Note: Descriptions are shown in the official language in which they were submitted.
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
METHODS FOR ALLEVIATING
DISCOMFORT OF A HOT FLASH AND COMPOSITIONS THEREFOR
BACKGROUND OF THE INVENTION
The present invention relates to a method of alleviating discomfort
experienced by a woman during a hot flash. The present invention also
relates to the method of use of topical compositions that may be used to
alleviate such discomfort. More particularly, the present invention relates to
a method of alleviating discomfort, especially the feeling of intense heat,
experienced by a woman during a hot flash and the topical application of a
composition having cooling ingredients in -order to alleviate such
discomfort.
1. Field of the Invention
It is believed that a vast majority, perhaps as much as 80 percent, of
women experience the discomfort of the "hot flash/flush" associated with
menopause. A hot flash is believed to be the result of the hormonal
changes, particularly the decline in estrogen levels, that occur during
menopause. (Although some sources differentiate between a "hot flash"
and "hot flush," both conditions will be referred to herein collectively as
"hot
flash" or "hot flashes.")
A hot flash is marked by an increase in body temperature
accompanied by an intense feeling of unbearable heat, particularly
internally radiating body heat. A hot flash may also be accompanied by an
increase in heart rate, dizziness, anxiety, faintness, a sense of unease,
tingling sensations, pressure in the head, nausea, perspiration, and
feelings of breathlessness. The feeling of heat is often concentrated in the
area of the face and neck, and sometimes spreads to the area of the upper
chest. Although a hot flash may last for as short as a minute, a hot flash
usually lasts as long as two to three minutes, and may last as long as an
hour. Regardless of the duration of the hot flash, the discomfort due to the
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
intense feeling of heat is extremely uncomfortable and disconcerting to a
woman experiencing the hot flash.
2. Description of the Related Art
Perhaps the most common treatment of a hot flash is Hormone
Replacement Therapy (HRT), more specifically Estrogen Replacement
Therapy (ERT). Some sources recommend vitamin supplements, such as
vitamin E and bioflavonoids, to treat a hot flash. These treatments are
systemic methods of treatment that require foresight. In addition in the
case of HRT/ERT, one needs a prescription from a medical professional.
U.S. Patent No. 5,730,957 to Rizk describes the use of a cooling
composition having dimethyl ether and water to alleviate the discomfort
associated with heat. This cooling composition utilizes the latent heat of
vaporization to provide its cooling action and also requires that the cooling
composition be at a temperature below ambient temperature and higher
than the freezing point of water. This patent also provides a method of
maintaining the cooling composition at such a temperature that requires a
pressurized dispensing container. In addition, the sole embodiment
described in the Rizk patent is a water-dimethyl ether composition
contained within an aerosol dispenser (col. 3, line 51 et seq.). In addition
to
the fact that maintaining the composition at a cold temperature is an
inconvenient and impractical requirement, the use of dimethyl ether has
known safety issues.
Some prior art provides for topical cooling of the skin. For example,
U.S. Patent No. 5,703,123 to Pelzer et al. describes the use of
compositions having asymmetric carbonates, thiocarbonates and/or
carbonates to create a physiologic cooling effect on the skin and on
mucosae in compositions such as food stuffs (e.g. beverages, jams,),
cosmetic agents (e.g. shaving products, skin care products, etc.),
household products (e.g. fabric softeners) and pharmaceutical preparations
2
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
(e.g. antiseptic ointments, cough mixtures). U.S. Patent No. 5,266,692 to
Grub et al. provides that ketals, such as 1-methone glycerol ketal or 3,3,5-
trimethylcyclohexanone glycerol ketal, have a physiological cooling effect
when applied to the skin or mucous membranes in preparations, such as
dentifrices, mouth washes, perfumes and shaving foams. In addition, U.S.
Patent No. 5,688,497 to Lozeau et al. discloses shaving aids that provide a
physiological cooling effect.
U.S. Patent No. 5,451,404 to Furman, the disclosure of which is
incorporated herein by reference, provides coolant compositions that may
be administered topically. Also, U.S. Patent No. 4,661,476 to Lane et al.
describes a method of cooling skin overheated by exposure to heat, sun or
wind that is the topical application of an aqueous gel having a starch-
polyacrylamide graft copolymer.
U.S. Patent No. 5,595,970 to Garfield et al. describes the use of a
nitric oxide substrate and/or nitric acid donor, either alone or in
combination
with a progestin or estrogen to alleviate climacterium symptoms such as
hot flashes. However, the compositions disclosed in Garfield et al. require
systemic administration.
