%, and preferably from
about 25% to about 60% by weight of the composition.
Pyrophosphate Diesters in Oral Compositions
A second discovery concerns a tartar control oral composition containing
carrier material and a specific type of pyrophosphate compound(s) of the formulabelow, wherein the composition is in a form which is suitable for oral administration
The pyrophosphate compound has the following formula:
R ~( ¦ ¦ \ R'
X / - X'
X"
R~/ n
=
wosslo76g4 2 1 7 1 5 3 ~ PCT/USg4/10227
15
where R and R' are independently selected from the group consisting of a
coolant component, a sweetener component, an antimicrobial agent and a flavorantcomponent; and where R and R' is hydrogen,
each R" is independently selected from the group consisting of R and R", an
5 adherent group, M+, M++, C+, and hydrogen;
X, X', and X" are independently selected from the group consisting of
oxygen, nitrogen, and sulfur;
n is an integer greater than or equal to l;
M+ and M++ are physiologically relevant metal cations; and
C+ is an organic cation; and
These terms are described above.
Preferred pyrophosphate derivatives have the formula:
R 1( ¦¦ \ R'
X / X'
~"
I
~ R'/ n
In the above formula:
R and R' are independently selected from the group consisting of l-menthol,
d-menthol, TK-I0, MGA, I-menthyl lactate, methyl salicylate, saccharin, mannitol,
sorbitol, glucose, sucrose, fructose, neohesperidin dihydrochalcone, eugenol, vanillin,
thymol, CGA, and linalool;
each R" is selected from the group consisting of R and R', C12-C18 diacyl
glycerol, partially hydrolyzed vinyl acetate-ethylene copolymer, cellulose, chitin,
glucosamine, silica gel, glycerol, lower alkyl vinyl ether maleic acids, sodium,potassium, calcium, zinc, magnesium, ammonium, protonated amines, partially or
fully protonated amine-containing polymers, and hydrogen;
X, X', and X" are independently selected from the group consisting of oxygen
(I)rerelled), nitrogen, and sulfur; and
n is an integer from 2 (p~efe,led) to 3.
WO 95/07684 PCT/US9~110227
~ 7 ~ ~3~ 16
"Menthol" and "menthyl" herein refer to d or l (most preferred) or racemic
mixtures of d and l.
R and R' groups can be the same as or different (preferred) from each other.
The R and R' components can be various cor binations, depending upon whether a
5cooling, flavoring, sweetening, and/or antimicrobial effect is desired. R or R' is
preferably a flavorant component selected from the group consisting of menthol,
methyl salicylate, eugenol, vanillin, thymol, cinnamal~ehyde glycerol acetal, and
linalool.
When R or R' is a flavorant or sweetener or antimicrobial, the other R or R' is
10a coolant component selected from the group consisting of l-menthol, d-menthol, 3-
I-menthoxypropane-1,2-diol ("TK-I0"), menthone glycerol acetal ("MGA"), and 1-
menthyl lactate.
When R or R' is a flavorant or coolant or sweetener, the other R or R' is an
antimicrobial component preferably selected from the group consisting of 2,4,4'-15trichloro-2'-hydroxy-diphenyl ether, 2-phenoxyethanyl, chlorhexidine, and thymol.
When R or R' is flavorant or coolant or sweetener, the other R or R' is
alternatively and preferably an antimicrobial component selected from the group
consisting of 2,4,4'-trichloro-2'-hydroxy-diphenyl ether ; 2-phenoxyethanol; 1,1-
hexamethylene bis [5-(p-chlorphenyl) biguanidine] di-D-gluconate; and thymol.
20Most preferred is 2,4,4'-trichloro-2'-hydroxy-diphenyl ether.
When R or R' is flavorant or antimicrobial or coolant, the other R or R'
alternatively is a sweetener component selected from the group consisting of
saccharin, mannitol, sorbitol, glucose, sucrose, fructose, and neohesperidin
dihydrochalcone.
25The present invention also includes the instance where one R group acts both
as an antimicrobial and a flavorant or coolant.
