U.S. patent application number 10/646825 was filed with the patent office on 2004-02-26 for autonomic nerve regulating agent.
This patent application is currently assigned to Kao Corporation. Invention is credited to Fukuda, Kazuyuki, Nagashima, Yoshinao, Sugata, Keiichi, Yada, Yukihiro.
Application Number | 20040039065 10/646825 |
Document ID | / |
Family ID | 18562022 |
Filed Date | 2004-02-26 |
United States Patent
Application |
20040039065 |
Kind Code |
A1 |
Nagashima, Yoshinao ; et
al. |
February 26, 2004 |
Autonomic nerve regulating agent
Abstract
The autonomic nerve regulating agent of the present invention,
which, has a sedative action, sleep inducing action, and stress
mitigating action in individuals, regardless of individual
variation in sensitivity to or preference for fragrance, contains
as an active ingredient a sesquiterpene alcohol with a boiling
point of 250.degree. C. or higher, particularly cedrol.
Inventors: |
Nagashima, Yoshinao; (Tokyo,
JP) ; Sugata, Keiichi; (Tokyo, JP) ; Yada,
Yukihiro; (Tokyo, JP) ; Fukuda, Kazuyuki;
(Tokyo, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Kao Corporation
Tokyo
JP
|
Family ID: |
18562022 |
Appl. No.: |
10/646825 |
Filed: |
August 25, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10646825 |
Aug 25, 2003 |
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09972887 |
Oct 10, 2001 |
|
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09972887 |
Oct 10, 2001 |
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PCT/JP01/00928 |
Aug 9, 2001 |
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Current U.S.
Class: |
514/729 ;
514/730; 514/739 |
Current CPC
Class: |
A61P 25/02 20180101;
A61K 9/007 20130101; A61P 25/22 20180101; A61K 31/045 20130101;
A61P 25/20 20180101 |
Class at
Publication: |
514/729 ;
514/730; 514/739 |
International
Class: |
A61K 031/045 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 10, 2001 |
JP |
2000-38260 |
Claims
1. A method for regulating autonomic nerve activity in a person in
need thereof, comprising administering a composition comprising a
sesquiterpene alcohol to said person in an amount effective for
regulating autonomic nerve activity, wherein said sesquiterpene
alcohol has a boiling point of at least 250.degree. C. and said
composition has an odor below a detectable threshold.
2. The method for regulating autonomic nerve activity claimed in
claim 1, wherein said autonomic nerve regulated activity is at
least one activity selected from the group consisting of sleep,
stress, parasympathetic activity, sympathetic activity and
mood.
3. The method claimed in claim 1, wherein the sesquiterpene alcohol
is selected from the group consisting of cedrol, cedrenol,
farnesol, patchouli alcohol, eugenol, .alpha.-santalol,
.alpha.-bisabolol, .beta.-caryophyllene alcohol, vetiverol,
sclareol, geranyl linalool, isophytol, nerolidol, globulol and
guaiol.
4. The method claimed in claim 1, wherein the sesquiterpene alcohol
is cedrol.
5. The method claimed in claim 4, wherein the cedrol is at least
97% pure.
6. The method claimed in claim 1, wherein the sesquiterpene alcohol
is in a vaporizable state.
7. The method claimed in claim 1, wherein the sesquiterpene alcohol
is administered by inhalation.
8. The method claimed in claim 7, wherein the sesquiterpene alcohol
is present in air at a concentration of from 0.01 to 100 ppb.
9. The method claimed in claim 1, wherein the composition is
administered orally.
10. The method claimed in claim 1, wherein composition is
administered transdermally.
11. The method claimed in claim 10, wherein the composition is
administered by bathing in a mixture comprising water and the
composition, and further wherein the sesquiterpene alcohol is
present at a concentration of from 5 to 1000 ppm in said
mixture.
12. The method claimed in claim 1, wherein the composition is
administered by spraying onto a bedding or a wall covering.
13. The method claimed in claim 1, wherein the composition is
administered to a plurality of persons by dispersing said
composition in a space and further wherein the sesquiterpene
alcohol is in a vaporizable state.
14. The method claimed in claim 1, wherein the composition is
administered by wearing a mask, wherein said mask comprises a
heating element, a hot steam generating element and the
sesquiterpene alcohol.
15. A composition consisting essentially of a sesquiterpene alcohol
in air, wherein said sesquiterpene alcohol is present at a
concentration of from 0.01 to 100 ppb, and further wherein said
sesquiterpene alcohol has an odor below a detectable threshold, a
boiling point of at least 250.degree. C. and is in a vaporizable
state.
16. A lotion consisting essentially of an sesquiterpene alcohol,
wherein said sesquiterpene alcohol is present at a concentration of
from 0.01 to 0.05 weight percent, has an odor below a detectable
threshold and has a boiling point of at least 250.degree. C.
17. An emulsion consisting essentially of an sesquiterpene alcohol,
wherein said sesquiterpene alcohol is present at a concentration of
from 0.01 to 7.50 weight percent, has an odor below a detectable
threshold and has a boiling point of at least 250.degree. C., and a
carrier.
18. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier or excipient and composition, said composition
comprising a sesquiterpene alcohol, wherein said composition has an
odor below a detectable threshold and said sesquiterpene alcohol
has a boiling point of at least 250.degree. C.,
19. The pharmaceutical composition claimed in claim 18, further
comprising an emulsifier, oil, glycol, sugar, starch or mixture
thereof.
20. A vaporization system comprising a vaporization promoting
element selected from the group consisting of a heat generating
source, hot steam, ultrasonic waves, negative ions, and
combinations thereof, a carrier, and a sesquiterpene alcohol with
an odor below a detectable threshold and a boiling point of at
least 250.degree. C.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to an autonomic nerve
regulating agent having sedative action, sleep improving action,
stress mitigation action, and the like.
