Note: Descriptions are shown in the official language in which they were submitted.
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
METHOD FOR REDUCING ACNE OR IMPROVING SKIN TONE
CLAIM OF PRIORITY
This application claims priority of U.S. Patent Application Serial No.
10/017,180
filed December 7, 2001 which is a continuation-in-part of U.S. Patent
Application Serial
No. 10/012,627, filed December 7, 2001, the disclosures of which are hereby
incorporated
by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods for ( 1 ) reducing the number and
severity of acne lesions on the skin of a mammal; (2) ameliorating the
inflammation of
acne lesions on the skin of a mammal; (3) improving the skin tone of a mammal,
(4)
treating skin disorders; (5) treating stress related skin diseases; (6)
reducing stress and
improving the emotional well being of an acne sufferer; (7) reducing sebaceous
gland
output; and (8) increasins compliance of the administration of anti-acne
products. The
method comprises the administration of a sensory regimen in an amount
effective to
downregulate the activity of the hypothalamus-pituitary-adrenal (HPA) axis in
combination with the administration of an anti-acne composition.
2. Description of the Prior Art
Advances in technology in the last century have brought benefits to society
but
have resulted in greater prevalence of stress in the daily lives of people at
all levels of
society. Our stress response mechanisms have not adapted at the same pace as
advancing technology. The effect of stress on health and well being is well
documented
in "Why Zebra's Don't Get Ulcers - An Updated Guide to Stress, Stress Related
Diseases and Coping" by Robert M. Sapolsky, ISBN 0-7167-3210-6, Chapter l,
(S'"
Edition 2000) and in "The Concepts of Stress and Stress System Disorders -
Overview
of Physical and Behavioral Homeostasis", JAMA, March 4, 1992, Vol. 267, No. 9.
For
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
example, it is known that chronic stress (an accumulation of acute stresses)
can cause or
aggravate many conditions including immunosuppression and vulnerability to
infectious diseases, gastric conditions, sleep problems, depression, premature
birth in
expectant mothers, low birth weight, degeneration of brain neurons leading to
memory
and learning problems, elevated blood pressure, heart complications and stroke
due to
elevated blood lipid levels and other health complications.
While stress has a major effect on systemic health conditions, it also has
been
proposed to play a role in one's skin condition. Skin diseases such as
psoriasis, atopic
dermatitis, itch, blotchiness, poor wound repair have all been proposed to be
linked to
stress in some way. Some relevant references include Buske-Kirschbaum et al.,
Psychosomatic Medicine (1997), 59: 419-426; Denda et al., Am. J. Physiol.
Regulatory
Integrative Comp. Physiol. 278: 8367-8372, (2000); Dhabhar et al., Proc. Natl.
Acad.
Sci., 1999, 96:1059-1064; Kabat-Zinn et al., Psychosomatic Medicine (1998) 60:
625-
632; Tausk et al., Arch. Dermatol., 2001 137: 78-82; Kiecolt-Glaser et al.,
Journal
Behavioral Medicine 1986 9:5-21, Garg et al., Arch. Dermatol. 2001 137: 53-59;
Slominski et al., Physiological Reviews, 2000 80: 979-1020; Panconesiet et
al.,
Psychodermatology, 1996: 399-421; Scholzen, et al., Exp. Dermatol. 1998 81-96,
the
disclosures of which are hereby incorporated by reference.
Another skin condition potentially linked to stress is acne vulgaris. Acne
vulgaris is a skin condition that affects over 85% of all people. The
following are four
primary factors that lead to the formation of acne vulgaris; (1) increased
sebum output
resulting in oily, greasy skin; (2) increased bacterial activity normally due
to an
overabundance of Propionibacterium aches; (3) plugging (hypercornification) of
the
follicle or pilosebaceous duct; and (4) production of inflammation by
substances
leaking into the dermis which cause inflammatory reactions. A more detailed
description can be found in Cunliffe, William J., Acne, London: Martin Duitz
Ltd.,
1989, Chapter 1, which is incorporated by reference.
These primary factors can be affected by some degree by varying hormone
levels in people. One of the major reasons why acne is prevalent among the
teen-age
2
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
populations is the dramatic increase in androgen output amongst that
population which
leads to increase sebum production. In addition, as hormone levels change in
females
during different times of their menstrual cycle, there is also a potential
correlation with
onset of acne lesions tied into their menstrual cycle.
Stress, which is present among both genders and all age groups, but clearly
present among the teen-age and 20 -30 year old populations, also can
exacerbate and
lead to acne problems via a number of different pathways. For example, chronic
stress
can lead to a reduction in the overall immune system, which would affect the
skin's
ability to fight off the Propionibacterium acnes bacteria.
It is known that a functioning immune system contributes to overall good
health,
including healthy skin. Researchers at Shiseido and Harvard Medical School and
Massachusetts General Hospital, see, for example, www.shiseido.co.in have
hypothesized that use of make-up promotes a positive state of mind which in
turn
promotes beautiful skin through stimulation of the nervous system and internal
secretions. Conversely they hypothesize that skin condition can deteriorate
because of
stress.