Until now, there has not been a method of alleviating the discomfort
of hot flashes experienced by women that is non-systemic, easy to use and
relatively inexpensive.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method of
alleviating the discomfort associated with a hot flash.
It is another object of the present invention to provide such a method
for alleviating the feeling of intense heat associated with a hot flash.
3
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
It is a further object of the present invention to provide such a
method that includes the topical application of a composition having a
cooling agent.
The present invention, in brief summary, is a method of alleviating
the discomfort associated with hot flashes that comprises the step of
applying to the body, particularly to the chest, face and neck area and/or to
the wrist and arm area, a topical cooling composition having at least one
cooling agent.
DETAILED DESCRIPTION OF THE INVENTION
Hot flashes are most commonly associated with the discomforting
symptom of an intense feeling of heat that begins in the face, neck, or
chest regions and then radiates to other parts of the body. However, prior
to the intense feeling of heat, many women experience a premonition of an
impending hot flash that is accompanied by symptoms, such as a feeling of
unease or anxiety, a feeling of pressure in the head, or tingling sensations.
During this time, there is a concurrent increase in heart rate, digital blood
flow, and vasodilation of blood vessels of the skin. At this point, women will
experience an intense feeling of heat and .which may further be
accompanied by feelings of dizziness, nausea and breathlessness.
For most women who experience hot flashes, these foregoing
symptoms are very unpleasant. Indeed, for some women the extent of
these symptoms experienced during a hot flash can be downright
unbearable.
The first detectable change is an increase in finger blood flow with a
concomitant enhancement of skin conductance, as well as a change in
temperature of the skin of the face and neck. The increase in skin
conductance is followed rapidly by a sharp rise (1-7°C) in finger
temperature. The degree to which finger temperature rises during a hot
flash is inversely proportional to the base-line finger temperature before the
4
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
flash. Thus, a 0.5°C increase in finger temperature in a woman with a
base-line finger temperature of 35°C may be as good a measure of the
occurrence of a hot flash as a 5°C increase in finger temperature in a
woman with base-line finger temperature of 29°C, because of the non-
linear relationship between skin temperature and blood flow.
As vasodilation and sweating ensue, internal body temperature
drops. The magnitude of decrease in core temperature ranges from 0.1°C
to 0.9°C. The onset of sweating is rapid and is particularly profuse in
the
face and scalp. It may occur in five minute bursts accompanying short,
discrete hot flashes, or continue in waves for more than thirty minutes
during prolonged hot flashes.
A hot flash is the inverse of a fever. In mammals, the control of body
temperature resembles a negative feedback system in which a set point
temperature serves as reference for the themoregulatory mechanism. A
fever can be understood as the upward adjustment of this temperature set
point. In a febrile episode, the set point is first elevated, initiating
vasoconstruction, shivering and behavorial modifications, such as the
addition of blankets. This results in an elevation of body temperature to a
level that is maintained for a period of time. A hot flash, on the other hand,
is a transient downward adjustment of the set point, which results in the
sensation of heat. At the end of a hot flash, the set point returns to normal.
The trigger for a change in set point may be a series of nerve impulses. A
fever, even with a rapid onset, may last for hours, days or even weeks. In
contrast, the duration of a hot flash is in the order of minutes.
The present invention provides a method of alleviating discomfort
experienced by a woman during a hot flash that occurs during menopause
including alleviating the feeling of intense heat. The present invention
further provides a method of alleviating symptoms of physical discomfort
resulting from increased heart rate and digital blood flow associated with
5
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
hot flashes. The method of the present invention includes the step of
applying topically to the woman a cooling composition having at least one
cooling agent.
Although to practice the method of the present invention, a woman
experiencing a hot flash may apply the topical cooling composition to any
part of her body that feels overheated, it is preferred that the cooling
composition is applied topically to the head and/or neck areas. It is more
preferred that the cooling composition is applied topically to the face and
neck areas. It is most preferred that the cooling composition is applied
topically to the temples.
To practice the present invention, the cooling composition, which is
considered a topical composition, may be a solution, gel, cream, lotion,
emulsion, solid stick, towelette or spray. It is preferred that the topical
cooling composition is a stick, spray or a towelette. However, the topical
cooling composition may be any form that may be quickly and easily
applied to the head and neck areas.