[0003] 2. Discussion of the Related Art
[0004] When the balance between the activities of the
parasympathetic nervous system and the sympathetic nervous system
is upset by physical and mental stress, the resulting
disequilibrium in the autonomic nervous system can lead to mental
aggravation, making it difficult to fall asleep very easily (sleep
induction) and resulting in shallow sleep. It is believed that
stimulating the physiological predominance of the parasympathetic
activity over the sympathetic activity can reduce stress and calm
aggravated mental states, thus inducing favorable sleep.
[0005] Methods that have long been used to thus stimulate the
predominance of the parasympathetic activity over the sympathetic
activity include the oral or percutaneous administration of active
ingredients to humans, as well as aromatherapy involving
vaporizable fragrance compositions to allow the vapors to be
inhaled. Recent proposals include methods in which bitter orange
essential oil (Japanese Laid-Open Patent Application Kokai)
H4-128234) and jasmine lactone (Japanese Laid-Open Patent
Application (Kokai) H6-40911) are administered by absorption via
the nasal mucosa, oral mucosa, or pulmonary tissue for better sleep
induction.
[0006] The use of the low-boiling components of cedar wood oil
(such as .alpha.-pinene, .alpha.-cedrene, .beta.-cedrene, and
caryophyllene) as a sedative essential oil has also been proposed
(Japanese Laid-Open Patent Application (Kokai) H5-255688).
[0007] It is not altogether clear whether or not the effects of
such fragrances or essential oil components are determined solely
by their action on the autonomic nervous system, and it has been
assumed that action mediated by other physiological routes,
including the lower central nervous system, may be involved.
[0008] There is substantial individual variation in the sensitivity
to and preference for scents (fragrances) such as bitter orange
essential oil and jasmine lactone. While these may have sedative
and sleep inducing action for some people, they may on the contrary
be disagreeable or irritating to others. There is thus a need for a
component or method capable of universally improving autonomic
nervous imbalances (in other words, restoring the balance to a
physiologically ideal state) whose effects are not biased by odor
perceptions.
[0009] The low-boiling components of cedar wood oil have a strongly
characteristic fragrance, and their sedative actions are also
subject to considerable individual variation in terms of people's
sensitivity and preferences in the same manner as bitter orange
essential oil and the like.
SUMMARY OF THE INVENTION
[0010] An object of the present invention is to provide an
autonomic nerve regulating agent, sleep improving agent, and agent
for mitigating stress (henceforth referred to as autonomic nerve
regulating agents) which have a sedative action and the like for
individuals whose sympathetic activity is predominant, irrespective
of the variation in individual sensitivity or preference for
fragrances, and conversely have action in restoring the
physiological balance to within normal range in individuals whose
parasympathetic activity is predominant.
[0011] The inventors have discovered that emotions (moods) can be
effected or modified by some compounds which belong to
sesquiterpene alcohols. These compounds are substantially odorless,
that is, having an odor below the detectable threshold (in other
words, causing no notice of preference). Nevertheless, they have
sedative or sleep improving action on individuals whose sympathetic
activity is predominant (said action stimulating the predominance
of the parasympathetic activity over the sympathetic activity).
Also they conversely have action in stimulating the predominance of
the sympathetic activity over the parasympathetic activity to
restore the physiological balance to within normal range in
individuals whose parasympathetic activity is predominant, and have
an odor substantially below the detectable threshold.
[0012] That is, the present invention provides an autonomic nerve
regulating agent, a sleep improving agent, or a stress mitigating
agent, comprising sesquiterpene alcohol with a boiling point of
250.degree. C. or higher with essentially no detectable odor. By
having an odor substantially below the detectable threshold, the
autonomic nerve regulating agents described herein can be
administered to people without resulting in negative or adverse
reactions to the odors and fragrances commonly associated with
aromatherapy.
[0013] Another object of the present invention is to provide a
vaporization system comprising a vaporization-promoting element and
a composition comprising a sesquiterpene alcohol having an odor
substantially below the detectable threshold and with a boiling
point of 250.degree. C. or higher.
[0014] The present invention also affords an autonomic nerve
regulating method, a sleep improving method, and a stress
mitigation method.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIGS. 1A through 1F illustrate the measurement results for
the various test parameters of the autonomic nerve regulating agent
in Example 1.
[0016] FIGS. 2A through 2F illustrate the measurement results for
the various test parameters of the autonomic nerve regulating agent
in Example 2.
[0017] FIGS. 3A through 3D illustrate the measurement results for
various test parameters of the autonomic nerve regulating agent
(sleep improving agent) in Example 3.
[0018] FIG. 4 illustrates a method for massaging the face.
[0019] FIGS. 5A through 5F illustrate the measurement results for
the various test parameters of the autonomic nerve regulating agent
(massaging agent) in Example 4.
[0020] FIG. 6 illustrates the measurement results for R-R interval
in ECG (electrocardiogram) when using the vaporization system
(mask) in Example 5.
[0021] FIG. 7 illustrates the measurement results for Lsum/Hsum
when using the vaporization system (mask) in Example 5.
[0022] FIG. 8 illustrates the measurement results for Hsum when
using the vaporization system (mask) in Example 5.
[0023] FIGS. 9A through 9D illustrate the results of emotion
spectrum analysis when using the vaporization system (mask) in
Example 5.
[0024] FIG. 10 illustrates the measurement results for sleeping
efficiency when using the vaporization system (mask) in Example
6.
[0025] FIG. 11 illustrates the measurement results for intermittent
awakening when using the vaporization system (mask) in Example
6.
[0026] FIG. 12 illustrates the measurement results for sleeping
efficiency when using the cedrol-treated bedding in Example 7.