While a recognized benefit of the use of cosmetic and beauty products is that
they can contribute to a more positive mental outlook, in general, use of
cosmetic and
beauty products has not been demonstrated to have a significant effect on the
activity of
the HPA axis to a degree wherein the quality of life an individual is
improved. Indeed
products that are intended to resolve a skin condition typically contain
benefit agents
that improve the skin condition by treating the outer layers of the skin. In
addition,
most products are either fragrance-free or lightly fragranced, which again
would limit
the product's ability to deliver any type of emotional benefit through sensory
stimuli.
It is a common perception that emotional stress negatively affects skin
condition. See for example, Journal of Investigative Dermatology Vol. 114, No.
4,
April 2000 Abstract No. 415, p. 820 which is hereby incorporated by reference.
In this
abstract the researchers investigated the exacerbation of acne by emotional
stress
through looking at the effect of secretion of a neuropeptide ("substance P")
secreted
3
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
from nerve ending in response to emotional stress. In immunohistochemical
studies in
which they incubated human facial skin with substance P, they found expression
of
leukocytes (ELAM-1 ) and expression of a neuropeptide-degrading enzyme (NEP)
in
sebaceous glands. These findings imply that substance P could result in
neurogenic
inflammation and an effect on the sebaceous glands, such that acne may be
exacerbated.
Other hormones are secreted in response to stressors which can be used as an
indicator of stress. For example, the region in the brain known as the
hypothalamus
drives the activity of the mammalian stress response. Specifically, the
hypothalamus
drives the production of "stress hormones" including catecholamines and
glucocorticoids. The hypothalamus responds to a stressor by activating the
sympathetic
nerve endings in the adrenal medulla to produce adrenaline. The hypothalamus
produces corticotrophin-releasing hormone ("CRH") which acts upon the
pituitary to
release adrenocorticotrophic hormone ("ACTH") which in turn acts upon the
adrenal
cortex to promote the production of cortisol. The CRH and sympathetic systems
participate in a positive feedback loop so that activation of one system
activates the
other. Since increased cortisol secretion is an indication that the HPA axis
has been
activated, conversely, a decrease in cortisol secretion would indicate a
downregulation
of HPA axis activity.
As discussed above, it is desirable to have a sustained reduction of stress
related
hormones in order to reduce acne, improve skin tone, and have a better quality
of life.
Although there are over the counter commercially available anti-acne agents
for topical
use, such as salicylic acid, sulfur, lactic acid, glycolic acid, pyruvic acid,
urea,
resorcinol, N-acetylcysteine, retinoic acid, benzoyl peroxide, octopirox,
triclosan,
azelaic acid, phenoxyethanol, phenoxypropanol, flavinoids, derivatives
thereof, and
combinations thereof, they tend to be slow acting and may have negative side
effects.
In general, current products are effective in reducing the clinical
observation of acne but
since it does not completely eliminate it the consumer is not completely
satisfied with
the treatment of their condition. Topical medication may also result in other
4
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
undesirable effects such as irritation and dryness. Accordingly, there remains
a need to
improve the effectiveness of currently available commercial acne products.
In addition to the products that are available over the counter, there are
also a
number of different pharmaceutical treatments that have been developed for the
treatment of acne. These include, but are not limited to both topical and oral
agents, for
example isotretinoin and tretinoin, adapalene, tazarotene, azelaic acid,
minocycline,
doxycycline, antibacterials such as erythromyacin and clindamycin, vitamins
such as
zinc, folic acid and nicotinamide, as well as combinations of these
antibacterials with
over the counter anti-acne agents. However, there is a continuing desire to
increase the
effectiveness of these pharmaceutical compounds and to improve the user's
quality of
life.
This invention will solve the problem of improving acne and acne related
conditions through use of sensory stimuli in combination with the use of an
anti-acne
agent. The methods according to the present invention reduce emotional stress,
downregulate the HPA axis and improve the quality of life of the acne patient.
SUMMARY OF THE INVENTION
The present invention relates to a method for reducing the number and severity
of acne lesions on the skin of a mammal. The method comprises the step of
administering a sensory regimen in an amount effective to downregulate the
activity of
the HPA axis of said mammal in combination with the administration of an anti-
acne
composition comprising an effective amount of an anti-acne agent.
In other embodiments, the invention relates to methods for ameliorating the
inflammation of acne lesions on the skin of a mammal and methods for improving
the
skin tone of a mammal using the method described above.
In yet another embodiment, the invention relates to a method for the treatment
of skin disorders comprising the step of administering a sensory regimen in an
amount
effective to downregulate the activity of the HPA axis of said mammal in
combination
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
with the administration of an anti-acne composition. Preferably, the method
can
provide at least at least two of the following treatments: (a) reducing the
number and
severity of acne lesions on the skin of a mammal; (b) ameliorating the
inflammation of
acne lesions on the skin of a mammal; and (c) improving the skin tone of a
mammal.
