Note: Descriptions are shown in the official language in which they were submitted.
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ANTIPERSPIRANT COMPOSITIONS CONTAINING A
COPPER SALT AND METHODS OF USING
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to U.S. Provisional Patent Application
61/069,389
filed March 14, 2008, the entire contents of which are incorporated herein by
reference.
TECHNICAL FIELD
This application relates to antiperspirant compositions, and more particularly
to
antiperspirant compositions containing a copper salt and a penetration
enhancer. Certain
compositions further include an aluminum or zirconium salt.
.............
BACKGROUND
Antiperspirant compositions based on aluminum and zirconium are well known.
For example, Shin et al. (U.S. Pat. No. 4,774,079) describe antiperspirant
compositions
based on aluminum ehlorohydrate, aluminum chloride, and an aluminum zirconium
polychlorohydrate complex. Parekh et al. (U.S. Pat. No. 6,902,724) describe an
aluminum halide antiperspirant with enhanced efficacy. Carrillo et al. (U.S.
Pat. No.
6,991,781) describe an enhanced. efficacy antiperspirant based on aluminum-
zirconium
salts. It is generally believed that the mechanism of antiperspirants, such as
these,
involves the formation of aluminum or Zirconium hydroxide precipitates, which
plug the
sweat ducts and block sweat from reaching the skin surface.
Separately, salicylic acid, has been used in certain antiperspirant
formulations,
For instance, a salicylic acid gel base has been used as a vehicle for
aluminum chloride
hexahydrate in the treatment of hyperhidrosis, as described in A. Benohanian
et al.,
International Journal of Dermatology, 37, 701-703 (1998), the entire
disclosure of which
is hereby incorporated by reference. Salicylic acid has also been used in
antiperspirant
compositions based on aluminum and zirconium (see, e.g., Motley et al., U.S.
Pat. No.
5,516,511). 1
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Despite these advances, more effective topical antiperspirant compositions are
needed, particularly for those patients suffering from excessive perspiration,
and for those
patients who do not respond well to available conventional therapies.
SUMMARY
This disclosure describes antiperspirant compositions including a copper salt
and
a penetration enhancer. Certain compositions fiuther include a salt of
aluminum or
zirconium, or a mixture thereof.
Certain implementations may include the following features. The copper salt
can
be a copper(HI) salt. The copper salt can be copper chloride or copper
chloride dehydrate.
The copper salt may be dissolved in the composition. In some implementations,
the
copper salt can be included in the composition in an amount from about 0.1% to
about
25% by weight of the total volume of the composition. For example, the copper
salt may
be included in the composition in an amount from about I% to about 16% by
weight, of
the total volume of the composition, e.g. about 2%, about 4%, about 8%, or
about 15%.
Certain implementations may also include the following features. The
penetration
enhancer may be included in an amount from about 0.1 % to about 50% by weight,
of the
total volume of the composition. For example, the penetration enhancer may be
included
in an amount from about 1 % to about 20%, e.g. from about l % to about 10%,
e.g. about
4%. The composition may include water. For example, water may be included in
an
amount from about 0.4% to about 10% by volume, of the total volume of the
composition. The composition may include an alcohol, e.g. a straight-chain,
branched, or
cyclic alcohol having from about 1 to about 8 carbon atoms. The alcohol may be
ethyl
alcohol. The alcohol may be present in an amount from about 0.1 % to about 50%
by
volume, of the total. volumeof the solution, e.g. from about 1% to about 40%,
e.g. about
20%.
In implementations, the composition may also include an organic carrier. The
organic carrier may be selected from the group consisting of straight-chain,
branched, and
cyclic alcohols, polyols (including diols and glycols), esters, and carbonates
having from
about l to about 6 carbon atoms, and combinations thereof The organic carrier
can be
propylene glycol.