To practice the present invention, the topical composition must have
at least one cooling agent. The cooling agent must be suitable for topical
application. As stated above, U.S. Patent No. 5,730,957 to Rizk discloses
a cooling mixture of water and dimethyl ether. The cooling agents of the
present invention are not a mixture of dimethyl ether and water. In
addition, the cooling mixture of the Rizk patent must be delivered at a
temperature less than ambient temperature and higher than the freezing
point of water. The cooling agents suitable and contemplated for use in the
present invention do not have any such temperature requirements. Also,
the cooling mixtures of the Rizk patent achieve their cooling effect through
the latent heat of transformation, or evaporation, of both the dimethyl ether
and the water components. The cooling agents of the present invention, in
contrast, stimulate the cold receptors of the nervous system, and, thus,
6
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
achieve a cooling effect that is not dependent upon the temperature of the
cooling agent relative to ambient temperature.
Cooling agents that may be used in the present invention include
menthol, and the alkyl-substituted methanols disclosed in U.S. Patent No.
4,069,345 to Gascoyne et al. The cooling agent may also be acyclic
sulphones or acyclic sulphoxides, phoshine oxides, alkyl-substituted
alicyclic carboxylic acids, esters and amides, cyclohexan-amides, cyclic
and acyclic amides, substituted ureas and sulphonamides. Examples of
the foregoing are disclosed in U.S. Patent Nos. 4,318,900; 4,296,093;
4,136,164; 4,070,496; and 4,070,449 to Rowsell et al. Further, the cooling
agent may also be N-hetero substituted-p-menthane-3-carboxamides as
disclosed in U.S. Patent No. 4,190,643 to Watson et al. Still further, the
cooling agent may be monomenthyl succinates, alkali metal salts of
monomenthyl succinate, alkaline earth metal salts of monomenthyl
succinate, and mixtures thereof. Examples of the foregoing are disclosed
in U.S. Patent Nos. 5,725,865 and 5,843,466 to Mane et al. Yet further, the
cooling agent can be an asymmetric carbonate, thiocarbonate or urethate
as disclosed in U.S. Patent No. 5,703,123 to Pelzer et al. The cooling
agent can also be a 2-(2-alkoxy-1-methylethyl)-5-methyl cyclohexanol
derivative as disclosed in U.S. Patent No. 5,756,857 to Kuribayashi et al.
Each patent cited in this paragraph is incorporated herein by reference.
When the cooling agent is a ketal, such as menthone glycerin acetal
and the ketals disclosed in U.S. Patent No. 5,266,692 to Grub et al., which
is incorporated herein by reference, the onset and duration of the effect of
the cooling agent may be affected by manipulating the substituents on the
keta I .
When the cooling agent is menthol lactate, the topical cooling
composition preferably comprises an alkali metal carbonate and/or
bicarbonate and/or alkaline earth metal carbonate as set forth in U.S.
7
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
Patent No. 5,783,725 to Kuhn et al., which is also incorporated herein by
reference, to improve stability of the topical cooling composition.
It is believed that when the cooling composition comprises two or
more of the cooling agents, the cooling effect achieved by the cooling
composition is enhanced. For example, U.S. Patent No. 5,451,404 to
Furman discloses cooling compositions that are suitable for use in
practicing the present invention. One example of a topical cooling
composition of the Furman '404 patent comprises an effective amount of a
first cooling component that is a ketal of the formula
R3 O'
~1
~Z /
O
in which R' represents a C2-C6-alkylene radical having at least 1, but not
more than 3, hydroxyl groups) and either R2 and R3 independently of one
another represent C~-Coo-alkyl which is optionally substituted by 1 to 3
radicals selected from the group comprising hydroxyl, amino and halogen,
or C5-C7-cycloalkyl, or C6-C~2-aryl, with the proviso that the total of the C
atoms of R2 and R3 is not less than 3, or R2 and R3 together represent an
alkylene radical which, together with the carbon atom which carries the
radicals R2 and R3, forms a 5-7-membered ring, and a second coolant
component selected from the group consisting of menthol, carboxamides
and mixtures thereof.
