Note: Descriptions are shown in the official language in which they were submitted.
CA 02269473 1999-04-20
WO 98/17237 PCT/US97/18508
1
ORAL COMPOSITIONS CONTAINING STANNOUS GLUCONATE
TECHNICAL FIELD
The present invention relates to a method of preventing or controlling colds
and similar maladies, such as flu, through the use of an oral composition
containing
stannous gluconate applied to the gingival or oral mucosal tissue of the
subject
susceptible to colds.
BACKGROUND OF THE INVENTION
The common cold, although not usually a serious illness, is a highly
prevalent,
discomforting and annoying infliction. The term "common cold" is applied to
minor
respiratory illnesses caused by a variety of different respiratory viruses.
While
rhinoviruses are the major known cause of common colds, accounting for
approximately 30 percent of colds in adults, viruses in several other groups
are also
important. While immune responses occur, and infection with some respiratory
tract
viruses therefore could be prevented by a vaccine, development of a polytypic
vaccine to cover all possible agents is impractical. Thus, the problem of
controlling
acute upper respiratory disease presents complex challenges, and the long-
desired
discovery of a single cure for the common cold is an unrealistic expectation.
With rhinovirus infection, symptoms of nasal discharge, nasal congestion, and
sneezing usually commence on the first day _of illness and progress to maximum
severity by the second or third day. The costs of treating colds with over-the-
counter
medications in the United States is estimated at an annual cost of over I.5
billion
dollars. The direct costs of treatment in outpatient clinics is estimated at
almost four
billion dollars. Indirect costs, based on the amount of loss in wages because
of re-
stricted activity are substantially higher.
At present, only symptomatic treatment is available for the common cold; the
majority of these drugs are taken orally. Exemplary prior art oral
compositions for
treatment of nasal and other cold, flu, allergy and sinus symptoms and the
discomfort, pain, fever and general malaise associated therewith generally
contain an
analgesic (aspirin or acetaminophen) and one or more antihistamines,
decongestants,
cough suppressants, antitussives and expectorants. Other specific
pharmaceutical
actives for nasal symptoms (e.g., congestion) generally contain either
oxymetazoline
r or phenylephrine. These actives are generally delivered topically to the
nasal mucosa
via a nasal spray. For individuals with certain medical conditions such as
heart
disease, hypertension, diabetes or thyroid disorders, oral drugs such as
decongestants
could pose a risk of unfavorable drug interactions and may cause an adverse
reaction.
CA 02269473 1999-04-20
WO 98/17237 PCT/US97/18508
2
It would, therefore, be highly desirable to deliver relief from specific nasal
symptoms
via compositions without the need for such pharmaceutical actives.
It has been discovered that topical application of stannous gluconate to the
gingival or oral mucosal tissues of a subject susceptible to colds and/or flu
helps to
reduce the incidence of such maladies.
It is therefore an object of the present invention to provide topical oral
compositions which provide treatment to prevent colds and flu.
SLTMMARY OF THE INVENTION
The present invention relates to a method of reducing colds and cold-like
symptoms, such as flu, in subjects susceptible to such maladies by applying a
composition containing an effective amount of stannous gluconate to the
gingival or
oral mucosal tissues.
DETAILED DESCRIPTION OF INVENTION
The compositions of the present invention contain certain essential components
as well as non-essential components.
Stannous Gluconate
Stannous gluconate is an essential component of the present compositions.
This material is a known stannous chelate and may be provided to the present
compositions as the chelate or as separate soluble stannous and gluconate
salts and
the chelate formed in-situ. Such salts include stannous chloride and sodium
gluconate. Stannous gluconate is present in the present compositions at a
level of
from about 0.1% to about 11%, preferably from about 0.2% to about 4%.
Acceptable Carrier
The carrier for the active components) can be any vehicle suitable for use in
the oral cavity. Such carriers include the usual components of mouthwashes,
gargles,
toothpastes, tooth powders, prophylaxis pastes, lozenges, gums and the like
and are
more fully described hereina8er. Dentifrices and mouthwashes are the preferred
systems.
In addition to the active agent(s), the present compositions may contain
antiplaque/gingivitis agents such as quaternary ammonium compounds, water
insoluble agents such as triclosan, teas, as defined herein later, stannous
salts and zinc
salts. These types of agents are described in U.S. patent 4,894,220; January
16,
1990 to Nabi et al, U.S. Patent 4,656,031, April 7, 1987 to Lane et al; and
U.S.