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In addition to a copper salt and a penetration enhancer, the composition may
include an aluminum salt, a zirconium salt, or a mixture thereof The aluminum
or
zirconium salt may be a hydrate. For example, the composition may include
aluminum
trichloride hexahydrate. In certain implementations, the aluminum or zirconium
salt may
be included in an amount from about 0.1 %Q to about 25% by weight of the total
volume of
the composition. For example, the aluminum or zirconium salt may be included
in an
amount from about l% to about 10%, e.g. about 4%.
Implementations include methods for reducing or preventing perspiration and
for
treating hyperhidrosis. Implementations also include methods for treating or
preventing
undesirable odors associated with human sweat glands and skin. Certain methods
comprise applying an effective amount of a composition containing a copper
salt and a
penetration enhancer to the skin of a human subject. In. some methods, the
composition
may also include an aluminum or zirconium salt (or a mixture thereof); Other
methods
include first applying an effective amount of a composition containing a
copper salt and a
penetration enhancer followed by applying an effective amount of a composition
containing an aluminum or zirconium salt (or a mixture thereof). In some
methods, the
subject may suffer from social sweating associated with normal daily
activities. In
composition containing an aluminum or zirconium salt (or a mixture thereof).
In some
methods, the subject may suffer from exercise-induced sweating.
Certain implementations may have one or more of the following advantages. The
compositions can combine in an additive or synergistic manner the effects of
copper with
the effects of the penetration enhancer. The effects of copper may also be
additive or
synergistic with the effects of aluminum or zirconium. The compositions may be
effective in reducing perspiration and in treating excessive perspiration or
hyperhidrosis,
particularly with, but not limited to, subjects not responding well to other
treatments.
The compositions may reduce perspiration for an extended time after
application so that
application may be necessary only a few times per week, or month, to achieve
and
maintain the desired degree of reduced perspiration. The compositions may be
effective
for treating the axillae, hands, feet, lower back, groin, and other areas.
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The details of one or more implementations are set forth in the description
and
examples below. Other features, objects, and advantages will be apparent from
the
description, examples, and the claims.
DETAILED DESCRIPTION
This disclosure describes antiperspirant compositions comprising a copper salt
and a penetration enhancer.
The term "dissolved" as used herein means that the copper is substantially
dissolved in and/or colloidally dispersed in the composition. Concentrations
of
constituents are by weight of total volume of the composition (weight/volume)
for solid
constituents such as metal salts, metal salt hydrates, and salicylic acid, and
are by volume
of the total volume of the composition (volume/volume) for liquid constituents
such as
water and alcohol. In each case, concentrations are initial concentrations,
i,e, those at the
time the composition is made (e.g. shortly after the constituent is added to
the
composition). It is understood, and within the scope of this invention, that
concentrations
of certain constituents at later times may be different than the initial
concentrations (e.g.
due to evaporation).
As used herein, the term "copper salt" includes copper ions in the form of or
derived from One or more copper salts, including copper salt hydrates. The
copper salts
used herein are chiefly salts or salt hydrates of copper(II). Examples of
copper Salts
useful herein include, without limitation, chlorides, bromides, iodides,
sulfates, nitrates,
cyanides, acetates, acetylacetates, oxalates, carbonates, formates,
oleates,and maleates,
or hydrates thereof, (for example, but not limited to, copper(II) chloride
dihydrate
(CuCl2(H20)2) and copper(II) sulfate pentahydrate (Cu(S03)(H20)5)). Other
inorganic
and organic salts may also be used, such as those found inS.M. Berge et:al., J
Pharma
Sci., 66(1), 1-19 (1977), and Reringto a The Science and Practice of Phar
racy, R.
Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia,
PA (2005)
at p. 732, Table 3 8-5.
While not wanting to be bound to any particular theory, it is thought that the
antiperspirant effect of tlhe copper salts described herein is chiefly due to
the therapeutic
inhibition of cell metabolic activity by the metal or metal ion. Target cells
of this
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inhibition include cells that are part of, and related to, the sweat glands
and associated
structures. This proposed mechanism is different from the conventional
mechanism of
aluminum and zirconium salts. A significant portion. of the inhibitory
biological action of
copper is thought to come from its redox properties. Copper can catalyze the
production
of very reactive radical ions such as the hydroxyl radical. An increase in
free radicals of
this type is known as oxidative stress, and is an active area of research in a
variety of
diseases where copper may play an important role, For instance, oxidative
stress can
inhibit cell growth or cause cell death, as reported, for example, by L.M.