Mixed pyrophosphate diesters are also included herein, ie, where the
compound contains one R group which is a coolant and one R group which is a
flavor. The mixed pyrophosphate compound, then, provides three benefits: tartar
30control, flavor and cooling. Alternatively, one R group can be a flavor or coolant
and the other R group can be a safe, hydroxyl-containing antimicrobial group. If an
antimicrobial group is included, three benefits can be achieved by inclusion of only
this one type of active in the oral composition: good taste (coolant/flavor), tartar
control and antimicrobial effect. Without meaning to be bound by theory, this
35compound is believed to lead to a reduction in plaque formation on the teeth and/or a
decrease in the incidence and/or severity of gingivitis and/or prevention or reduction
of mouth odor. Further without meaning to be bound by theory, it is believed that
2~ 71~3~
WO 95/07684 PCT/IJS94110227
17
the tartar control effect is achieved by the parent compound or by inorganic
pyrophosphate which is released when the parent compound is cleaved by
phosphatase enzyme present in the oral cavity.
When thymol in particular is included as one of the R groups, both a flavor
5 effect and a low level antimicrobial effect are conveyed in addition to tartar control.
If the other R group is then a coolant, a fourth benefit (cooling taste) is believed to
be conveyed.
Compounds of this type may provide antitartar activity without attendant
unpleasant taste. Oral compositions containing pyrophosphates can convey a bitter
10 taste. A pyrophosphate such as this one which can control tartar and at the same
time taste good (or have improved taste) is surprising and beneficial.
Another advantage of this compound is that a single compound can provide
multiple benefits: tartar control, improved taste (cooling and/or flavoring and/or
sweetening) and/or an antimicrobial effect.
It is also believed that one or more of these four effects, cooling, flavor,
antimicrobial, and tartar control, may surprisingly be sustained effects. Here,
"sustained" means that one or more of these effects continues for some time after
administration or use of the oral composition containing the present pyrophosphate
diesters. Thus, compound remaining in the oral cavity, for example, adhered either
on the plaque itself or on the teeth, would continue to be cleaved by phosphatase
enzyme, which is commonly present in saliva and in plaque. As the compound is
broken down, the coolant, flavor, tartar control, and/or antimicrobial effect would
continue, likely at a low but noticeable level. It can also be called an "extended"
effect, as in "extended cooling". By phosphatase enzyme is meant acid or alkaline
phosphatases and pyrophosphatases.
Preferred is from about 0.01% to about 15%, more preferably from about
0.05% to about 10%, most preferably from about 0.5 to about 5%, by weight of thecomposition, ofthe pyrophosphate compound. Also ple~e,led is from about 85% to
about 99.99%, more preferably from about 90% to about 99.05%, most preferably
from about 95% to about 99.5%, by weight of the composition, of carrier material.
The oral composition herein is preferably toothpaste (most prefel ~ ed),
mouthrinse, or liquid dentifrice. Sodium fluoride is preferably included in dentifrice
compositions herein. Components to be added should be safe for oral use. By "safe"
is meant without undue adverse side effects (such as toxicity, irritation or allergic
response) commensurate with a reasonable benefit/risk ratio when used in the manner
of this invention.
WO 95/07681 PCTIUS9'1/10227
5~
Preferred pyrophosphate diesters are selected from the group consisting of
1,2-bis-menthyl-dihydrogen pyrophosphate; 1,2-bis-thymyl-dihydrogen
pyrophosphate, 1,2-bis-vanillyl-dihydrogen pyrophosphate, 1,2-bis-eugenyl-
dihydrogen pyrophosphate, 1,2-bis-methyl salicylyl-dihydrogen pyrophosphate; and5 mixtures thereof. More pl efe, l ed are I ,2-bis-[3-methyl-6-isopropyl-cyclohexyl]-
dihydrogen pyrophosphate (or 1,2-bis-menthyl-dihydrogen pyrophosphate); and 1,2-bis-thymyl-dihydrogen pyrophosphate. Most preferred is 1,2-bis-[3-methyl-6-
isopropyl-cyclohexyl]-dihydrogen pyrophosphate.
Also preferred are the "mixed pyrophosphate diesters", which include 1-
thymyt-2-menthyl-dihydrogen pyrophosphate; 1-(3-1-menthoxypropane-1,2-diol)-2-
thymyl-dihydrogen pyrophosphate 1-(2,4,4'-trichloro-2'-hydroxy-diphenyl ether)-2-
eugenyl-dihydrogen pyrophosphate; I-eugenyl-2-thymyl-dihydrogen pyrophosphate;
and l-menthyl-2-methyl salicylyl-dihydrogen pyrophosphate. Of those, the more
p~ e~, I ed are I -thymyl-2-menthyl-dihydrogen pyrophosphate and 1-(3-1-
menthoxypropane-1,2-diol)-2-thymyl-dihydrogen pyrophosphate.
