Note: Descriptions are shown in the official language in which they were submitted.
w 09s/07683 2 1 70989 PCTrUS9~/loO~
COMPOSITION CONTAINING PHOSPHATE DERIVATIVES
BACK GRO~D OF T~DE nNVENTION
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 adminictration. These compositions preferably contain a
safe and effective amount of one or more active materials such as those which
provide nutritional, therapeutic, antimicrobial, pharm~ceutical, 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
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
time7 thereby limiting consumer usage and compliance with l,eal-"en~ regimens.
An additional aspect of consumer acceptability and compliance is the
consumer's perception of efficacy. Consumer s~ticf~ction 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, adminictration or expectoration.
It has been discovered that phosphate derivatives comprising flavor, coolant,
and/or sweetener components may be incorporated into oral or topical compositions
to deliver pleasing aesthetics and high consumer acceptability. It has also beendiscovered 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
also serve to improve the aesthetics of the compositions and provide a sensory signal
to the user.
It is therefore an object of the present invention to provide compositions that
are aesthetically pleasing to the consumer. It is also an object of the present
invention to provide compositions which provide a sensory signal to the user, and
preferably contain a safe and effective amount of one or more actives.
WO 95/07683 PCT/US941100~
~7 ~Quq 2
These and other objects of the present invention will become readily apparent
from the detailed description which follows.
All percentages and ratios used herein are by weight, and all measurements
are made at 25C, unless otherwise specified.
SU~/[MARY OF TEIE rNVENTION
The present invention relates to compositions comprising:
(a) from about 0.001% to about 25% of one or more phosphate
derivatives having the formula:
~R" ,f
wherein R is selected from the group consisting of a coolant component, a
sweetener component, and a flavorant component;
wherein R' and R" are independently selected from the group consisting of R,
an adherent component, M+, M++, C+, and hydrogen;
wherein X, X', and X" are independently selected from the group consisting
of oxygen, nitrogen, and sulfur;
wherein n is an integer from 1 to 3; and
(b) from about 75% to about 99.999% of carrier materials; and wherein
further the compositions are in a form suitable for oral or topical
atlminictration.
DETAILED DESCR~PTIQN OF THE INVENTION
The subject invention relates to a composition comprising one or more
phosphate derivatives, and carrier materials wherein the compositions are in a form
25 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,
antimicrobial, pharmaceutical, medicinal, and/or aesthetic benefit and those
30 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
WO 95/07683 PCT/US9~/1004~
2~ 7~4~q
-3-
oral cavity for any period of time, 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 effective 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 tle~l,.,e~-~, 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 pl ere~ d
amounts to be utilized are described in detail hereinafter.
- 15 Phosph21te Deriv~ltives:
The present invention compositions contain one or more phosphate
derivatives. These compounds may be form~ ted 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 att~cllment sites.
Furthermore, the phosphate derivatives described above may be bound via
Coulombic interaction with charged compounds or materials, inclu~ing polymers.
The present compositions may deliver the desired coolant, flavorant and/or
sweetener qualities through the action of the phosphate derivative itself. The
compositions may also provide a sllct~ined effect through the release of the coolant,
flavorant and/or sweetener component from the molecule after cleavage of the
phosphate from the coolant flavorant and/or sweetener by phosphatase enzymes.
The phosphatase enzymes include but are not limited to acid, basic, and
pyrophosphatases.
The term "coolant component" as used herein refers to coolant compounds
havirlg a hydroxy, amino, or thiol functionality which is capable of forming an ester,
amido, or thioester linkage with a phosphorus(V) atom. Preferred coolant
components are selected from the group consisting of menthol, 3-l-
menthoxypropane- 1 ,2-diol ("TK- 10"), menthone glycerol acetal ("MGA"), and
WO 95/07683 PCT/US9~/100
'2~7'34a9 4
menthyl lactate. The terms "menthol" and "menthyl" as used herein include dextro-
and levorotatory isomers of these compounds and racemic mixtures thereof.
The term "flavorant component" as used herein refers to flavorant compounds
having a hydroxy, amino, or thiol functionality which is capable of forming either an
5 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, cinn~m~ldehyde glycerol acetal ("CGA"), and linalool.
The term "sweetener component" as used herein refers to sweetener
compounds having a hydroxy, amino, or thiol functionality which is capable of
10 forming either an ester, amido, or thioester linkage with a phosphorus(V) atom.