Gaetke and C.I.
Chow, Toxicology, 189(1-2), 147-63 (2003); and G. Filomeni et al., J. Biol.
Chem.,
282(16), 12010-21 (2007). Copper may interfere with other vital cellular
functions,
including highly energy-dependant membrane pumping functions, which occur in
sweat
glands. It is therefore thought that copper (e.g. Cu(II) and Cu(1)) may
damage, disrupt, or
even cause apoptosis or cell death of some the sweat gland cells, thereby
reducing or
eliminating sweat production.
As used herein, the term "penetration enhancer" means an agent which enables
or
increases entrance of substances primarily into the lumen of the sweat gland
duct. A.
penetration enhancer may also increase percutaneous absorption through the
epidermis,
to the dermis, and into the bloodstream. Penetration enhancers of the
disclosed
compositions include salicylic acid and urea. Other penetration enhancers,
such as
dimethylsulfoxide (DMSO) may also be used. Other suitable penetration
enhancers such
as those listed in Remington (2006), at page 959 (see Table 47-9), may also be
used,
including surfactants such as sodium lauryl sulfate, sodium laurate, sodium
dodecylsulfate, polyoxyethylene-20-cetylether, and polyoxyethylene-9-lauryl
ether, bile
salts and derivatives such as sodium glycocholate, fatty acids and derivatives
such as
oleic acid and caprylic acid, and other agents such as citric acid, EDTA,
decylmethyl
sulfoxide, glycerol, azone, and cyclodextrin.
As described herein, salicylic acid and urea may act as penetration enhancers
of
the active antiperspirant ingredient. Salicylic acid is a keratolytic agent,
causing cells of
the epidermis to slough off, and causing keratin lined skin pores and ducts to
remain
more open. Salicylic acid is known in the treatment of eczema, keratosis
pilaris,
psoriasis, and related skin conditions. While not wanting to be bound to any
particular
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theory, it is thought that salicylic acid may enhance biological access or
absorption of the
active antiperspirant ingredient, as disclosed in A, Benohanian et al,, above,
by improving
access to and/or maintaining enhanced opening (patency) of the sweat gland
ducts. It is
thought that urea may have a similar effect since urea is also a widely used
keratolytic
agent for treating the skin conditions mentioned above. Salicylic acid may
also have
other beneficial properties, such as promoting normal skin (non-perspiration
related)
hydration levels, as also disclosed in A. Benohanian et at., above.
Certain implementations include an organic carrier or vehicle. A suitable
organic
carrier will have certain desirable properties including the ability to (i)
dissolve or
disperse the copper salt and the penetration enhancer; (ii) enable a stable,
homogeneous
composition to be formed; (iii) dry soon after being applied to the skin; and
(iv) leave
little to no residue after drying. Suitable organic carriers may also be
selected for
viscosity, lubricity, and other properties. Suitable organic carriers used
herein include
straight-chain, branched, and cyclic alcohols, polyols (including diols and
glycols),
esters, and carbonates having from about I to about 6 carbon atoms. Examples
include,
without limitation, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-
methoxyethanol, 2-ethoxyethanol, ethylene glycol, 1,2-propylene glycol,
diethylene
glycol,isopropanol, isobutanol, diethylene glycol monoethylether,1,3-butylene
glycol,
2,3-butylene glycol, dipropylene glycol, and 2,4-dihydroxy-2-methylpentane.
Other
suitable organic carriers (including excipients and colloidal systems) may
also be used,
such as those listed in B.J. Bowman et al., Colloidal Dispersions, Chap. 21,
in Remington
(2006); and M.M Crowley, Solutions, Emulsions, Suspensions, and Extracts,
Chap. 39 in
Remington (2006). For clarity, certain organic carriers may also act as
penetration
enhancers.