The invention also relates to a method for the treatment of stress-related
skin
diseases such as atopic dermatitis, sebhorreic dermatitis, psoriasis, itch,
wound healing,
fine lines, wrinkles, pigmentation, and combinations thereof. The method
comprises
the step of administering a sensory regimen in an amount effective to
downregulate the
activity of the HPA axis of said mammal in combination with the administration
of an
active agent. As used herein, the term "active agent" means therapeutic agents
known
in the art to be useful in the treatment and or amelioration of the symptoms
of these
skin conditions.
In yet another embodiment, the invention also relates to a method for reducing
stress and improving the emotional well being of an acne sufferer. The method
comprising the step of administering a sensory regimen in an amount effective
to
downregulate the activity of the HPA axis of said mammal in combination with
the
administration of an anti-acne composition comprising an effective amount of
an anti-
acne agent.
The invention also relates to a method for reducing the visual appearance of
shine. The method comprises the step of administering a sensory regimen in an
amount
effective to downregulate the activity of the HPA axis of said mammal.
In yet another embodiment, the invention relates to a method for reducing
sebaceous gland output comprising the step of administering a sensory regimen
in an
amount effective to downregulate the activity of the HPA axis of said mammal
in
combination with the administration of an anti-acne composition comprising an
effective amount of an anti-acne agent.
In another embodiment, the invention relates to a method for increasing
compliance of anti-acne products comprising the step of administering a
sensory
regimen in combination with the administration of an anti-acne composition.
6
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
As discussed above, the methods according to the present invention can be used
to ( 1 ) reduce the number and severity of acne lesions on the skin of a
mammal; (2)
ameliorate the inflammation of acne lesions on the skin of a mammal; (3)
improve the
skin tone of a mammal, (4) treat skin disorders; (5) treat stress related skin
diseases;
(6) reduce stress and improve the emotional well being of an acne sufferer;
(7) reduce
sebaceous gland output; and (8) increase compliance of the administration of
anti-acne
products. The method comprises the step of administering a sensory regimen in
an
amount effective to downregulate the activity of the HPA axis of said mammal
in
combination with the administration of an anti-acne composition comprising an
effective amount of an anti-acne agent.
As used herein, "mammals" include any of a class of warm-blooded higher
vertebrates that nourish their young with milk secreted by mammary glands and
have
skin usually more or less covered with hair, and non-exclusively includes
humans, dogs
and cats.
The term "effective amount" refers to the duration of the sensory regimen
sufficient to create the desired response, i. e., reduction or down-regulation
of the
activity of the HPA axis and reduction of total daily adrenocortical hormone.
The
effective amount will vary with the age, physical, and emotional condition of
the
mammal being treated, the nature of concurrent therapy, the specific regimen
employed, and like factors.
The sensory regimen can be any regimen that is relaxing to the user.
Generally,
the sensory regimen is selected from the group consisting of auditory stimuli,
visual
stimuli, tactile stimuli, gustatory stimuli and olfactory stimuli, and
combinations
thereof.
Suitable auditory stimuli include, but are not limited to, music and sounds of
nature that are soothing or relaxing to the consumer. The term music is used
herein to
include instrumental and lyrical compositions; tunes; melodies; harmonies;
songs; beats
7
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
and frequencies such as those from metronomes, tuning forks, bells, beat
machines,
chimes; poetry and rhymes. The music may be of any genre, including, but not
limited
to, classical, soft rock, easy listening, progressive, country, and show
tunes. The sounds
of nature include, but are not limited to, animal sounds, such as whales
singing or birds
chirping; insect sounds, such as crickets; and sounds of the environment, such
as a
running stream or a waterfall. Sounds that have consistently soft dynamics
with
minimal melodic and harmonic variability, having little or no conventional
beat pitch,
little or no vocal, slow tempo, little or no percussion or strong rhythym are
particularly
effective in relaxing or soothing the user. Sounds that use a binaural beat
created by
using two pure frequencies, usually one in each ear, are useful in improving
the mood
of the user. Binaural beats in the frequency range of delta, theta and alpha
brain wave
frequencies are useful for relaxing the user and beats in the frequency range
of beta
wave activity are useful for promoting mental alertness in the user. The
auditory stimuli
may include, but are not limited to, a cassette tape, video tape, compact
disc, interactive
toys and games, websites, and a computer audio file.
The visual stimuli may include, but are not limited to, soft lights, candles,
videos, movies, paintings, murals, books, landscapes, interactive toys and
games,
websites, and computer image files that are soothing or relaxing to the
consumer. The
soft lights may be of any color, such as blue, green, pink, purple, and the
like. Cool
colors, such as blue and green hues, are preferred to soothe the user and aid
relaxation;
and warmer colors, such as oranges and reds are preferred to uplift the user.
Pastel
shades, which are low saturation hues, are useful in soothing the user. The
light may be
provided in the kit as a bulb, which can be inserted into a lamp at home, or
may be
provided in the kit as a lamp. Lights that utilize fiber optics may also be
useful in the
kits of this invention. The fiber optic lights may, as is known in the art,
change colors
intermittently. Soft lighting of approximately S00 lux is useful in relaxing
the user,
particularly in the evening hours prior to bedtime. Bright light of around
2000 lux or
greater is useful in improving the mood of the user when used in the wakeful
period of
8
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
the day such as at awakening or any other time during the day prior to the few
hours
preceding bedtime.