[0027] FIG. 13 illustrates the measurement results for intermittent
awakening when using the cedrol-treated bedding in Example 7.
[0028] FIG. 14 illustrates the measurement results for R-R interval
in ECG with the licking of candy containing cedrol in Example
8.
[0029] FIG. 15 illustrates the measurement results for Hsum with
the licking of candy containing cedrol in Example 8.
[0030] FIG. 16 illustrates the measurement results for Lsum/Hsum
with the licking of candy containing cedrol in Example 8.
[0031] FIGS. 17A through 17D illustrate the results of emotion
spectrum analysis with the licking of candy containing cedrol in
Example 8.
[0032] FIG. 18 is a table of the measurement results for vapor
pressure of cedrol.
[0033] FIG. 19 is a curve of the vapor pressure of cedrol.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0034] The autonomic nerve regulating agents of the present
invention comprise a sesquiterpene alcohol with a boiling point of
250.degree. C. or higher at atmospheric pressure, as compounds
which have sedative action and sleep improving action for
individuals whose sympathetic activity is predominant, and which
conversely have action in stimulating the sympathetic activity to
predominance over the parasympathetic activity in individuals whose
parasympathetic activity is predominant, as well as in improving
emotions such as anger, stress, sense of joy or sadness, and
relaxation (specifically, relieving stress and anger, enhancing a
sense of joy, mitigating sadness, and enhancing a sense of
relaxation). At least part of the mechanism resulting in such
action is attributed to reception via the primary olfactory nervous
system and stimulation of the autonomic nervous system through the
lower central nervous system, with the additional possibility that
the higher central nervous system is stimulated via the lower
central nervous system.
[0035] As used in the present invention, "autonomic nervous
regulation" indicates improvement of disequilibrium in the
autonomic nervous system within a nonmorbid range, defined as at
least one, preferably at least two, and even more preferably at
least three of the following phenomena (1) through (6), as
determined in accordance with the following examples in subjects
whose sympathetic activity is greater than usual:
[0036] (1) meaningful decrease of systolic blood pressure
(SBP);
[0037] (2) meaningful decrease of diastolic blood pressure
(DBP);
[0038] (3) meaningful extension of R-R interval in ECG;
[0039] (4) meaningful increase of Hsum in R-R interval
fluctuations;
[0040] (5) meaningful decrease of Lsum/Hsum in R-R interval
fluctuations; and
[0041] (6) meaningful reduction of respiratory rate.
[0042] Examples of sesquiterpene alcohols with a boiling point of
250.degree. C. or higher having action capable of inducing such
phenomena include cedrol (boiling point 295.degree. C.), cedrenol
(boiling point 270.degree. C.), farnesol (boiling point 263.degree.
C.), patchouli alcohol (boiling point 140.degree. C./8 mmHg),
eugenol (boiling point 254-255.degree. C.), .alpha.-santalol
(boiling point 302.degree. C.), .alpha.-bisabolol (boiling point
265.degree. C.), .beta.-caryophyllene alcohol (boiling point
287-297.degree. C.), vetiverol (bailing point 264.degree. C.),
sclareol (boiling point 340.degree. C. or higher), geranyl linalool
(boiling point 340.degree. C.), isophytol (boiling point
310.degree. C. or higher), and nerolidol (boiling point 276.degree.
C.), as well as globulol and guaiol. Of these, sesquiterpene
alcohols having an odor substantially below the detectable
threshold, are preferred, while cedrol is particularly preferred
because it affords excellent effects in the invention and is
readily available. Cedrol of low purity is considerably affected by
other fragrance components and is hard to obtain in crystalline
form with good handling properties. The purity is thus preferably
at least 70%, more preferably at least 80%, even more preferably at
least 90%, still more preferably at least 95%, and especially at
least 97.0%.
[0043] "An odor substantially below the detectable threshold" means
an odor that cannot be detected by at least 5, and preferably 8 or
more, individuals among 10 Japanese individuals with normal
olfactory function.
[0044] The volatile, low boiling components thought to be
responsible for the odors and fragrances associated with, for
example, cedar wood oil, jasmine lactone and bitter orange
essential oil are not present in the autonomic nerve regulating
agents described herein at concentrations ordinarily detectable by
humans. Sesquiterpene alcohols that are free of low boiling
components are essentially odorless. These autonomic nerve
regulating agents may include sesquiterpene alcohols having a
boiling point of greater than 150.degree. C., preferably greater
than 200.degree. C., and most preferably greater than 250.degree.
C.
[0045] The amount of the sesquiterpene alcohol with a boiling point
of 250.degree. C. or higher (at atmospheric pressure) that is used
in the present invention can be determined as desired according to
the intended application of the autonomic nerve regulating agents
(such as miscellaneous goods, including base cosmetics, make-up
cosmetics, hair cosmetics, bathing agents, poultices, massaging
agents, indoor fragrances, and masks; food products and beverages,
including functional food products; tooth paste or mouth washes;
various fiber products, including seat covers, bedding, wall paper,
furniture, and clothing) or according to the formulation that is
used (such as solutions, solids, powders, sprays, gels, and
pastes). When used as a lotion, for example, the amount is
preferably 0.01 to 0.05 wt % in consideration of the dissolution
stability of the sesquiterpene alcohol. When used as an emulsion or
cream, the amount is preferably 0.01 to 7.50 wt % in the
consideration of the emulsion stability. When used in the form of a
bathing agent, the type of formulation and the amount may be
selected so as to result in a concentration of at least 0.01 ppm,
preferably 0.1 to 1000 ppm, and even more preferably 5 to 1000 ppm,
in-the bath water;
[0046] Where in this application a range is provided all values and
subranges between the stated ranges are expressly included. For
example the range 0.01 to 7.50% includes all between lying values
including, for example, 5, 2, 1, 0.5 and 0.05 etc. %.