In various implementations, water, an alcohol, or both water and an alcohol
may
be added to the composition to alter the solubility, viscosity., lubricity,
and other
properties of the composition. Suitable alcohols include straight-chain,
branched, and
cyclic alcohols having from about 1 to about 8 carbon atoms. Exemplary
alcohols
include, without limitation, methanol, ethanol, isopropanol, n-propanol, n-
butanol,
isobutanol, tern-butyl alcohol, 1-hexanol, 1-octanol, and cyclohexanol. Other
suitable
alcohols may also be used.
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Aluminum and zirconium salts may have a synergistic or cumulative
antiperspirant effect with copper, since the former metals are thought to work
via a
different mechanism than capper:. Specifically, aluminum and zirconium salts
are widely
known to form plugs in the sweat glands or otherwise physically block sweat
from
reaching the surface of the skin, as disclosed, for example, by Kolodzik et
al. (U.S. Pat.
No. 6,835,373). Therefore, in some implementations, compositions comprising a
copper
salt and a penetration enhancer also include an aluminum salt, a zirconium
salt (which
include hydrates thereof) or a mixture thereof. For example, aluminum
trichloride
hexahydrate (.A1C1i(H20)6) may be used. Other aluminum or zirconium salts
known to
those skilled in the art may also be used, including halides, oxide-halides,
hydroxyhalides
such as chlorohydrates, and mixtures thereof In certain implementations,
compositions
of a copper salt with an aluminum and/or zirconium salt also include one or
more
substituents listed above, including an organic carrier, water, and an
alcohol.
Methods of using the compositions disclosed herein are also described, In some
implementations, methods of reducing or preventing perspiration, of treating
hyperhidrosis, and of treating or preventing undesirable odors associated with
human
sweat glands and skin include applying to the skin of a human an effective
amount of a
composition comprising a copper salt and a penetration enhancer. In other
implementations, a method of reducing or preventing perspiration, of treating
hyperhidrosis, or of treating or preventing undesirable odors associated with
human sweat
glands and skin include first applying a composition comprising a copper salt
and a
penetration enhancer followed by applying a composition comprising an aluminum
or
zirconium salt (or a combination thereof}. In some implementations, the
subject may
suffer from social sweating associated with normal daily activities. In some
implementations, the subject may suffer from exercise-induced sweating.
The compositions described herein will typically be administered locally and
topically at the desired location, for example, but not limited to, the
axillae, hands, feet,
and groin areas. The compositions may be administered by direct application or
with a
suitable skin applicator. The composition may also be administered via or as
part of any
other suitable vehicle, applicator, or deodorant or antiperspirant
formulation, including,
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without limitation, a dropper (e.g. an eye-dropper or pipette), a sponge-top
type
applicator, a spray, aerosol, roll-on, stick, gel, lotion, cream, salve, or
powder.
In accordance with the present invention, there may be employed conventional
dermatology, pharmacology, and chemistry techniques within the skill of the
art. The
invention is further described in the following examples, which do not limit
the scope of
the claimed invention.
EXAMPLES
Example 1: Preparation of Solutions
To make 1000 ml of solution, a sufficient amount (typically about 400m1 to
about
800ml depending, in part, on the amount of other constituents being added) of
propylene
glycol was added to a measuring beaker. While stirring at room temperature,
the
following ingredients were added: 38,4m1 H20, 38.4ml ethanol (anhydrous),
43.3g
salicylic acid, and the following amount ofCuCi2(H20)2:
Solution No. Amount of CuCl2(H2O)2 Approximate Concentration of
Added (g) Copper Salt (as hydrate) (%, w/v)
1 20g 2
2 40g 4
3 lOOg 10
4 150g 15
Additional propylene glycol was then added until the total volume was 1000 ml.
Any undissolved CuCl2(H2O)2 pellets were cr shed, and the solution was allowed
to stir
at room temperature until the copper salt was substantially dissolved
(typically for about
12-72 hours or longer). The resulting solutions were transparent and greenish
blue in
color (in general, the more copper salt present, the deeper the color). The
solutions were
stored in glass bottles at room temperature.