Combinations of light and sound that have frequency patterns in the range of
delta, theta and alpha brain wave frequencies are useful for relaxing the user
and those
that have patterns in the frequency range of beta wave activity are useful for
promoting
mental alertness in the user.
The tactile stimuli useful in the present invention includes, but is not
limited to,
computer software, interactive toys and games, bubble baths, lotions, and
personal care
compositions. "Personal care compositions" refers to personal cosmetic,
toiletry, and
healthcare products such as wipes, washes, baths, shampoos, gels, soaps,
sticks, balms,
sachets, pillows, mousses, sprays, lotions, creams, cleansing compositions,
powders,
oils, bath oils and other bath compositions which may be added to a bath.
Personal care
compositions may also include, but are not limited to, aerosols, candles, and
substances
that may be used with vaporizers. The aforementioned wipes, washes, baths,
shampoos, gels, soaps, sticks, balms, sachets, pillows, mousses, sprays,
lotions, creams,
cleansing compositions, oils, bath oils, aerosols, candles and substances
which may be
used with vaporizers are commercially known to those who have a knowledge of
preparing personal care compositions. One example of a suitable personal care
composition is Johnson's Bedtime Bath~.
The computer software may be of an interactive nature, such that the consumer
relaxes while utilizing the software. Such software includes video games,
crossword
puzzles and the like.
Gustatory experiences also help reduce stress. Therefore, the method of the
invention
may include food and beverages, such as, but not limited to, fruits, candies,
crackers,
cheese, teas, and the like.
The method of the invention may also include olfactory sensory experiences,
such as fragrances. Fragrances that the user finds pleasant and to have a
calming effect
on their mood are useful in the practice of this invention. Suitable
fragrances include
9
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
relaxing fragrances, but are not limited to those perfume compositions
described in UK
application 0031047.4, now International Publication No. W002/49600 A1, the
disclosure of which is hereby incorporated by reference. Also suitable are the
fragrances described in co-pending U.S. Patent Application Serial No.
09/676,876,
filed September 29, 2000 entitled "Method For Calming Human Beings Using
Personal
Care Compositions", the disclosure of which is hereby incorporated by
reference.
Generally, the fragrance can be any fragrance that is perceivable and relaxing
to the
user and will downregulate the activity of the HPA axis. When the fragrance is
present
in the anti-acne composition, the stability of the fragrance in the presence
of the anti-
acne agent should be such that it remains perceivable and relaxing to the
user.
It is desirable to combine multiple sensory experiences useful for
downregulating HPA activity and consequently reduce adrenocortical hormone
below a
baseline level. For example, a daily regime may include a fragrance; soft
light; bubble
bath containing fragrance; and relaxing music. The fragrance may be sniffed
intermittently during the day while sitting in a softly lit room and listening
to the
relaxing music. The bubble bath containing fragrance may be used in the
morning or at
night when bathing or showering while listening to the relaxing music.
In a particularly prefered embodiment, the sensory regimen is administered
daily for at least one week and comprises smelling a relaxing fragrance while
soaking
in a bath and listening to relaxing music. Further benefits are noticed when
the sensory
regimen includes soft lighting as described above.
The anti-acne compositions useful in the methods according to the invention
include compositions containing anti-acne agents known in the art. Suitable
anti-acne
agents include, but are not limited to, salicylic acid, sulfur, lactic acid,
glycolic acid,
pyruvic acid, urea, resorcinol, N-acetylcysteine, retinoic acid, benzoyl
peroxide,
octopirox, triclosan, azelaic acid, phenoxyethanol, phenoxypropanol,
flavinoids,
derivatives thereof, and combinations thereof. Benzoyl peroxide and salicylic
acid are
preferred anti-acne agents. These anti-acne agents are used in amounts well
known in
the art for treatment of acne. For example, salicylic acid is generally used
in amounts
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
ranging from about 0.5 to about 2% by weight of the composition. When benzoyl
peroxide is used it is generally present at from about 2.5% to about 10% by
weight of
the composition.
In addition to the products that are available over the counter, there are
also a
number of different pharmaceutical treatments that have been developed for the
treatment of acne which are useful in the methods according to the invention.
These
include, but are not limited to both topical and oral agentsisotretinoin,
adapalene
tretinoin, tazarotene and azelaic acid. The pharmaceutical anti-acne compounds
are
used in a dosing amount that is in accordance with the prescribed directions
of the
physician. While oral isotretinoin is effective for treating acne conditions,
it is also
know to have negative effects, such as depression, accordingly administration
of
isotretinoin in combination with the sensory regimen according to invention
would be
particularly beneficial.
In another embodiment of the invention, antibacterial agents known to be
useful
for treating acne and other skin disorders can be incorporated into the anti-
acne
compositions in combination with the anti-acne agents described above.
Examples of
suitable antibacterial agents include, but are not limited to, erythromycin
and
clindamycin. Generally, the antibacterial agent is used in amount that is in
accordance
with the prescribed directions of the dermatologist.