Patent 5,004,597, April 2, 1991 to Majeti et al. All incorporated herein by
reference
in their entirety.
The abrasive polishing material contemplated for use in the present invention
can be any material which does not excessively abrade dentin. These include,
for
CA 02269473 1999-04-20
WO 98/17237 PCT/US97/18508
3
example, silicas including gels and precipitates, calcium carbonate, dicalcium
orthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium
polymetaphosphate, insoluble sodium polymetaphosphate, hydrated alumina, and
resinous abrasive materials such as particulate condensation products of urea
and
formaldehyde, and other such as disclosed by Cooley et al. in U.S. Patent
3,070,510,
December 25, 1962, incorporated herein by reference. Mixtures of abrasives may
also be used.
Silica dental abrasives, of various types, can provide the unique benefits of
exceptional dental cleaning and polishing performance without unduly abrading
tooth
enamel or dentin. Silica abrasive materials are also exceptionally compatible
with
sources of soluble fluoride and polyphosphonates. For these reasons they are
preferred for use herein.
The silica abrasive polishing materials useful herein, as well as the other
abrasives, generally have an average particle size ranging between about 0.1
to 30
microns, preferably 5 and 15 microns. The silica abrasive can be precipitated
silica or
silica gels such as the silica xerogels described in Pader et al., U.S. Patent
No.
3,538,230, issued March 2, 1970 and DiGiulio, U.S. Patent No. 3,862,307, June
21,
1975, both incorporated herein by reference. Preferred are the silica xerogels
marketed under the tradename "Syloid" by the W. R. Grace & Company, Davison
Chemical Division. Preferred precipitated silica materials include those
marketed by
the J. M. Huber Corporation under the tradename, "Zeodent", particularly the
silica
carrying the designation "Zeodent 119". These silica abrasives are described
in U.S.
Patent No. 4,340,583, July 29, 1982, incorporated herein by reference.
The abrasive in the compositions described herein is present at a level of
from
about 6% to about 70%, preferably from about 15% to about 2'% when the
dentifrice is a toothpaste. Higher levels, as high as 90%, may be used if the
composition is a toothpowder.
The compositions of the present invention may also contain a soluble fluoride
ion source such as sodium, potassium, lithium fluorides, stannous fluoride,
and
sodium monofluorophosphate among many others. The fluoride source should be
sufficient to provide from about 50 to about 3500 ppm fluoride in a toothpaste
or
mouthrinse.
Flavoring agents can also be added to dentifrice compositions. Suitable
flavoring agents include, among many others, oil of wintergreen, oil of
peppermint,
oil of spearmint, and oil of clove. Sweetening agents which can be used
include
aspartame, acesulfame, saccharin, dextrose, levulose and sodium cyclamate.
Flavoring and sweetening agents are generally used in dentifrices at levels of
from
CA 02269473 1999-04-20
WO 98/17237 PCT/US97/18508
4
about 0.005% to about 2% by weight.
Dentifrice compositions can also contain emulsifying agents. Suitable
emulsifying agents are those which are reasonably stable and foam throughout a
wide
pH range, including nonsoap anionic, nonionic, cationic, zwitterionic and
amphoteric
organic synthetic detergents. Many of these suitable surfactants are disclosed
by
Gieske et al. in U.S. Patent No. 4,051,234, September 27, 1977, incorporated
herein
in its entirety by reference.
Water is also present in the toothpastes of this invention. Water employed in
the preparation of commercially suitable toothpastes should preferably be
deionized
and free of organic impurities. Water generally comprises from about 10% to
50%,
preferably from about 20% to 40%, by weight of the toothpaste compositions
herein.
These amounts of water include the free water which is added plus that which
is
introduced with other materials such as with sorbitol.
In preparing toothpastes, it is necessary to add some thickening material to
provide a desirable consistency. Preferred thickening agents are carboxyvinyl
polymers of the type mentioned previously herein, xanthan gum, carrageenan,
hydroxyethyl cellulose and water soluble salts of cellulose ethers such as
sodium
carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose.
Natural
gums such as gum karaya, gum arabic, and gum tragacanth can also be used.
Colloidal magnesium aluminum silicate or finely divided silica can be used as
part of
the thickening agent to fiarther improve texture. Thickening agents in an
amount
from 0.5% to 5.0% by weight of the total composition can be used.