Preferred sweetener components are saccharin, m~nnitol, sorbitol, glucose, sucrose,
fructose, and neohesperidin dihydrochalcone.
The term "adherent component" as used herein refers to either monomers,
oligomers, or polymers having hydroxy, amino, or thiol functionalities which are15 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 ~tt~r.ll~d to a
coolant, flavor, or active portion. Preferred compounds are selected from the group
20 consisting of C12-C18 diacyl glycerol, partially hydrolyzed vinyl acetate/ethylene
copolymer, cellulose, chitin, glucose, glucosamine, silica gel, glycerol, and lower
alkyl vinyl ether-maleic acids.
The terms "M+" and "M++" as used herein refer to physiologically relevant
metal cations. The phrase "physiologically relevant metal cations" as used herein
25 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 pot~csium
Plere.,ed "M++" cations are calcium, zinc, m~gnesi~lm, manganese, copper, and
stannous.
The term "C+" as used herein refers to an "organic" cation. An "organic"
30 cation as used herein refers to cations that contain positively charged nitrogen,
phosphorus, oxygen, or sulfur atoms. Such cations may contain more than one
positively-charged site and in the case of oligomers or polymers cont~ining nitrogen,
phosphorus, oxygen, or sulfur atoms, many positively-charged centers may exist.
P- erel I ed "organic" cations include ammonium, protonated amines such as
35 protonated glucosamine, and partially or fully protonated amine-containing polyrners
such as protonated chitosan.
WO 95/07683 2 1 70 4 89 PCTlUS9~/loO~
5
The phosphate derivatives of this invention are represented by the following
formula:
~' ~X -~
Jn
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
10 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
15 the group consisting of calcium, zinc, and m~gn~ m, m~ng~nese, copper and
stannous.
P, e~r. t:d phosphate derivatives have the formula:
~O ~
~ X~X~
I;
~ R Jn
In the above formula:
R is selected from the group consisting of menthol, TK-10, MGA, 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 co-polymer, cellulose,
chitin, glucosamine, silica gel, glycerol, lower alkyl vinyl ether-maleic acids, sodium,
potassium, calcium, zinc, magnesium, manganese, copper and stannous, ammonium,
WO 95/07683 PCT/US9~/100
aq 6
protonated amines, partially or fùlly 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 I to 3.
In addition, R' may equal R", preferably wherein R' and R" are independently
selected from the group consisting of calcium, zinc, magnesium, m~ng~ese, copperand stannous.
Most preferred phosphate derivatives are menthyl monophosphate, eugenyl
monophosphate, thymyl monophosphate, I-menthyl diphosphate, bis l-menthyl
pyrophosphate, and l-menthyl triphosphate. The phosphate derivatives are used inthe 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.
C~rrier M:lterials:
In formulating the compositions of this invention the phosphate derivative
will be incorporated into a carrier which may be completely inert or which may
contain other active ingredients. The term "carrier materials", as used herein, means
one or more compatible substances suitable for ~dminictration to a human or lower
animal. The term "compatible", as used herein means that the components of the
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 sufficiently high purity and sufficiently
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
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 s~ctçn~n~e. 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,
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
Wo 95/07683 2 ~ 7 0 4 8 ~ PCT/USg~ll004~
7
nose, mouth, or throat, whether by direct or indirect application. Such compositions
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 oi~ lotions, gels, and creams.
Preferred compositions of the present invention are health care compositions such as
dentifrices, oral rinses, liquid oral dosage forms and nasal sprays.
The present compositions preferably comprise from about 75% to about
99.999%, and preferably from about 85% to about 99.99%, 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, surfactants, buffers, lubricants, thickeners, ernlll.~ifiers, flavoring
agents, colorants, humect~nt.~, sweeteners, co-solvents, binders, di~integratingagents, flow-inducing agents, coolants, plasticizers, wetting agents, antioxidants,
stabilizers, and tableting agents.
Dentifrices
Dentifrice compositions may be of the liquid, paste, powder or gel type.
These compositions will usually comprise a finely divided abrasive or polishing
material, e.g. precipitated chalk, silica, m~gnesjllm silicate, calcium
polymetaphosphate"~luminum hydroxide or other similar materials well known in the
art. Abrasive materials are more fully des~i,ibed in U.S. Patent 3,070,510, Cooley et
al., December 25, 1962, which is incorporated herein by reference. Toothpaste
compositions additionally contain a surfactant or foaming agent. Suitable surf~ct~nt~
are those which are reasonably stable and foam throughout a wide pH range,
including non-soap anionic, nonionic, cationic, zwitterionic and amphoteric organic
synthetic detergents. These surf~ct,.nts are disclosed by Gieske et al. in U.S. Patent
4,051,234, issued September 27, 1977, also incorporated herein by reference.