In the method of the invention, the anti-acne compositions are utilized as
directed on the products, usually by topical application to the affected area
several times
daily. The effectiveness of the anti-acne composition is significantly
improved through
combining the use of sensory regimen with the topical application of the anti-
acne
agents.
As discussed above, it has been discovered that the administration of the
above
described sensory regimen in combination with the administration of the above
described anti-acne composition can be used can be used to ( 1 ) reduce the
number and
severity of acne lesions on the skin of a mammal; (2) ameliorate the
inflammation of
acne lesions on the skin of a mammal; and (3) improve the skin tone of a
mammal.
11
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
Further, the reduction of acne, the amelioration of inflmmation of acne
lesions and/or
improved skin tone resulting from the inventive methods leads to an improved
quality
of life. Accordingly, in another embodiment the methods of the invention can
be used
for reducing stress and improving the emotional well being of an acne
sufferer, the
method comprising the step of administering a sensory regimen in an amount
effective
to downregulate the activity of the HPA axis of said mammal in combination
with the
administration of an anti-acne composition. In one embodiment, the stress is
chronic
stress.
In another embodiment, the methods according to the invention can be used for
the
treatment of skin disorders. As described above, the method comprises the step
of
administering a sensory regimen in an amount effective to downregulate the
activity of
the HPA axis of said mammal in combination with the administration of an anti-
acne
composition, wherein said treatment comprises at least two of the following:
(a)
reducing the number and severity of acne lesions on the skin of a mammal; (b)
ameliorating the inflammation of acne lesions on the skin of a mammal; and (c)
improving the skin tone of a mammal.
The methods according to the invention can also be used for the treatment of
stress-related skin diseases selected from the group consisting of atopic
dermatitis,
sebhorreic dermatitis, psoriasis, itch, wound healing, fine lines, wrinkles,
pigmentation,
and combinations thereof, comprising the step of administering a sensory
regimen in an
amount effective to downregulate the activity of the HPA axis of said mammal
in
combination with the administration of an active agent. In one embodiment, the
stress-
related skin disease is caused by chronic stress.
In another embodiment, the invention relates to a method for reducing the
visual
appearance of shine on human skin comprising the step of administering a
sensory
regimen in an amount effective to downregulate the activity of the HPA axis of
the
human. Such a method may further comprise the administration of an anti-acne
composition.
12
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
It has also been discovered that the administration of the above described
sensory regimen in combination with the administration of the above described
anti-
acne composition can be used can be used to reduce sebaceous gland output.
Finally,
because the administration of the sensory regimen is asethically pleasing to
the user, the
methods according to the invention can be used to increase compliance of the
administration of anti-acne products.
Examples are set forth below to further illustrate the nature of the invention
and
the manner of carrying it out. However, the invention should not be considered
as
being limited to the details thereof.
EXAMPLES
Example 1- Effect of Relaxing Fragrance on Skin Condition
Two groups of panelists (11 people per group) having mild to moderate acne (>
7 inflamed lesions, > 5 non-inflamed lesions, and < 2 nodules on the face)
participated
in a study to determine the effect of the addition of a relaxing fragrance in
a benzoyl
peroxide skin cream which they applied to their face daily. The basic
formulation for
the benzoyl peroxide skin cream used by Group I is listed below:
Benzoyl Peroxide Skin Cream #1
In ear diem Percenta a
Laureth -4 0.4%
H drox ro yl Methylcellulose 0.2%
Carbomer 934P 1.75%
Disodium EDTA 0.2%
Sodium H droxide 0.29%
Benzoyl eroxide "BPO") 75%) 6.67%
Water q.s.
The formulation for Benzoyl Peroxide Skin Cream #2 used by Group II was
made by subtracting 0.2% water from the benzoyl peroxide skin cream #1 and
replacing it with 0.2% fragrance (Quest PD-1861).
13
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
On day one, the participants' faces were evaluated for severity of acne in
terms
of the number of lesions and the type of lesions present.
Over the next two weeks, once a day, after washing with PURPOSETM
GENTLE CLEANSING WASH, commercially available from Johnson & Johnson
Consumer Companies, Inc., the panelists in each group squeezed approximately a
pea
sized amount of the benzoyl peroxide skin cream into the palm of the hand and
applied
it to the entire facial area except eye, lip, and mouth areas. The panelists
were not
permitted to wash their faces for at least three hours after applying the
cream.
At the end of the 2 week study, the panelists were asked what their overall
preference of the benzoyl peroxide skin cream they were using was and whether
they
agreed to the following statements:
What was your overall preference?
1. The product treated whiteheads.
2. The product treated blackheads.
3. The product reduced the size of pimples.
4. The product made my skin feel smooth.
5. The product made my skin feel soft.
6. The product made my skin have even color.
7. The product made my skin have even texture.
8. The product was gentle to my skin.
9. The product was non-irritating to my skin.
10. The product was quickly absorbed by my skin.
11. The product did not make my skin flaky or have an ashy appearance.
12. The product reduced my skin pore size.
13. The product reduced my skin redness.
14. The product was good for dry skin.
The scale for overall preference was 0 (poor) to 10 (like extremely).