The preferred cooling agents for the present invention include
menthol, menthone glycerin acetal (a non-limiting example of the foregoing
is available from Haarmann & Reimer GmbH under the trademark
FRESCOLAT~ MGA), menthyl lactate (a non-limiting example of the
foregoing is available from Haarmann & Reimer GmbH under the
trademark FRESCOLAT'~' ML), menthyl pyrrolidane carboxylic acid (PCA)
8
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
(a non-limiting example of the foregoing is available from Quest
International under the tradename QUESTICE L), N-2,3,-Trimethyl-2-
isopropyl butanamide (a non-limiting example of the foregoing is available
from ChiRex, Inc. under the tradename WS-23), N-ethyl-p-menthan-3-
carboxamide (a non-limiting example is available from ChiRex, Inc. under
the tradename WS-3), 3-1-methoxypropane-1,2-diol, (1-(2-
hydroxyphenyl)4-(3-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-2-one), C~ to
C5 derivatives of 2-(2-alkoxy-1-methylethyl)-5-methyl cylcohexanols, 1-
menthanyl carbonates and mixtures of the foregoing. Menthone glycerin
acetal is the most preferred cooling agent. One reason why menthyl
pyrrolidane carboxylic acid is a preferred cooling agent is because it
exhibits moisturizing properties as well as coolant properties.
The cooling composition of the present invention comprises from
about 0.01 wt% to about 10 wt% of the cooling agent, preferably from about
0.01 wt% to about 5 wt%, more preferably from about 0.1 wt% to about 2
wt%, even more preferably from about 0.1 wt% to about 1 wt%, and most
preferably from about 0.2 wt% to about 0.8 wt%.
As stated above, the cooling composition is preferably a stick, spray
or towelette. It is preferred that the cooling composition is a water-based
system. In addition, it is preferred that the when the cooling composition is
a water-based composition, the cooling composition further comprises an
alcohol, such as ethanol, isopropyl alcohol and propanol. Alcohols act as a
solvent and also exert a cooling effect that enhances the benefits of the
present invention. When the cooling composition is a water-based system,
it is preferred that the cooling composition comprises from about 5 wt% to
about 15 wt% of an alcohol. The remainder of the cooling composition may
be water. When a water-based system is used, it is preferred that the
cooling composition comprises from about 0.01 wt% to about 5 wt% of the
cooling agent.
9
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
The cooling composition may also be an anhydrous system. In an
anhydrous system comprising alcohol, such as ethanol, isopropyl alcohol or
propanol, it is preferred that the alcohol comprises the majority of the
cooling composition other than the cooling agent. In an anhydrous,
alcohol-free system, such as a cosmetic stick, the composition is
comprised of esters, waxes and/or oils in place of the water and alcohol.
When the cooling composition is an anhydrous system, the cooling
composition may comprise up to 10 wt% of the cooling agent. It is more
preferred that the cooling composition comprises from about 0.1 wt% to
0 about 1 wt% of the cooling agent.
The cooling composition, whether a water-based system or an
anhydrous system, may further include ingredients such as sunscreens,
odor masking agents, natural/botanical extracts, alpha-hydoxy acids,
5 polyhydroxy alpha-hydroxy acids, alpha-keto acids, vitamins, anti-
mycobacterial agents, analgesics, lipidic compounds, moisturizers or
lubricants.
When the cooling composition contains a natural/botanical extract, it
0 is preferred that the natural/botanical extract comprises a soy extract, a
black cohosh extract, or a ginseng extract, or mixtures thereof. More
preferably, the natural/botanical extract will be a mixture of all three of
the
foregoing extracts.
5 Since many women experience feelings of anxiety during hot
flashes, it is believed that when the cooling composition comprises a
fragrant component, which is preferably a natural extract, the alleviation of
the discomfort associated with hot flashes is augmented. It is believed that
the aromatherapeutic benefits of the fragrant component will provide a
0 calming effect, and thus synergistically enhance the cooling composition's
effect on relieving the discomfort, both emotional as well as physiological,
associated with hot flashes.
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
The cooling composition may also include emulsifiers, thickeners
and preservatives. Emulsifiers (solubilizers) that can be used in the cooling
compositions of the present invention can be cationic, anionic, non-ionic,
amphoteric, zwitterionic, or combinations thereof. However, it is preferred
that the emulsifier is a polysorbate emulsifier. Non-limiting examples of
polysorbate emulsifiers are Polysorbate 20 and Polysorbate 80. Examples
of thickeners that can be used are, xanthan gum, magnesium aluminum
silicate (a non-limiting example of the foregoing is available under the
tradename Veegum), cellulosic thickeners, and polymeric thickeners, such
as CARBOPOL, PEMULENT"" copolymers and acrylate copolymers. A
non-limiting example of an acrylate copolymer that may be used in the
present invention is an acrylate/C~o to C3o alkyl acrylate copolymer.