[0047] Various additives commonly used in a variety of applications
(such as oils, fillers, colorants, polymers, humectants, UV
absorbents, pH adjusting agents, antioxidants, surfactants, and
fragrances) can be blended as desired in the autonomic nerve
regulating agents of the present invention according to the
intended application and the formulation that is used.
[0048] The autonomic nerve regulating agents of the present
invention can be administered to humans through respiration, the
oral mucosa, the nasal mucosa, orally, transdermal penetration, or
via the respiratory tract. Autonomic nerve regulating agents of the
present invention, such as orally administered tablets, need not
necessarily contain the sesquiterpene alcohol in a vaporizable
state. However, for administration to a large, unspecified number
of individuals, an extremely low concentration of sesquiterpene
alcohol is preferably dispersed in the space and its vicinity where
the administration takes place, so as to allow it to be
administered through the nasal mucosa or respiratory tract through
the natural respiration of the individuals. The autonomic nerve
regulating agents of the present invention thus preferably contain
a sesquiterpene alcohol such as cedrol in a vaporizable state. The
vaporizable state means a state in which the material is dispersed
in the form of vapor, minute solid particles, or droplets into the
air, either through natural vaporization or as a result of
treatment such as heating, ultrasonic irradiation, steam heating,
or negative (or minus) ionization with a vaporization-promoting
element.
[0049] The method of using the autonomic nerve regulating agents of
the present invention can also be determined as desired according
to the intended application and the formulation that is used. For
example, when used in the form of a pad soaked with a sesquiterpene
alcohol having a boiling point of 250.degree. C. or higher, the pad
may be heated by means of heat generated by a
vaporization-promoting element such as an electric heater to allow
the sesquiterpene alcohol to be vaporized, or it can be heated by
hot steam produced by a vaporization-promoting element such as the
mask described in Japanese Laid-Open Patent Application (Kokai)
2000-42125, which comprises a water vapor-producing element, to
allow the sesquiterpene alcohol to be vaporized. When a
sesquiterpene alcohol having a boiling point of 250.degree. C. or
higher is solubilized in aqueous media, liquid droplets containing
the sesquiterpene alcohol can be vaporized through the application
of ultrasonic waves from a vaporization-promoting element such as
an ultrasonic humidifier, or the sesquiterpene alcohol can be
vaporized through negative ionization by means of a device for
breaking up water which involves exploiting the Lenard effect. In
these cases, the sesquiterpene alcohol should be vaporized at a
concentration of between 0.01 to 100 ppb in the air, as too low a
concentration will not afford the desired results, while too high a
concentration will result in the condensation of fine particles in
the air.
[0050] The sesquiterpene alcohols in the present invention may also
be vaporized naturally at ambient temperature without the
aforementioned treatment. That is, embodiments using sesquiterpene
alcohol in a vaporizable state are not limited to the use of a
vaporization-promoting element, and can also include simply
spraying the autonomic nerve regulating agent containing
sesquiterpene alcohol on bedding or wall paper; so-called "leave
on" types of cosmetics which are applied to the skin without being
washed off; and compositions which are used by being left for a
certain period of time in the mouth (such as tooth paste or
candy)
[0051] As noted above, through their action on the autonomic
nervous system, the sesquiterpene alcohols in the present invention
are capable of mitigating physical or mental stress and of soothing
aggravated mental states. Also they are capable of improving the
quality of sleep, such as shortening the sleep latency (the time it
takes an individual to fall asleep), reducing the number of
intermittent awakening and shortening the time needed to wake up,
improving sleep efficiency (=total sleep time/time in bed),
enhancing the good feeling upon waking, and prolonging the period
of deep sleep (non-REM sleep). The present invention is thus
suitable for use as a sleep improving agent.
[0052] As used in the present invention, "sleep improvement"
indicates the qualitative or quantitative improvement of sleep
within the nonmorbid range, defined as at least one, preferably at
least two, and more preferably three or more of the following (1)
through (4), as determined in accordance with the following
examples in subjects who suffer from poor sleep:
[0053] (1) meaningful shortening of sleep latency;
[0054] (2) meaningful reduction of number of intermittent
awakening;
[0055] (3) meaningful increase of sleeping efficiency; and
[0056] (4) meaningful improvement in terms of tension and fatigue
based on POMS.
[0057] The sesquiterpene alcohols of the present invention also
have an effect on the expression of emotions (moods) and the state
thereof, which is influenced by the higher central nervous system
governing preferences. Specifically, they allow composure to be
recovered, anger/stress or sadness to be controlled, and a sense of
joy and relaxation to be enhanced. The present invention is thus
suitable for use to relieve stress.
[0058] Such changes of emotion can be determined by emotion
spectrum analysis based on brain waves (T. Mushy et al., "Emotion
spectrum analysis method (ESAM) for monitoring the effects of art
therapy applied on demented patients," Cyber Psychology &
Behavior, 3, 441-446 (2000), the relevant portions thereof which
describe emotion spectrum analysis are incorporated herein by
reference).
[0059] As used in the present invention, "stress mitigation"
indicates that mental or physical stress is mitigated within the
nonmorbid range, defined as improvement in at least one, preferably
at least two, and more preferably three or more of the parameters
of "anger/stress," "joy," "sadness," and "relaxation" by emotion
spectrum analysis as determined in accordance with the following
examples for subjects experiencing stress.
[0060] By providing effects such as sleep improvement and stress
mitigation, the present invention can also improve menopause, PMS
(premenstrual syndrome), physical vitality and appetite.