Water is also present in the dentifrice compositions. Water employed should
preferably be deionized and free from organic impurities. Water generally comprises
from about 10% to about 50%, and preferably from about 20% to about 40%, by
weight of the compositions. These amounts of water include the free water which is
added plus that which is introduced with other materials such as with sorbitol.
Optional ingredients in dentifrice compositions include flavoring agents,
colorants, buffers, lubricants, thickeners, emulsifiers or plasticizers, and humectants.
Dentifrice carrier materials typically comprise from about S0% to about 94%, andpreferably from about 60% to about 80%, by weight of the dentifrice compositions.
Oral Rinses
WO 95/07683 PCT/US9~/100~-1
~7 ~4~q 8
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
5 formed by dissolving a powder or tablet containing stannous gluconate in water just
prior to use.
Oral rinse compositions typically are based on a water/ethanol solution having
a ratio of water:ethanol of from about 20:1 to about 2:1. Humect~ntc7 such as
glycerin and sorbitol, are usually included to give a moist feel to the mouth.
10 Conventional oral rinse compositions generally comprise, by weight of the
composition, from about 0% to 60% ethyl alcohol, 0% to 20% of a hllmect~nt o%
to 2% emulsifying agents, 0% to 0.5% sweetçning agents, 0% to 0.3% flavoring
agents and the balance water.
Liquid Oral Dosage 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, ~ lent.c,
natural and artificial sweeteners, coloring agents, and flavoring agents. Antioxidants
such as butylated hydroxy anisole or butylated hydroxy toluene, and preservatives
such as methyl or propyl paraben or sodium benzoate may also be inclnded Specific
examples of carriers and excipients that may be used to forrnulate oral dosage forms,
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,
suspending or emulsifying agents"especli~/ely, 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 plt;relled carrier is a suspension or solution
WO 95/07683 2~1 7 0 4 ~ ~ PCT/US9~/100
9
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
5 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
10 this invention can vary over quite a wide range depending upon the total weight and
volume of the ec~enti~l 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
15 also contain a co-solvent inslu~ing 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
20 volume/volume percent of the co-solvent.
~/ Nasal Sprays
Carriers suitable for nasal administration provide a product which is delivered
to the nasal pa~s~ges Such carriers may be for example, aqueous or aerosol and are
more fully described in Remington's Pharmaceutical Sciences (17th Edition, 1985),
25 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
ointrnents, nasal gels, or other vehicles suitable for nasal ~lminictration.
Preferred nasal dosage forms are solutions, suspensions, and gels, which
normally contain sodium chloride in a major amount of water (preferably purified30 water). Other ingredients including but not limited to: pH adjusters such as sodium
hydroxide; em~ ifiers or dispersing agents; buffering agents such as sodium
bicarbonate; preservatives such as benzyl alcohol, parabens, benzalkonium chloride,
chlorhexidine gluconate and disodium EDTA; agents for re~ fing isotonicity such
as sodium chloride, boric acid, potassium phosphate and propylene glycol; wetting
35 agents; thickening agents such as methylcellulose, zanthan gum, carboxymethylcellulose, and carbomer; humectants such as sorbitol, propylene glycol, sorbitol, and
WO 95/07683 PCT/US9~/100~ 1
'q ~o
glycerol; surfactants such as polyoxyethylene derivatives of fatty acid partial esters
of sorbitol anhydrides; and mixtures thereof, may also be present.
Solid Oral Dosa~e Forms
The present composition may also be in a solid oral dosage form. Tablets can
5 be compressed, triturated, freeze dried, sugar-coated, film-coated or multiplecompressed. The tablets may contain suitable binders, lubricants, diluentc,
di.cintegrating agents, coloring agents, flavoring agents, preservatives and flow-
inducinF~ agents. In general, carrier materials suitable for the preparaLion of unit
dosage forms for oral a~1minictration are well-known in the art. Their selection will
10 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),
15 incorporated herein by reference. Techniques and compositions for making tablets,
capsules, and pills are described in Remin~on's Pharm~ceutic~l Sciences (Arthur
Osol, editor), 1553-1593 (1980), incorporated herein by reference.