Example 2: Treatment ofAxillae
A human female subject was identified as suffering from social sweating
associated with various daily activities. She also had undenrable axilaary
odor(s) in day
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today social situations. Approximately 1-3mls of Solution 2 of Example 1 was
applied at
each treatment to the axillae of the subject, either directly or using an
applicator. The
subject treated herself at bedtime. Within two successive daily bedtime
applications,
sweat production and any associated malodor had markedly decreased. Once
achieved,
this antiperspirant effect could be maintained by similar reapplications
approximately
once per week.
Example 3: Treatment of Feet
A human female subject was identified as suffering from exercise-induced
sweating. Approximately 1-3mls of Solution 3 of Example 1 was applied at each
treatment to the feet of the subject, either directly or using an applicator.
The subject
treated herself at bedtime, Within two successive daily bedtime applications,
sweat
production markedly decreased. Once achieved, this antiperspirant effect could
be
maintained by similar reapplications approximately two to three times per
week.
Example 4: Treatment of Hands
A human male subject was identified as suffering from exercise-induced
sweating. Approximately 1-3misof Solution 3 of Example 1 was applied at each
treatment to the hands of the subject. either directly or using an applicator.
The subject
treated himself at bedtime. Within two successive daily bedtime applications,
sweat
production markedly decreased. Once achieved, this antiperspirant effect could
be
maintained by similar reapplications approximately two to three times per
week.
Example 5: Treatment of Hands and Feet (Added Strength)
To patients not responding favorably to treatments of Examples 4-5, a stronger
solution was used. Approximately 1-3mls of Solution 4 of Example 1 was applied
at
each treatment to the hands and feet of two human subjects respectively,
either directly or
using an applicator. The subjects treated themselves at bedtime. Within two
successive
daily bedtime applications, sweat production markedly decreased. Once
achieved, this
antiperspirant effect could be maintained by similar reapplications
approximately two to
three times per week.
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Example 6: Treatment of the Lower Back
A human male subject was identified as suffering from exercise induced
sweating. Approximately lrnl of Solution 2 of Example I was applied at each
treatment
to the lower back of a human male subject, either directly or using an
applicator. The
subject treated himself nightly. Two or three such applications resulted in
approximately
80-90% reduction in sweating, as measured by a comparison of the total amount
of sweat
absorbed by a cloth. The measurements were made immediately following defined
regimens of exercise. The baseline was determined by comparing the data from
the pre
and post-treatment periods. This significant antiperspirant effect could be
maintained by
similar reapplications approximately once or twice per week.
Example 7: Synergy with Aluminum
Three human male volunteers aged 54-62 years who had not responded well to
commercial over-the-counter aluminum-based antiperspirants. Solutions 5, 6 and
7 were
prepared in accordance with Example 1, with the substitution or addition
ofAlCl3(H2Q)6
where indicated.
Solutions 5, 6 and 7 were applied to one axilla of each of the three
individuals,
sequentially, over consecutive two-week periods. The degree of perspiration
was
determined from the diameter of sweat rings on cotton shirts worn by the
subjects after
defined regimens of exercise. The degree of perspiration reduction. was
determined from
the ratio of sweat-ring diameters of the treated vs. non-treated axilla
(average values of
the three subjects). The results are summarized in Table 1.
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Table 1
Solution No, Ingredients Reduction in Perspiration
.5 AICl3(H20)6: 4% 3%
Salicylic Acid: 4%
Ethanol: 20%
Water: 0.4 %
6 CuCI2(H20)2: 4% 22%
Salicylic Acid: 4%
Ethanol: 20%
Water: 0.4 %
7 AIC13(I120)6 4% 85%
CuCI2(H20)2: 4%
Salicylic Acid: 4%
Ethanol: 20%
Water: 0.4 %
Note: Percentage of water is the percentage of water added in addition to
water
added from the metal salt hydrate.