It is also desirable to include some humectant material in a toothpaste to
keep
it from hardening. Suitable humectants include glycerin, sorbitol, xylitol,
and other
edible polyhydric alcohols at a level of from about 5% to about 70%.
Another preferred embodiment of the present invention is a mouthwash
composition. Conventional mouthwash composition components can comprise the
carrier for the active agents of the present invention. Mouthwashes generally
comprise from about 20:1 to about 2:1 of a water/ethyl alcohol solution and
preferably other ingredients such as flavor, sweeteners, humectants and
sudsing
agents such as those mentioned above for dentifi-ices. The humectants, such as
glycerin and sorbitol give a moist feel to the mouth. Generally, on a weight
basis the
mouthwashes of the invention comprise 0% to 60% (preferably 10% to 25%) ethyl
alcohol, 0% to 20% (preferably 5% to 20%) of a humectant, 0% to 2% (preferably
0.01% to 0.15%) emulsifying agent, 0% to 0.5% (preferably 0.005% to 0.06%)
sweetening agent such as saccharin, 0% to 0.3% (preferably 0.03% to 0.3%)
flavoring agent, and the balance water.
CA 02269473 1999-04-20
WO 98/17237 PCT/US97/18508
Suitable lozenge and chewing gum components are disclosed in U.S. Patent
No. 4,083,955, April 11, 1978 to Grabenstetter et al., incorporated herein by
reference.
Other optional components useful in the present invention are pyrophosphate
salts such as those described in U.S. 4,515,772, May 7, 1985 to Parran et al.
a
incorporated herein by reference. Also useful are nonionic antimicrobials such
as
triclosan described in U.S. 4,894,220, January 16, 1990 to Nabi et al. Both
patents
are incorporated herein by reference.
Another agent which can be used in the present compositions is an alkali metal
bicarbonate, such as sodium bicarbonate. These are stable items of commerce
and
can be used together with a peroxide compound in separate compartments such as
disclosed in U.S. 4,849,213 and U.S. 4,528,180, both to Schaeffer,
incorporated
herein by reference in its entirety.
Other preferred compositions of the subject invention are controlled-release
drug delivery systems for placement in the periodontal pocket. Such systems
include,
but are not limited to, the cellulose hollow fibers disclosed in U. S. Pat.
No.
4,175,326, issued to Goodson on Nov. 27, 1979; the ethylcellulose films
disclosed in
U.S. Pat. No. 4,568,535 issued to Loesche on Feb. 4, 1986; the absorbable
putty-like
material disclosed in U.S. Pat. No. 4,568,536 issued to Kronenthal, Maftei and
Levy
on Feb. 4, 1986; the biodegradable microspheres and matrix disclosed in U.S.
Pat.
No. 4,685,883 issued to Jernberg on Aug. 11, 1987; the microparticle or
microcapsule suspensions disclosed in U.S. Pat. No. 4,780,320 issued to Baker
on
Oct. 25, 1988; the polymeric devices disclosed in European Patent Applicatin
No.
0,140,766 of Goodson, published May 8, 1985; and the lactide/glycolide
executions
described in U.S. Patent No. 5,198,220, March 30, 1993 to Damani; these
patents
are incorporated herein by reference. Such controlled-release delivery systems
generally include a solid matrix, usually of polymeric material, loaded with
one or
more active agents, the matrix entrapping stannous gluconate. Typically, the
active
agents diffuse from the solid material into the periodontal pocket over time.
Preferred controlled-release drug delivery systems comprise from about
0.001% to about 50%, more preferably from about 0.01% to about 25%, more
preferably still from about 0.1% to about 15%, still more preferably from
about 1%
to about 10%, of stannous gluconate and a controlled-release carrier.
The pH of the present compositions and/or its pH in the mouth can be any pH
which is safe for the mouth's hard and soft tissues. Such pH's are generally
from
about 3 to about 10, preferably from about 5 to about 9.
METHOD OF MANUFACTURE
CA 02269473 1999-04-20
WO 98/17237 PCT/US97/18508
6
The carrier compositions of the present invention can be made using methods
which are common in the oral products area.
For example, toothpaste compositions may be prepared by mixing part of the
humectant and water together and heating to 66°-71°C. The
fluoride source, if
present, is then added along with the sweetener, the opacifier and the flavor.