[0061] The use of a compound with odor substantially below the
detectable threshold, particularly cedrol, from among the
sesquiterpene alcohols employed in the present invention allows the
autonomic nerve regulating agents of the present invention to
produce the aforementioned effects in individuals or an unspecified
number of individuals, regardless of their disposition towards
fragrances. The autonomic nerve regulating agents of the present
invention can accordingly be used not only in private spaces such
as bedrooms and bathrooms, but also in public spaces such as
meeting rooms, private rooms, airplanes, vehicles, hotels, nursing
facilities, hospitals, nursing homes, public health facilities,
department stores, airports, libraries, stations, and business
offices, in any configuration or at any period of time (such as
morning, afternoon, evening, before bed, after bed, during work, or
during exercise) or for any physical condition (such as during
fatigue, good health, or stress).
[0062] A sesquiterpene alcohol with a boiling point of 250.degree.
C. or higher can be directly vaporized as needed by a vaporization
system comprising the aforementioned vaporization-promoting element
and a composition such as an automatic nerve regulating agent,
stress mitigating agent, and sleep improving agent comprising a
sesquiterpene alcohol with a boiling point of 250.degree. C. or
higher in a vaporizable state as needed combined with a desired
carrier or medium.
[0063] It is not necessary to operate the vaporization-promoting
element throughout the entire sleeping period in order to achieve
the sleep improving effects, for example. Satisfactory effects will
be achieved with shorter periods of time, such as about 30 minutes
to 2 hours of operation, before going to bed and a short time after
falling asleep.
[0064] This application is based on and claims benefit of priority
to International Application PCT/JP01/00928 filed on Feb. 9, 2001
and Japanese priority document JP 2000-38260 filed on Feb. 10,
2000, each of which is incorporated by reference in its
entirety.
EXAMPLES
[0065] The present invention is illustrated in further detail in
the following examples.
Reference Example 1
[0066] The vapor pressure of purified cedrol (molecular weight 222
g.multidot.mol.sup.-1) used in the following examples was
determined by a static method and a gas flow method (temperature:
22, 50, and 75.degree. C. for solids; 100 and 125.degree. C. for
liquids).
[0067] In the static method, samples were taken from hermetically
sealed containers, a constant temperature was established, and the
equilibrium vapor pressure at that temperature was directly
measured using a pressure gauge (OECD Test Guidelines 104: Static
Measurement of Vapor Pressure).
[0068] In the gas flow method, carrier gas (nitrogen gas) was
allowed to flow so as to come into contact with a solid or liquid
sample at a certain temperature to saturate the sample vapor, and
the vapor density (vaporization quantity/volume) was measured so as
to determine the vapor pressure hypothetically in accordance with
ideal gas principles. The vapor density herein referred to is
calculated from the sample vaporization rate (rate of loss)
determined using an electrical balance, and the carrier gas flow
rate determined using a flow rate gauge. However, since the sample
vapor saturation is usually incomplete, the vapor density level is
dependent on flow rate, so the vapor density was measured at
varying flow rates for extrapolation to a zero flow rate to
determine the saturated vapor density. The following formula was
used to determine the vapor pressure from the vapor density,
P=(k/v)V.pi./M
[0069] (where P is the vapor pressure (mmHg), k is the vaporization
rate (mg/min), v is the carrier gas flow rate (ml/min), k/v is the
vapor density (mg/ml.), V is the carrier gas molar volume (L/mol),
.pi. is the system pressure (mmHg), and M is the sample molecular
weight; 1 mmHg=1.33.times.10.sup.2 Pa).
[0070] The results are given in FIG. 18, and are plotted on a graph
(FIG. 19).
[0071] The results show that cedrol can be vaporized at ambient
temperature (unheated).
Example 1
[0072] The subjects were ten women in their twenties complaining of
fatigue (sympathetic overactivity), who were asked to inhale, for
30 seconds, cedrol dissolved in dipropylene glycol (10 wt %
concentration), while ECG at rest (chest V5 lead), blood pressure
(tonometry), and respiration (pulmonary volume instantaneously
measured by respiratory rate sensor) were monitored. The changes in
parameters before and after measurement were compared. Frequency
analysis of R-R interval fluctuations was performed for low
frequency components integrating amplitudes 0.02 to 0.12 Hz (sum of
low frequency: Lsum) and high frequency components integrating
amplitudes 0.12 to 2.00 Hz (sum of high frequency: Hsum)--using the
rapid Fourier transform. As used here, the Hsum is an indicator of
parasympathetic nervous activity, and the Lsum/Hsum is an indicator
of sympathetic nervous activity.
[0073] The measurement results were statistically analyzed by
Welch's t-test or Student's t-test based on the F test.
[0074] Results
[0075] 1) The systolic blood pressure (SBP) was meaningfully lower
(5%) after inhalation compared to before inhalation (FIG. 1A).
[0076] 2) The diastolic blood pressure (DBP) was meaningfully lower
(5%) after inhalation compared to before inhalation (FIG. 1B).
[0077] 3) The ECG R-R interval was meaningfully longer (5%) after
inhalation compared to before inhalation (FIG. 1C).
[0078] 4) The Hsum was meaningfully greater (5%) after inhalation
compared to before inhalation (FIG. 1D).
[0079] 5) The Lsum/Hsum was meaningfully lower (5%) after
inhalation compared to before inhalation (FIG. 1E).
[0080] 6) The respiratory gate (RR) was meaningfully lower (5%)
after inhalation compared to before inhalation (FIG. 1F).
[0081] Conclusions
[0082] The above results demonstrate that the inhalation of cedrol
by the subjects resulted in sedative effects in various parts of
the body, suppressed sympathetic overactivity, and resulted in the
predominance of the parasympathetic activity.