Lozenges and Chewing Gums
Other embodiments of the subject invention include lozenges and chewing
20 gums. Lozenge compositions comprise a lozenge carrier (i.e. a candy base). Candy
bases are disclosed in U. S. Patent 4,472,373, Ryan, issued September 18, 1984, and
in U.S. Patent 4,083,955, Graben~tetter 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
25 gum carriers may comprise, for example, a gum base, flavoring agents, and
sweetening agents.
Other Carriers
The invention compositions may be forrr~ ted with a wide variety of carrier
materials in addition to those already disclosed. Some examples of substances which
30 can serve as carrier materials are sugars such as lactose, glucose, and sucrose;
starches such as col,ls~alcl1 and potato starch; cellulose and its derivatives such as
sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered
tr~g~c~nth; malt; gelatin; talc; stearic acid; magnesium stearate; dicalcium phosphate;
calcium sulfate; mineral oil and vegetable oils such as peanut oil, cottonseed oil,
35 sesame oil, olive oil, corn oil, and oil of theobroma; silicones such as siloxanes,
silicon oils, fluids, gums and greases, and 1 or 2 part Room Temperature
Vulcanizable; polyols such as propylene glycol, glycerin, sorbitol, m~nnitol,
WO95/07683 2 t 70~ 8~ PCT/US94/l004~
Il
polyethylene oxide, and polyethylene glycol; agar; karaya gum; 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
5 compositions. Preferred coolants in the present compositions are the paramenthane
carboxyamide agents such as N-ethyl-p-menthane-3-carboxamide, (known
cornmercially 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.
10TK-10 is also described in U.S. Patent 4,459,425 to Amano et al., issued July 10,
1984; and WS-3 and other parmenthane carboxyamides agents are 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 theirentirety.
15When desired or necessary, suitable binders, lubricants, and rli~integrating
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,
20 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
25 one or more actives. Some actives that are useful in these compositions include (but
are not limited to) antimicrobial agents such as iodine, sulfon~midec, mercurials,
bisbiguanides, or phenolics; antibiotics such as tetracycline, neomycin, kanamycin,
metronidazole, or clindamycin; anti-inflammatory agents such as aspirin,
~cet~minophen, naproxen, ibuprofen, flurbiprofen, indometh~cin, eugenol, or
30 hydrocortisone; immlme-supp~essi~e or stim~ tory agents such as methotrexate or
levamasole; dentinal desensitizing agents such as potassium nitrate, strontium
chloride or sodium fluoride; odor masking agents such as peppermint oil or
chlorophyll; immune reagents such as immunoglobulins or soluble antigens; local
anesthetic agents such as lidocaine or benzocaine; nutritional agents such as amino
35 acids, essential fats, vitamins and minerals; antioxidants such as thymol, alpha-
tocopherol and butylated hydroxy toluene; lipopolysaccharides; complexing agentssuch as polymyxin; quaternary ammonium compounds such as benzalkonium chloride
WO 95/07683 PCT/US9~/100~
Z~ q 1'~ ~
and cetyl pyridinium chloride; aromatics such as camphor, eucalyptus oil, and
aldehyde derivatives such as benzaldehyde; denture adhesives such as lower alkylvinyl ether-maleic acid or anhydride copolymers and their salts; coolants havingtherapeutic efficacy 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-il-fl~mm~tory 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 preparations such as dentifrices and oral rinses,
and cough/cold preparations in liquid oral dosage forms. Actives commonly utilized
in coughtcold plepal~tions include but are not limited to deconges~allls such aspseudoephedrine hydrochloride, phenylpropanolamine hydrochloride, and ephedrine
hydrochloride; antituc.cives such as dextromethorphan, chlophe(li~nol~
carbetapentane, noscapine, codeine, hydrocodone, hydromorphone; ~n~lgesi~s such
as açet~minophen and ibuprofen; expectorants or mucolytics such as glyceryl
guaiacolate, guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and
ambroxol; a~tihist~mines such as chlorpheni,~",i"e maleate, ~7~t~cline, doxylamine
succinate, brompheniramine maleate and diphenhydramine hydrochloride; and non-
sed~ting ~ntihict~mines such as astemizole, acrivastine, ketotifen, and terfen~ine.
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, and U.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 albuterol; and stim~ ntc
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 fromabout 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
provide from about 10 to about 5000 ppm ofthe fluoride ion. Preferred fluorides are
WO 95/07683 2 1 7 ~ ~ 8 9 PCT/US91/100~
13
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.