Additional ingredients suitable for use in an oral composition can be included
in the present compositions. These are described above. Ingredients which interfere
with or block the effects of the present compounds are preferably not included.
The most pl efel l ed compound for use herein is 1,2-bis-[3-methyl-6-
isopropyl-cyclohexyl]-dihydrogen pyrophosphate or I ,2-di-[( I R)-menthyl]-
dihydrogen pyrophosphate C20H40O7P2 (here called "BMPP"). This chemical
compound is included in Milobedzki and Janczak, Roczniki Chem. 11 [1931] 840
and Jacobsohn, Comptes Rendu Soc. Biol.~ 104 [1930] 432; Biol. J., 230 [1931] 304,
which are incorporated herein by reference.
It has been found in the present invention that BMPP, which has a menthol
component, when taken into the oral cavity in, for example, a mouthrinse, has a
sweet initial flavor and a surprisingly long lasting (eg, up to one hour and perhaps
beyond) cooling effect. This flavor was quite surprising since pyrophosphates and
menthol are known to have an unpleasant taste. BMPP is also believed to reduce
and/or prevent tartar formation.
BMPP can be synthesized by coupling the phosphate, menthyl
monophosphate ("MMP"), via a dehydration reaction using dicyclohexylcarbodiimide("DCC"). Other compounds herein can also be made using dehydration reactions.
Alternatively, BMPP can be synthesized by reacting MMP with an intermediate
formed in the preparation of MMP.
Also included herein is a method of reducing tartar by applying to the dental
enamel the above described oral composition. Also included is a method of creating
W095/07684 2 1 7 1 53 ~ PcT/usg4/ln227
19
a sustained cooling, sweetening~ flavoring or antimicrobial effect in the oral cavity
and adjoining areas of the body by applying to the dental enamel an oral composition
according to the above-described composition. Also included is a method of
reducing or preventing plaque or gingivitis or mouth odor by applying to the dental
5 enamel an oral composition according to he above-described composition.
The following examples further describe and demonstrate embodiments
within the scope of the present invention. These examples are given solely for the
purpose of illustration and are not to be construed as limitations of the present
invention as many variations thereof are possible without departing from the spirit
10 and scope of the present invention. Percentages are by weight unless otherwise
stated.
Example I
Toothpaste Composition
A toothpaste composition according to the present invention is prepared
having the following components:
Component Wei~ht %
Eugenol Monophosphate 0.300
Purified Water 10.422
Sorbitol 60.565
Sodium Fluoride 0.243
Saccharin 0.130
Colorant 0.500
Silica 20.000
Spearmint Flavor 0.500
Carbopol 934 0.300
Xanthan Gum 0.475
Trisodium Phosphate 1.450
Monosodium Phosphate 0.590
Sodium Alkyl Sulfate Solution 4.000
(27.9% in H2O)
Titanium Dioxide 0.525
Add sorbitol to water and mix. Dissolve salts, eugenol monophosphate,
sodium fluoride, saccharin, tridosium phosphate, monosodium phosphate, and then
add colorant. Adjust to pH 7Ø Separately combine silica, carbopol, and xanthan35 gum and then slowly add this mixture to the composition while mixing continuously.
Add sodium alkyl sulfate. Add spearmint flavor. Mix for ten more minutes.