Example 2
[0083] The subjects were ten insomniac women in their twenties
(under considerable pressure to get to sleep, with parasympathetic
predominance to excess), who were asked to inhale, for 30 seconds,
cedrol dissolved in dipropylene glycol (10 wt % concentration),
while ECG at rest (chest V5 lead), blood pressure (tonometry), and
respiration (pulmonary volume instantaneously measured by
respiratory rate sensor), and skin blood flow of forehead (measured
by laser Doppler methods) were monitored. The changes in parameters
before and after measurement were compared. Frequency analysis of
R-R interval fluctuations and statistical analysis of the
measurement results were done in the same manner as in Example
1.
[0084] Results
[0085] 1) The systolic blood pressure (SBP) was meaningfully higher
(5%) (within physiologically normal range) after inhalation
compared to before inhalation (FIG. 2A).
[0086] 2) The diastolic blood pressure (DBP) was meaningfully
higher (5%) (within physiologically normal range) after inhalation
compared to before inhalation (FIG. 2B).
[0087] 3) There was no meaningful change in ECG R-R interval after
inhalation compared to before inhalation (FIG. 2C).
[0088] 4) The Hsum tended to be lower (5%) inhalation compared to
before inhalation (FIG. 2D).
[0089] 5) The Lsum/Hsum tended to be higher after inhalation
compared to before inhalation (FIG. 2E).
[0090] 6) There was no meaningful difference in respiratory rate
(RR) after inhalation compared to before inhalation (FIG. 2F).
[0091] Conclusion
[0092] The above results demonstrate that the inhalation of cedrol
by the subjects resulted in a return to a state of equilibrium in
various parts of the body, and suppressed parasympathetic
overactivity while simultaneously elevating the sympathetic
underactivity, thereby resulting in a suitable autonomic nervous
balance.
Example 3
[0093] The subjects were ten women in their twenties suffering from
poor sleep. ECG (chest V5 lead), brain waves (C3, O1 in the
international 10-20 method), respiration (impedance method: abdomen
and chest), superficial electromyogram (bipolar lead of left and
right mentalis muscles), and ocular movement (bipolar lead without
horizontally linking left and right eye-sockets) were monitored
from the time the subjects went to bed until they woke in a 40
m.sup.2 room. The cedrol was administered by placing Petri dishes
filled with cedrol on 95.degree. C. hot plates so that
approximately 100 mg was vaporized per hour (about 1 ppb/hr), from
the time subjects went to bed until they woke. Measurements were
taken for 7 days. No administration took place on the first two
days, in order to allow subjects to become acclimated to the
measuring instruments and environment (control). On the third day,
administration was managed without anything placed on the hot
plates (placebo). After 3 days, cedrol was administered on the 7th
day.
[0094] The subjects were interviewed about their condition on
waking using a questionnaire based on POMS (profile of mood states)
to assess mood. The changes in the parameters measured during the
administration of cedrol and placebo treatment were compared.
Awakening and sleep stages were determined in accordance with
international standards for determining sleep stages (Sleep Brain
Wave Atlas, pp. 3-9, Ishiyaku Shuppan KK, published September,
1971, the relevant portions thereof which describe sleep analysis
and standards are incorporated herein by reference). Frequency
analysis of R-R interval fluctuations and statistical analysis of
the measurement results were done in the same manner as in Example
1.
[0095] Results
[0096] 1) Hsum was meaningfully increased (5%) during non-REM sleep
when cedrol was administered compared to the placebo treatment
(FIG. 3A).
[0097] 2) The cumulative incidence of stages 3 and 4 of sleep was
meaningfully greater (5%) when cedrol was administered compared to
the placebo treatment (FIG. 3B).
[0098] 3) The respiratory rate (RR) was meaningfully lower (5%)
during nor-REM sleep when cedrol was administered compared to the
placebo treatment (FIG. 3C).
[0099] 4) POMS revealed meaningful (5%) improvement in tension and
fatigue when cedrol was administered on the 7th day compared to
before administration and the 3rd day (placebo treatment) (FIG.
3D).
[0100] Conclusion
[0101] The above results reveal that subjects who slept while
inhaling the fumes of cedrol (100 mg/hr) had a meaningfully deeper
sleep, a longer non-REM sleep cycle, and a better quality of sleep,
indicating a shift to parasympathetic predominance.
Example 4
[0102] The subjects were ten women in their twenties experiencing
fatigue (sympathetic overactivity), who were asked to massage their
faces as shown in FIG. 1 of Japanese Laid-Open Patent Application
(Kokai) H10-113369 using the massage cream preparation in Table 1
once a day before sleep for 4 continuous weeks. Specifically, as
shown in FIG. 4, (step 1) approximately 2 mL massage cream was
spread on the hands and applied to the face, (step 2) the face was
massaged 2 to 3 times with all four fingers (index to pinky) of
both hands in a line from the corners of the mouth to the wings of
the nose (direction (a) in FIG. 4), (step 3) the face was massaged
2 to 3 times in circles outward from the canter of the cheeks
(direction (b) in FIG. 4), (step 4) the face was massaged 2 to 3
times in arcs outward from the center of the forehead (direction
(c) FIG. 4), (step 5) steps 2 through 4 were repeated 3 times, and
(step 6) the face under the eyes was massaged 3 times in arcs
gradually extending outward (direction (d) in FIG. 4).
[0103] The ECG at rest (chest V5 lead), blood pressure (tonometry),
and respiration (pulmonary volume instantaneously measured by
respiratory rate sensor) were monitored in the morning before and 4
weeks after the beginning of massaging, so as to compare changes in
the parameters. Frequency analysis of R-R interval fluctuations and
statistical analysis of the measurement results were done in the
same manner as in Example 1.