S Various polymers and mixtures thereof are also usefi~l 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,
199~, 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
or pot~csil~m 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% P207-4 preferably from about 1.5% to about 6%, and more preferablyfrom about 0.5% to about 6%, to the compositions. It is to be appleciated that the
level of P2074 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 pharm~ceutical actives may also be included in
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 stannou
ion are described fully in U.S. Patent 5,004,S97 to Majeti et al., issued April 2, 1991,
incorporated herein by reference in its entirety. Disinfectant agents like triclosan and
antiseptic agents like thymol may also be included in the dental plepalalions.
Pharm~ceutical actives commonly utilized in gastrointestin~l products are
G those agents which are safe and effective when administered orally for treating
disorders of the upper gastrointestin~l tract which result in symptoms of upper
gastrointestinal tract distress. Compositions for relieving gastrointestin~l distress
35 may include antacid agents, acid secretion prevention agents, other pharm~ceutic~l
actives and mixtures thereof.
WO 95/07683 PCT/US91/100-1~
4~q 14
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 càrbonate, calcium phosphate, aluminum
5 magnesium hydrated sulf~te~ magnesium aluminate, magnesium alumino silicates,
magnesium carbonate, magnesium glycinate, magnesium hydroxide, m~pnesil-m
oxide, magnesium trisilicate, sucralfate, sodium bicarbonate, and mixtures thereof.
Acid secretion prevention agents include cimetidine, ranitidine, famotidine,
omeprazole, and mixtures thereof. Other useful pharrn~reutical actives include
10 ~ntifl~tlllent agents such as simethicone and bismuth-cont~ining agents such as,
bismuth subsalicylate, bismuth aluminate, bismuth citrate, bismuth subcitrate, bismuth
nitrate, bismuth subcarbonate, bismuth subgalate, and mixtures thereof. The
pharrn~celltical actives comprise from about 1% to about 99%, and preferably from
about 25% to about 60% by weight of the composition.
The one or more actives are used in the present compositions at levels of
from about 0.001% to about 99%, and preferably from about 0.01% to about 90%,
by weight of the compositions.
The following examples further describe and demonstrate embodiments
within the scope of the present invention. These examples are given solely for the
20 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
and scope of the present invention. Percentages are by weight unless otherwise
stated.
Example I
25 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 0.300
WO 9S/07683 2 1 7 ~ 4 8 ~ PCT/US9~/100~
15
Xanthan Gum o 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 7.0-8.5. Separately combine silica, carbopol, and
10 xanthan 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
Oral Mouth Rinse Composition
An oral mouth 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 l o.ooo
Purified Water 73.1218
Benzoic Acid 0.0045
Cetylpyridinium Chloride 0.045
Domiphen Bromide 0.005
Sodium Saccharin 0.060
Colorant 0.040
Sodium Ber-70~te 0.0537
To ethanol, add all ingredients except thymol monophosphate and mix for 5
30 min~ltes~ Add thymol monophosphate last and then adjust the pH of the composition
to pH 6.5-8.5.
Example III
Liquid Oral Dosa~e Form
A liquid oral dosage form composition according to the present invention is
35 prepared having the following components:
Component Wei .ht %
wo95/07683 2- ~ 7 ~9 16 PCT/US9~/100~
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 1 0.000
Mix together sucrose and about 1/3 the amount of water and heat to about
15 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
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.
20 Lastly, add flavor solution. Adjust water level for proper batch size. Adjust pH to
about 6.5-8.5. Mix for 30-35 minutes.
l~xample IV
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 5.085
Aspartame 0.178
Sodium Saccharin 0.092
3-l-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
wo 9s/07683 2 1 7 0 4 8 9 PCT/US9~/l004~
17
Blue speckles 0.7so
Talc 2.000
Magnesium Stearate 2.500
(a) prepared as described below
S 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).
Preparation 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 l-menthol in 186 mL of phosphorus oxychloride. After allowingthe stirred suspension to warm to room temperature over 1 hour, the mixture is
recooled to OC, 500 mL of ether is added, and the mixture is carefully hydrolyzed
with 500 mL of water. After 1.5 hours at OC, the mixture is allowed to warm to
roorn temperature overnight. The aqueous layer is then extracted with diethyl ether
(3 x 500 mL) and the combined ether layers are extracted with a I N sodium
hydroxide solution (4 x l L.). After 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, the ether solution is dried with sodium
sulfate, the mixture is filtered, and the solution is concen~ ed 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.