Example II
wo 95/0768~ 5 3 ~ 20 PC ~ ~USg~/10227
Oral Mouth Rinse Composition
An oral moutll rinse composition according to the present invention is
prepared having the following components:
Component Weight %
Thymol Monophosphate 0.300
Ethanol (190 proof) 16.250
Polysorbate 80 0.120
Glycerin 10.000
Purified Water 73.1218
Benzoic Acid 0.0045
Cetylpyridinium Chloride 0.045
Domiphen Bromide 0.005
Sodium Saccharin 0.060
Colorant 0.040
Sodium Benzoate 0.0537
To ethanol, add all ingredients except thymol monophosphate and mix for 5
minutes. Add thymol monophosphate last and then adjust the pH of the compositionto pH 6Ø
Example lll
20 Liquid Oral Dosa~e Form
-
A liquid oral dosage form composition according to the present invention is
prepared having the following components:
Component Weight %
Menthyl Triphosphate 0.300
Sucrose (xfine granular) 51.000
Polysorbate 80 0.020
Glycerin 2.000
Propylene Glycol 15.000
Sodium Citrate, dihydrate 0.522
Citric Acid 0.338
Potassium Sorbate 0.100
Dextromethorphan Hydrobromide 0.133
Guaifenesin 1.333
Flavor 0.300
Distilled Water 18.954
Alcohol 10.000
WO 95/07684 2 1 7 1 5 30 PCT/US94/10227
21
Mix together sucrose and about 1/3 the amount of water and heat to about
60OC until sucrose is dissolved. Mix in polysorbate 80 and glycerin. Separately mix
together propylene glycol, sodium citrate dihydrate, menthyl monophosphate citric
acid and about 1/3 the amount of water. Separately mix together potassium sorbate
5 and about 1/3 the amount of water. Add flavor. Mix together sucrose solution with
propylene glycol solution. Mix together this solution and potassium sorbate solution.
Lastly, add flavor solution. Adjust water level for proper batch size. Adjust pH to
about 6Ø Mix for 30-35 minutes.
Example IV
10 Chewable Tablet
A chewable tablet composition according to the present invention is prepared
having the following components:
Component Weight %
Calcium Carbonate and mannitol 88.0
(50:50 wgt ratio)
Powdered Mannitol 4.785
Aspartame 0.178
Sodium Saccharin 0.092
Prosweet 0.300
3-1-menthoxypropane- 1,2-diol 0.300
N-ethyl-p-menthane-3-carboxamide 0.025
Menthyl monophosphate (a) 0.300
Peppermint Flavor 0.400
Vanilla flavor 0.300
Cola flavor 0.070
Blue speckles 0.750
Talc 2.000
Magnesium Stearate 2.500
(a) prepared as described below
Mill N-ethyl-p-menthane-3-carboxamide to assure that it is in powder form.
Dry mix all ingredients, except magnesium stearate, until uniformly mixed. Add
magnesium stearate and mix for 1-2 minutes. Press desired amount into tablet (target
is 550 mg/tablet).
P,epa,~lion of Menthyl Monophosphate
In a two-liter, three-neck round bottom flask cooled in an ice/water bath and
equipped with a mechanical stirrer and an addition funnel, 153 ml of triethylamine is
added to 157 g. of menthol in 186 ml of phosphorus oxychloride. After allowing the
WO 95/07684 PCTIUS9~/10227
53Q ~ ~
stirred suspension to warm to room temperature over I hour, the mixture is recooled
to OC, 500 ml of ether is added, and the mixture is carefully hydrolyzed with 500 ml
of water. Af[er I .5 hours at OC, the mixture is allowed to warm to room temperature
overnight. The aqueous layer is then extracted with ether (3 x 500 ml) and the
5 combined ether layers are extracted with a I N sodium hydroxide solution (4 x I 1.).
A~er back-extracting the combined basic extracts with more ether (2 x 500 ml), the
basic solution is acidified with concentrated hydrochloric acid solution to pH 0. A
yellow, oily product is removed and the remaining aqueous layer is extracted with
three, one-liter portions of ether. The oil is dissolved in the combined ether extracts,
10 the ether solution is dried with sodium sulfate, the mixture is filtered, and the solution
is concentrated under vacuum to give a viscous syrup. After drying the product
further in a vacuum oven, a white powder is obtained which can be purified by
cryst~lli7~tion from an acetone/water mixture.