1 TABLE 1 Components Wt % Oil components: beeswax 6.0 cetanol 5.0
reduced lanolin 8.0 squalane 37.5 fatty acid glycerin 4.0
Emulsifiers: oleophilic glycerin monostearate 2.0 polyoxyethylene
(20 EO) sorbitan laurate ester 2.0 Aqueous phase: propylene glycol
5.0 purified water 30.0 cedrol 0.5 preservative/antioxidant proper
amount
[0104] Results
[0105] 1) The systolic blood pressure (SBP) was meaningfully lower
(5%) 4 weeks after the beginning of massaging compared to before
massaging (FIG. 5A).
[0106] 2) The diastolic blood pressure (DBP) was meaningfully lower
(5%) 4 weeks after the beginning of massaging compared to before
massaging (FIG. 5B).
[0107] 3) The ECG R-R interval was meaningfully longer (5%) 4 weeks
after the beginning of massaging compared to before massaging (FIG.
5C).
[0108] 4) The Hsum was meaningfully higher 4 weeks after the
beginning of massaging compared to before massaging (FIG. 5D).
[0109] 5) The Lsum/Hsum was meaningfully lower 4 weeks after the
beginning of massaging compared to before massaging (FIG. 5E).
[0110] The respiratory rate (RR) was meaningfully lower (5%) 4
weeks after the beginning of massaging compared to before massaging
(FIG. 5F).
[0111] Conclusion
[0112] The above results reveal that massaging the face using
massage cream containing a cedrol blend once a day for 4 continuous
weeks resulted in sedative effects in various parts of the body,
the suppression of sympathetic overactivity, and a shift to
parasympathetic predominance.
Example 5
[0113] The subjects were twenty women in their twenties
experiencing mental and physical stress, who were asked to wear the
following masks a) through d) (vaporization systems) around the
mouth and nose at a temperature of 25.degree. C. and a humidity of
50%;
[0114] (mask a)) mask incorporating a heating element (mask surface
temperature about 70.degree. C.) (mask described in Example 3 of
Japanese Laid-Open Patent Application (Kokai) 2000-42125);
[0115] (mask b)) mask comprising a support (filter paper)
impregnated on the surface with a prescribed amount of cedrol
(2.5.times.10.sup.-3 g) and a mask incorporating a heating element
(mask surface temperature about 70.degree. C.) (mask described in
Example 3 of Japanese Laid-Open Patent Application (Kokai)
2000-42125) the support being attached to the surface of the
heating element;
[0116] (mask c)) mask incorporating a hot steam generating element
(mask surface temperature about 70.degree. C.; steam rate 0.5
g/min) (mask described in Example 1 of Japanese Laid-Open Patent
Application (Kokai) 2000-42125); and
[0117] (mask d)) mask comprising a support (filter paper)
impregnated on the surface with a prescribed amount, of cedrol
(2.5.times.10.sup.-3 g) and a mask incorporating a hot steam
generating element (mask surface temperature about 70.degree. C.;
steam rate 0.5 g/min) (mask described in Example 1 of Japanese
Laid-Open Patent Application (Kokai) 2000-42125), the support being
attached to the surface of the hot steam generating element.
[0118] ECG (chest V5 lead) and emotion spectrum analysis based on
brain waves (T. Musha et al, ibid.) were performed for 3 minutes
from 17 to 20 minutes after the masks had been applied. Frequency
analysis of R-R interval fluctuations was performed for low
frequency components integrating amplitudes 0.02 to 0.12 Hz (sum of
low frequency: Lsum) and high frequency components integrating
amplitudes 0.12 to 2.00 Hz (sum of high frequency: Hsum) using the
rapid Fourier transform, as well as Lsum/Hsum.
[0119] The measurement results were statistically analyzed by
multiple comparative analysis of variance.
[0120] Results
[0121] (1) The ECG R-R integral was meaningfully longer with the
mask d) (hot steam+cedrol treatment) than with the other masks
[mask d) p<0.05; other masks p<0.01] (FIG. 6).
[0122] (2) The Hsum was meaningfully greater with the mask d) (hot
steam+cedrol treatment) than with the other masks [mask d)
p<0.05; other masks p<0.01] (FIG. 7).
[0123] (3) The Lsum/Hsum was meaningfully lower with the mask d)
(hot steam+cedrol treatment) than with the other masks [mask d)
p<0.05; other masks p<0.01] (FIG. 8).
[0124] (4) the emotional spectrum was meaningfully improved in
terms of anger/stress (FIG. 9A), joy (FIG. 9B), sadness (FIG. 9C),
and relaxation (FIG. 9D) with the mask d) (hot steam+cedrol
treatment.) than with the other masks [mask d) p<0.05: other
masks p<0.01].
[0125] Conclusion
[0126] The above results demonstrate that the effects achieved
through the inhalation of cedrol contained in the mask resulted in
better calmness and tranquillity (relaxation effects) when used
with hot steam than with heat. The effects appear to be peripheral
effects in the various body parts as well as effects on the
conscious level.
Example 6
[0127] The subjects were twenty women in their twenties
experiencing mental and physical stress, who were asked to wear the
following masks a) through d) (vaporization systems) around the
mouth and nose at a temperature of 23.degree. C. and a humidity of
50% while resting in a seated position for 30 minutes.