The scale for the statements was 1 (disagree) to 5 (strongly agree).
The results are shown in Table 1.
14
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
Table 1
Avera eg Score
uestion Group 2 Grou 1
Overall Preference** 7.3 5.9
Treat Whiteheads* 3.9 3.4
* *
Treat Blackheads*** 3.7 3.3
Reduced Size* * * 4.1 3.5
Smooth Skin* 4.5 3.5
Soft Skin* 4.1 3.2
Even Skin Color* 3.5 2.7
Even Skin Texture* 3.8 3.1
Gentle* 4.5 3.5
Non-irritating* 4.3 3.4
Quick Absorption* 4.5 3.5
No Flaky, Ashy Appearance*4.1 2.8
Reduced Pore Size* 3.7 2.9
Reduced Redness* * 3.8 3.3
*
Good For Dry Skin*** 3.5 3.0
* = 95% significance ** = 85% significance *** = 80% significance
Based on the data above, it is clear that the addition of fragrance to the
benzoyl
peroxide skin cream composition was perceived by the participants to
significantly
improve the performance of the product. Improvements were seen for every
symptom
that was inquired about.
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
Example 2 - Effect of Various Sensory Regimens on Skin Condition.
Since there was a benefit observed with the addition of a relaxing fragrance
in
the benzoyl peroxide skin cream containing an anti-acne agent, additional work
was
done to determine if additional relaxation treatments would further improve
the skin
condition and quality of life of the panelists. Groups l and 2 were identical
to those in
Example 1 and a third group with 12 panelists was studied where there were
multiple
additional relaxation elements to the regime.
The following protocol was used for Group 3: Group 3 applied the topical
Benzoyl Peroxide Skin Cream # 1 once per day, smelled a fragrance PD 1861
supplied
by Quest International while sitting and listening to relaxing music from the
music CD
entitled "Relax with Ocean Relaxing Surf' by Eclipse Music Group for 10
minutes
three times a day, and at night took a 35°C 15 minute bubble bath
containing fragrance
PD 1861 supplied by Quest International.
During the 10 minute fragrance / music treatment, participants were instructed
to take off the cap of a sorbarod and sniff the fragrance as often as they
wished.
Initially, they were to think about the fragrance and the emotions that it
brought and the
scents that compose the fragrance. They were instructed to re-sniff the
fragrance
whenever they forgot or needed to refresh the fragrance image in their mind.
While
they were sniffing the fragrance, they were listening to the music using a
personal CD
player. Panelists were either sitting or lying down in a dimly lit room.
During the bath
exposure, panelists were provided with a fragranced bath product to use during
the
session. They were required to listen to a CD using a personal CD player
during the
bath. They also were required to dim the lights during their experience. The
sensory
procedure schedule was as follows: session 1 was 10 minutes of music and
fragrance 30
minutes after waking; session 2 was 10 minutes of music and fragrance 4 hours
after
waking; session 3 was 10 minutes of music and fragrance 8 hours after waking;
session
4 was 15 minutes of fragranced bath and music 12 hours after waking (or just
prior to
bedtime).
16
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
After one week and at the end of the two-week period, the participants were
again evaluated for severity of acne. The results are shown in Tables 2 and 3.
Table 2 - Reduction in Inflammatory Lesions
Reduction In
Inflammatory
Lesions
Group Number One Week Two Weeks
1 19 20
2 15 23
3 17 28
Table 3 - Reduction in Total Lesions
Reduction In
Total Lesions
Group Number One Week Two Weeks
1 12 15
2 NS 20
3 NS 12
NS = no significant change
The data demonstrates that the number of inflammatory lesions is reduced
through the use of a skin cream with an anti-acne agent in it. Interestingly,
it also
appears that the addition of a relaxing fragrance, PD 1861 to the skin cream
further
reduced the number of lesions. The group that combined sensory experiences
with the
benzoyl peroxide skin cream demonstrated significant reduction in the number
of
inflammatory lesions after both the one and two week time points. Although,
there
appears to be less of a reduction in the total number of lesions after two
weeks, it is
important to note that inflammatory lesions are the most consumer noticeable
symptom
17
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
and product efficacy is often measured by the reduction in the number of
inflammatory
lesions.
It is interesting to note that there was a greater reduction of lesions on the
second week of this study with the panelists who had some level of sensory
treatment,
either the use of a fragrance in the benzoyl peroxide skin cream, or the
addition of
relaxation elements to their regime. This is consistent with our hypothesis,
as it would
be expected that there would be lag time between the "relaxation" effects that
would be
present in the body, before they were manifested on the skin. The fact that
there was a
greater improvement for the second week in both of the cases where sensory was
applied vs. the baseline skin cream supports this theory.