It is preferred that the cooling composition also includes a neutralizer
to adjust pH. The preferred neutralizer is sodium hydroxide. The pH of the
cooling composition should be adjusted according to the cooling agent
used. For example, it is preferred that when the cooling agent comprises
menthone glycerin acetal that the pH of the cooling composition is greater
than 7. In contrast, when the cooling agent comprises menthyl lactate, it is
preferred that the pH of the cooling composition is less than 7.
It is preferred that the cooling composition of the present
invention has a preservative. Suitable preservatives include disodium
EDTA, methyl paraben and benzyl alcohol. Other suitable preservatives
include EDTA salts, EDTA fatty acid conjugates, alkanols, especially
ethanol, isopropyl alcohol, benzyl alcohol, parabens, sorbates,
phenoxyethanol, urea derivatives and isothiazolinone.
An example of a contemplated composition that would be suitable
for practicing the present invention is as follows:
11
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
EXAMPLE 1
INGREDIENT Wt Percent of Total
Composition
Menthone glycerin acetal 0.01 to 5
Vehicle
Polysorbates 0.01 to 5
Methylparaben 0.01 to 5
Acrylates copolymer 0.01 to 4
Sodium Hydroxide 0.01 to 2
Alcohol 5 to 15
Disodium EDTA 0.01 to 0.8
Water QS
The cooling composition of the present invention described above is
used to alleviate the physical symptoms experienced by a woman during a
hot flash. It is contemplated that when the cooling composition may be
applied immediately when the woman either senses a hot flash about to
occur or after a hot flash begins. Although a woman may apply the cooling
composition to any surface area of her body that requires relief, it is
contemplated that the most useful areas for application will be the chest,
face and neck areas, particularly the areas around the temple and at the
base of the neck adjacent the spine. In addition, it is also believed that
topically applying the cooling composition to the wrist and arm areas will be
particularly useful in alleviating discomfort associated with a hot flash.
Although it is contemplated that the method of the present invention
will be used most often to alleviate the discomfort of a hot flash on an as
needed basis, it is believed that the method of the present invention may
be extended to prophylaxis. For example, many women have their slumber
disturbed by "night time" hot flashes. As stated above, the onset and
duration of action of the cooling agent may be manipulated via changes in
chemical structure. Accordingly, women who frequently experience such
12
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
night time hot flashes may apply, just prior to sleep, topical cooling
compositions having cooling agents with either delayed onset or prolonged
effect.
When the topical cooling composition is a spray (hereinafter "cooling
spray"), it is believed that the optimum benefits of the present invention are
achieved in the following manner. The user will spray the cooling spray
onto the palms) of the hands) or onto the fingertips. The user will then
transfer the cooling spray onto the skin. In order to avoid inhalation of the
cooling composition and to avoid contact of the cooling composition with
the eyes, it is recommended that the cooling composition should never be
directly sprayed onto or near the face area. When the topical cooling
composition is a stick, towelette, lotion, cream or gel, (hereinafter
collectively referred to as "non-spray cooling compositions)"), the
consumer may also manually apply the non-spray cooling composition to
the area of skin that feels uncomfortably warm or hot due to the hot flash.
It is preferred that the non-spray cooling composition is spread over the
surface of the skin, but not rubbed deeply into the skin. Extensive rubbing
of the skin may intensify the feeling of heat experienced by the consumer,
and is preferably to be avoided.
FXAMPI F 7
A study was conducted to test the effectiveness of the present
invention in alleviating discomfort and symptoms experienced by women
during a hot flash.
Forty-five women between 40 and 60 years of age participated in the
study. The participants experienced at least three to four hot flashes per
day. Some participants experienced as many as ten hot flashes per day.
In addition to hot flashes, the participants also reported experiencing
13
CA 02361046 2001-07-10
WO 00/45815 PCT/US00/02638
headaches, sleeplessness, mood changes, night sweats and/or erratic or
stopped menstrual periods.
The participants were given spray bottles containing Sample A.
Sample A comprised 0.65 wt% menthone glycerin acetal in a compatible
vehicle made according to Example 1 above. During a two-week period,
the participants applied Sample A to various parts of their body when
experiencing a hot flash. Those parts of the body to which the participants
applied Sample A included the face, chest, neck/throat, shoulders, back,
stomach, legs, arms, wrists and hands.
Over sixty percent of the participants expressed that Sample A was
effective in alleviating discomfort experienced during hot flash episodes. In
addition, over sixty percent of the participants expressed that Sample A
either met or exceeded their expectations of performance.
Various modifications and alterations to the present invention may
be appreciated based on a review of this disclosure. These changes and
additions are intended to be within the scope and spirit of the present
invention as defined by the following claims.
14