[0128] (mask a)) mask incorporating a heating element (mask surface
temperature about 70.degree. C.) (mask described in Example 3 of
Japanese Laid-Open Patent Application (Kokai) 2000-42125);
[0129] (mask b)) mask comprising a support (filter paper)
impregnated on the surface with a prescribed amount of cedrol
(2.5.times.10.sup.-3 g) and a mask incorporating a heating element
(mask surface temperature about 70.degree. C.) (mask described in
Example 3 of Japanese laid-Open Patent Application (Kokai)
2000-42125), the support being attached to the surface of the
heating element;
[0130] (mask c)) mask incorporating a hot steam generating element
(mask surface temperature about 70.degree. C.; steam rate 0.5
g/min) (mask described in Example 1 of Japanese Laid-Open Patent
Application (Kokai) 2000-42125); and
[0131] (mask d)) mask comprising a support (filter paper)
impregnated on the surface with a prescribed amount of cedral
(2.5.times.10.sup.-3 g) and a mask incorporating a hot steam
generating element (mask surface temperature about 70.degree. C.;
steam rate 0.5 g/min) (mask described in example 1 of Japanese
Laid-Open Patent Application (Kokai) 2000-42125), the support being
attached to the surface of the hot steam generating element. The
masks were then removed, the subjects were asked to lie down, and
the sleeping efficiency and intermittent awakening were assessed
using actigrams while the subjects slept until the following
day.
[0132] Statistical analysis of the measurement results was the same
as in Example 5.
[0133] Results
[0134] (1) Sleeping efficiency was meaningfully better with mask d)
(hot steam+cedrol treatment) than with the other masks [mask d)
p<0.05; other masks p<0.01] (FIG. 10).
[0135] (2) There were meaningfully fewer intermittent awakening
with mask d) (hot steam+cedrol treatment) than with the other masks
[mask d) p<0.05; other masks p 0.01] (FIG. 11).
[0136] Conclusion
[0137] The results demonstrate that the effects achieved through
the inhalation of Cedrol contained in the mask resulted in better
sleeping efficiency when used with hot steam than with heat.
Example 7
[0138] The subjects were twenty insomniac women in their fifties,
while sleep was assessed from 3 hours before bed until wakening for
4 weeks in a room (sleeping room) at a temperature of 23.degree. C.
and a humidity of 50%. The first week served as a control. For the
last 3 weeks, the test was conducted by replacing the curtains,
wall paper, flooring, pillows, sheets, and bedding with those which
had been coated with cedral (1.5 .mu.g/cm.sup.2).
[0139] The subjects ware actigrams for 4 continuous weeks on the
opposite of their leading arm to allow assessment of the sleeping
efficiency and intermittent awakening. Analyzed data for the cedrol
coatings were from the 15th to 21st days following application.
[0140] Statistical analysis of the measurement results was the same
as in Example 5.
[0141] Results
[0142] (1) Sleeping efficiency was meaningfully better with cedrol
treatment than during the control (p<0.01) (FIG. 12).
[0143] (2) There were meaningfully fewer intermittent awakening
with cedrol treatment than during the control (p<0.01) (FIG.
3).
[0144] Conclusion
[0145] The results demonstrate that sleeping in a room using fiber
products, furnishings, and bedding coated with cedrol resulted in
far better sleep than when sleeping in a room using fiber products,
furnishings, and bedding not coated with cedrol.
Example 8
[0146] The subjects were twenty women in their twenties
experiencing mental and physical stress, who were acclimated for 20
minutes to a temperature of 25.degree. C. and humidity of 50% as a
control. ECG (chest V5 lead) and emotion spectrum analysis based on
brain waves were conducted 20 minutes after the subjects licked one
candy of 5 g containing no cedrol (58.0 wt % granulated sugar, 17.0
wt % water, 25 wt % starch syrup, and a suitable amount of
coloring), or another candy of 5 g containing 0.01 wt % cedrol
(58.0 wt % granulated sugar, 17.0 wt % water, 24.99 wt % starch
syrup, 0.01 wt % cedrol, and a suitable amount of coloring),
[0147] Frequency analysis of the R-R interval fluctuations and
statistical analysis of the measurement results were the same as in
Example 5.
[0148] Results
[0149] (1) The ECG R-R interval was meaningfully longer (p<0.01)
when the subjects licked the candy containing cedrol than during
the control, and was also meaningfully longer (p<0.01) than when
the candy containing no cedrol was licked (FIG. 14).
[0150] (2) The Hsum was meaningfully greater (p<0.01) when the
subjects licked the candy containing cedrol than during the
control, and was also meaningfully greater (p<0.01) than when
the candy containing no cedrol was licked (FIG. 1b).
[0151] (3) The Lsum/Hsum was meaningfully lower (p<0.01) when
the subjects licked the candy containing cedrol than during the
control, and was also meaningfully lower (p<0.01) than when the
candy containing no cedrol was licked (FIG. 16).
[0152] (4) The emotion spectrum was meaningfully improved
(p<0.01) in terms anger/stress (FIG. 17A), joy (FIG. 17B),
sadness (FIG. 17C), and relaxation (FIG. 17D) when the subjects
licked the candy containing cedrol than during the control, and was
also meaningfully improved (p<0.01) than when the candy
containing no cedrol was licked.
[0153] Conclusion
[0154] The above results demonstrate that, the effects of the candy
containing cedrol resulted in better calmness and tranquillity
(relaxation effects) than the candy containing no cedrol. The
effects appear to be peripheral effects in the various body parts
as well as effects on the conscious level.
INDUSTRIAL APPLICABILITY
[0155] The autonomic nerve regulating agents of the present
invention comprise a sesquiterpene alcohol with a boiling point of
250.degree. C. or higher (at atmospheric pressure), and act on
individuals without any noticeable perception of odor. Typical
action includes bringing about the relative predominance of the
parasympathetic activity over the sympathetic activity in
individuals with sympathetic overactivity (that is, sympathetic
suppression and/or parasympathetic stimulation), as well as
bringing about the relative predominance of the sympathetic
activity over the parasympathetic activity in individuals with
parasympathetic overactivity. The invention can thus control the
balance between the parasympathetic and sympathetic activities,
regardless of individual sensitivity to or preference for
fragrances, can normalize autonomic nerve disequilibrium, and has
favorable effects on individuals such as sedative, sleep improving,
and stress mitigating effects.
* * * * *