Participants were also asked to fill out an Emotional questionnaire before and
after the study to determine if they felt the treatments made them feel
better. The
questions were as follows:
1. Overall, how would you describe your CURRENT PHYSICAL STATE?
Grading was from 0 to 10, with 0 being "not at all relaxed" and 10 being
"extremely relaxed";
2. Overall, how would you describe your CURRENT ENERGY LEVEL?
Grading was from 0 to 10, with 0 being "no energy" and 10 being "extremely
energized";
3. Overall, how would you describe your CURRENT EMOTIONAL STATE?
Grading was from 0 to 10, with 0 being "not at all relaxed" and 10 being
"extremely
relaxed";
4. Overall, how would you describe your CURRENT STRESS LEVEL?
Grading was from 0 to 10, with 0 being "no stress at all" and 10 being
"extremely
stressed".
The scores for each question before the study were compared to the scores for
the same questions after the study. The data is reported in Table 4 as percent
of score
18
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
improvement after treatment based on the average score for the entire group of
participants. The statistical significance for the data is in parenthesis.
Table 4 - Emotional Questionnaire
Percent
Of Score
Improvement
uestion Grou 1 Group 2 Group 3
1 8 (63) 5 (72) 37 (99)
2 13 (83) 5 (75) 34 (96)
3 9 (67) 3 (63) 43 (99)
4 -13 (95) 3 (65) 25 (97)
Group 3 had a higher percent of participants feel better as a result of the
treatment than
any other group.
A second survey was performed before and after the study to establish if the
participants felt the treatments were effective on their acne. The
questionnaire that was
used was the refined Skindex questionnaire that was published by Chren M,
Lasek R,
Flocke S Improved Discriminative and Evaluative Capability of a Refined
Version of
Skindex, a Quality-of Life Instrument for Patients with Skin Diseases. Arch
Dermatol.
1997; 133: 1433-1440 and is incorporated by reference. The statements were as
follows:
1 My skin hurts;
2 My skin condition affects how well I sleep;
3 I worry that my skin condition may be serious;
4 My skin condition makes it hard to work or do hobbies;
My skin condition affects my social life;
6 My skin condition makes me feel depressed;
7 My skin condition burns or stings;
8 I tend to stay at home because of my skin condition;
19
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
9 I worry about getting scars from my skin condition;
My skin itches;
11 My skin condition affects how close I can be with those I love;
12 I am ashamed of my skin condition;
13 I worry that my skin condition may get worse;
14 I tend to do things by myself because of my skin condition;
I am angry about my skin condition;
16 Water bothers my skin condition (bathing, washing hands);
17 My skin condition makes showing affection difficult;
18 My skin is irritated;
19 My skin condition affects my interactions with others;
I am embarrassed by my skin condition;
21 My skin condition is a problem for the people I love;
22 I am frustrated by my skin condition;
23 My skin is sensitive;
24 My skin condition affects my desire to be with people;
I am humiliated by my skin condition;
26 My skin condition bleeds;
27 I am annoyed by my skin condition;
28 My skin condition interferes with my sex life;
29 My skin condition makes me tired.
The statements were scored as follows: 1 = never; 2 = rarely; 3 = sometimes; 4
= often; 5 = all the time. The scores for each question before the study were
compared
to the scores for the same questions after the study. The data is reported in
Table 5 as
percent of score improvement after treatment based on the average score for
the entire
group of participants. The score changes are represented by those indicating
changes in
symptoms, function, emotions, and on an overall basis.
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
Table 5 - Qualit~,of Life Questionnaire
Percent Of
Score Improvement
Group Symptoms Functional Emotional Overall
(guestions guestions guestions
l, 7, 2, 4, 3, 6,
10, 16, 18, 5, 8, 11, 9, 12, 13,
23, 14, 17, 15, 20,
26,~ 19, 21, 24, 22 25 27
28,
1 2 8 -3 4
2 1 2 8 5
3 4 8 12 9
The Group 3 participants had improved scores on the questionnaire than the
other treatments. Positive effects from the combination of an anti-acne agent
with a
sensory regimen were seen symptomatically, functionally, emotionally, and on
an
overall basis.
Example 3 - Other Treatment Regimes
Since there were clinical and perceived benefits of combining anti-acne skin
creams with additional relaxation elements, additional studies were performed
in an
attempt to better delineate the relative contributions of both. In this
separate study,
Group 4 (13 panelists) applied benzoyl peroxide Skin Cream #3, which was
identical to
benzoyl peroxide skin cream #1, except the 6.67% of the 75% BPO was replaced
with
water. Group 5 (12 panelists), did not apply a benzoyl peroxide skin cream,
but rather
only participated in the identical Sensory regimen, as Group 3, which is
listed below.
The following protocol was used for Group #5: Group 5 smelled a fragrance PD
1861
supplied by Quest International while sitting and listening to relaxing music
from the
music CD entitled "Relax with Ocean Relaxing Surf ' by Eclipse Music Group for
10
21
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
minutes three times a day, and took a 35°C 15 minute bubble bath at
night containing
fragrance PD 1861 supplied by Quest International.
During the 10 minute fragrance / music treatment, participants were instructed
to take off the cap of a sorbarod and sniff the fragrance as often as they
wished.
Initially, they were to think about the fragrance and the emotions that it
brought and the
scents that compose the fragrance. They were instructed to re-sniff the
fragrance
whenever they forgot or needed to refresh the fragrance image in their mind.