Example V
15 Toothpaste Composition
A toothpaste composition according to the present pyrophosphate diester
invention is prepared having thc following components:
Component Wei~ht %
BMPP* 1.00
Purified Water Balance
Sorbitol 60.565
Sodium Fluoride (1100 ppm F-) 0.243
Saccharin 0.130
Colorant 0.500
Silica 20.000
Flavor 0.500
Carboxymethyl cellulose 0.300
Xanthan Gum 0.475
Trisodium Phosphate I .450
Monosodium Phosphate 0.590
Sodium Alkyl Sulfate Solution 4.000
(27.9% in H2O)
Titanium Dioxide 0.525
*=1,2-bis-[3-methyl-6-isopropyl-cyclohexyl]-dihydrogen pyrophosphate
Add sorbitol to water and mix. Dissolve salts, BMPP, sodium fluoride,
saccharin, trisodium phosphate, and monosodium phosphate. Adjust the pH to 7.0
and then add colorant. Separately combine silica, carboxymethyl cellulose, and
21715~0
WO 95/07684 PCT/US94110227
'~3
xanthan gum and then slowly add this mixture to the composition while mixing
continuously. Add sodium alkyl sulfate. Add the flavor (eg, spearmint, peppermint,
wintergreen, fruit) to the composition and mix for ten more minutes.
5 Preparation of BMPP
One mole of menthyl monophosphate (MMP) is reacted with two moles of
dicyclohexylcarbodiimide (DCC) in tetrohydrofuran (THF). Excess DCC is
hydrolyzed with water and the insoluble dicyclohexylurea byproduct is removed byfiltration. The THF is removed under vacuum and the product is extracted into ethyl
10 ether. The ethyl ether is dried with anhydrous sodium sulfate, the mixture is filtered
and the solution is concentrated under vacuum to give a white solid. The product is
recrystallized in wet ethyl acetate and dried in a vacuum oven then any remaining
MMP is removed with an acetone wash.
Example Vl
15 Oral Mouth Rinse Composition
An oral mouth rinse composition according to the present pyrophosphate
diester invention is prepared having the following components:
Component Weight %
BMPP* 1.00
Ethanol (190 proof) 16.250
Polysorbate 80 0.120
Glycerin 10.000
Purified Water Balance
Benzoic Acid 0.0045
Cetylpyridinium Chloride 0.045
Domiphen Bromide 0.005
Sodium Saccharin 0.060
Colorant 0.040
Sodium Benzoate 0.0537
30 *=1,2-bis-[3-methyl-6-isopropyl-cyclohexyl]-dihydrogen pyrophosphate
To ethanol, add all ingredients e:~cept BMPP and mix for 5 minutes. Add
BMPP last and then adjust the pH of the composition to pH 6Ø
Other pyrophosphate diester compounds of the present invention can be
J substituted for the BMPP above, such as 1,2-bis-thymyl-dihydrogen pyrophosphate,
1,2-bis-vanillyl-dihydrogen pyrophosphate, 1,2-bis-eugenyl-dihydrogen
pyrophosphate, and 1,2-bis-methyl salicylyl-dihydrogen pyrophosphate. The amount
w09s/076~4~ 7 ~ 5~ 24 PCT/US91/10227
of the pyrophosphate diester employed in the composition can vary within the limit
described herein.
Example VII
Oral Mouth Rinse Composition
An oral mouth rinse composition according to the present pyrophosphate
diester invention is prepared having the following components:
Component Weight %
Mixed pyrophosphate diester* 1.0
Ethanol (190 proof) 16.250
Polysorbate 80 0.120
Glycerin 10 000
Purified Water Balance
Benzoic Acid 0.0045
Cetylpyridinium Chloride 0.045
Domiphen Bromide 0.005
Sodium Saccharin 0.060
Colorant 0.040
Sodium Benzoate 0.0537
*=1-menthyl-2-(2,4,4'-trichloro-2'-hydroxy-diphenylether)-dihydrogen pyro-
phosphate
To ethanol, add all ingredients except the mixed phosphate ester and mix for
5 minutes. Add the mixed phosphate ester last and then adjust the pH of the
composition to pH 6.5.
Other pyrophosphate diester compounds of the present invention can be
25 substituted for the one above, such as 1-thymyl-2-menthyl-dihydrogen
pyrophosphate; 1-(3-1 -menthoxypropane- 1 ,2-diol)-2-thymyl-dihydrogen
pyrophosphate; 1-(2,4,4'-trichloro-2'-hydroxy-diphenyl ether)-2-eugenyl-dihydrogen
pyrophosphate; 1-eugenyl-2-thymyl-dihydrogen pyrophosphate; and 1-menthyl-2-
methyl salicylyl-dihydrogen pyrophosphate.