COMPOSITIONS OF USE
The present invention in its method aspect involves applying to the gingival
and/or oral mucosal tissue safe and effective amounts of the compositions.
Generally
an amount of at least about 5 grams of a mouthwash and at least about 0.5 of a
toothpaste or liquid dentifrice.
A preferred method of the subject invention involves the contact of a
composition of the subject invention with oral cavity soft tissue for at least
about 15
seconds, preferably from about 20 seconds to about 10 minutes, more preferably
from about 30 seconds to about 60 seconds. The method often involves
expectoration of most of the composition following such contact, preferably
followed
by rinsing, e.g., with water. The frequency of such contact is preferably from
about
once per week to about five times per day, more preferably from about thrice
per
week to about four times per day, more preferably still from about once per
day to
about thrice per day. The period of such treatment typically ranges from about
one
day to a lifetime. Generally, people may recognize that they will be exposed
to a
cold's virus and they then can use the products described herein either prior
to the
exposure, following exposure, or at the first signs of a cold.
The compositions used in the present method may also be used by the subject
as a gargle. Additionally, subjects taking significant doses of Vitamin C may
achieve
an enhanced colds benefit through the use of the compositions described
herein.
The following examples further describe and demonstrate preferred
embodiments within the scope of the present invention. The examples are given
solely for illustration and are not to be construed as limitations of this
invention as
many variations thereof are possible without departing from the spirit and
scope
thereof.
CA 02269473 1999-04-20
WO 98/17237 PCT/US97/18508
7
EXAMPLE I
Toothoastes
Weight % Weigh
Water 13.017 12.500
Sorbitol 45.425 44.552
Glycerin 10.198 I 0.198
Titanium Dioxide 0.525 0.525
Silica 20.000 20.000
Na Carboxymethyl Cellulose 1.050 1.050
Magnesium Aluminum Silicate 0.408 0.408
Na Alkyl Sulfate (27.9% Solution) 4.000 4.000
.
Na Gluconate 1.738 3.476
Stannous Chloride Dihydrate 1.794 1.794
Na Saccharin 0.200 0.200
Flavor 0.851 0.851
FD&C Blue #1 (1% Solution) 0.051 0.051
Sodium Fluoride 0.243 -
Na Hydroxide (50% Solution) 0.500 0.395
pH 4. S 4. 5
EXAMPLE II
Mouthrinses
Weight % Wei h~ t
Stannous Chloride Dihydrate 0.519 0.519
Sodium Gluconate 0.5? 1 1.041
Glycerin 8.000 12.000
Sorbitol (70% Aqueous Solution) _ _
Ethanol 10.000 10.000
Polysorbate 80 0.300 0.300
Sodium Saccharin 0.050 0.050
Flavor 0.150 0.150
Sodium Hydroxide 0.020 0.020
Benzoic Acid 0.050 0.050
FD&C Blue #I (1% Solution) 0.020 0.020
Sodium Monofluoro Phosphate 0. I83 -
Water 80.187 77.850
CA 02269473 1999-04-20
WO 98/17237 PCT/US97118508
8
EXAMPLE III
Topical Gels
Weight % Wei hg t%
Stannous Chloride Dehydrate 1.794 2.153
Sodium Gluconate 1.750 2.082
Glycerin 91.896 70.000
Sorbitol (70% Solution) - 21.765
Sodium Carboxymethyl Cellulose 0.600 0.800
Hydroxyethyl Cellulose - -
Flavor 1.000 1.000
Sodium Saccharin 0.200 0.200
Sodium Alkyl Sulfate (27.9%) 2.000 2.000
Sodium Monofluoro Phosphate 0.760 -
EXAMPLE IV
Mouthrinse Tablets
Stannous Chloride Dehydrate 0.5198 0.5198
Sodium Gluconate O.SOOg 0.7008
Flavor 0.1508 0.1508
Sodium Saccharin O.OSOg 0.2008
Mannitol 0.773 g -
Sodium Carboxymethyl Cellulose O.OSOg -
Sodium Benzoate 0.0308 0.0258
Citric Acid - 0.2008
Sodium Carbonate - 0.1008
Sodium Bicarbonate - 0.2008
Glycine - 0.0508
Sodium Monofluoro Phosphate 0.1838 -
2.255g 2.1448
Dissolve Dissolve
in 97.7458 in 97.8568
water water