While
they were sniffing the fragrance, they were listening to the music using a
personal CD
player. Panelists were either sitting or lying down in a dimly lit room.
During the bath
exposure, panelists were provided with a fragranced bath product to
use during the session. They were required to listen to a CD using a personal
CD player
during the bath. They also were required to dim the lights during their
experience. The
sensory procedure schedule was as follows: session 1 was 10 minutes of music
and
fragrance 30 minutes after waking; session 2 was 10 minutes of music and
fragrance 4
hours after waking; session 3 was 10 minutes of music and fragrance 8 hours
after
waking; session 4 was 15 minutes of fragranced bath and music 12 hours after
waking
(or prior to bedtime).
After one week and at the end of the two-week period, the participants were
again evaluated for severity of acne using the modified Cook Global Acne
Grading
Scale described above. The results are shown in Tables 6 and 7.
Table 6 - Reduction in Inflammatory Lesions
Reduction In
Inflammatory
Lesions
Group Number One Week Two Weeks
4 36 50
23 28
22
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
Table 7 - Reduction in Total Lesions
Reduction In
Total Lesions
Group Number One Week Two Weeks
4 29 33
14 7
The placebo Group 4 clearly improved significantly in terms of reduction of
inflammatory lesions. This is thought to be at least partially due to improved
hygiene
during the study, the consumer expectation of the "treatment", and potentially
to the
benzoyl peroxide Skin Cream #3 itself. This is somewhat shown by the fact that
the
use of the relaxation elements by themselves show dramatic reductions in the
number
of inflammatory lesions. It is important to note that the study in Example 3
was
performed at a different time of the year than Examples 1 and 2, so the
results of
Example 3 should not be compared to the results of Examples 1 and 2. As with
the
data relating to inflammatory lesions, the data for reduction in total number
of lesions
also showed that both treatments were effective, with the benzoyl peroxide
skin cream
#3, being more effective.
Groups 4 and 5 also answered the Emotional and Skindex questionnaires
described above about the ability of the treatments to make them feel better.
Their
results are listed in Tables 8 and 9 below.
Table 8 - Emotional Questionnaire
Percent Of Score Improvement
uestion Group 4 Group 5
1 13 (97) -8 (58)
2 -1 (66) 3 (88)
3 8 (70) 7 (84)
4 1 S (87) I 1 (90)
23
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
Table 9 - Quality of Life Questionnaire
Percent Of
Score Improvement
Group Symptoms Functional Emotional Overall
4 1 4 10 6
0 10 6 7
These tables show that the relaxation treatment by itself showed broad
emotional and well-being benefits to the panelists in this study. This is
consistent with
the clinical improvement that was seen in the panelist's acne condition.
Improvements
were also observed for Group 4, however, they did not seem to be as high as
commensurate with the clinical improvement observed. Clearly, the optimal
treatment
for this condition combines both clinical and psychological benefits.
Since one of the factors that lead to acne is an increased amount of sebum,
sebum production was measured for Groups 4 and 5 as well. It has been
postulated that
an increase in sebum could result after an increase in stress activity through
an
adrenocorticotrophic hormone pathway. An increase in sebum production could be
related to an increase in the visual appearance of shine. The results are
listed in Table
10.
Table 10 - Effect of Treatments on Sebum reduction
Study Cell Week 1 Reduction Week 2 Reduction
Group 4 26% -2%
Group 5 16% 8%
Once again, the benefits for sebum reduction are observed in the cell with the
relaxation elements in them. To further confirm this hypothesis, measures of
stress
markers were taken to determine changes in stress levels throughout the study.
24
CA 02469000 2004-06-O1
WO 03/049769 PCT/US02/38747
Some participants were also asked to collect approximately 1 ml of saliva by
drooling or spitting into independent vials at set points throughout each day
of the study
for the purpose of measuring cortisol concentrations. Area under the curve
measurements were taken as described in co-pending patent application "Methods
For
Measuring Stress In Mammals" 60/256,812 filed December 20th 2000 The area
under
the curve prior to the study was compared to the area under the curve after
treatment.
The results are shown in Table 11 as percent decrease in area under the curve
(reduction
in baseline cortisol levels).
Table 11
Percent Reduction In
Cortisol Area Under
The Curve
Treatment One Week Two Weeks
Group 4 19 5
Group 5 38 23
Group 5 had a decreased baseline cortisol level within one week, which lasted
through
the second week. This result correlated with the consumers' self -assessment,
as well
as the clinical data that was obtained. Separately, Group 4 (which had no
inherent
relaxation treatments beside the knowledge that the panelists were on a
"treatment"
study) showed a decrease in cortisol levels after one week. While a decrease
was still
seen after two weeks, the effect was not as sustained as was for Group 5
(having
participated in the sensory regimen).
While we have shown that the reduction of cortisol has led to improved skin
condition in the case of acne, this should also be effective for the treatment
of other
stress-related skin diseases, such as: atopic dermatitis, sebhorreic
dermatitis, psoriasis,
itch, wound healing, fine lines and wrinkles, pigmentation, etc.
