The autonomic nerve regulating agent of the present invention, which, has 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.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

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.

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:

(1) meaningful decrease of systolic blood pressure (SBP);

(2) meaningful decrease of diastolic blood pressure (DBP);

(3) meaningful extension of R--R interval in ECG;

(4) meaningful increase of Hsum in R--R interval fluctuations;

(5) meaningful decrease of Lsum/Hsum in R--R interval fluctuations; and

(6) meaningful reduction of respiratory rate.

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 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%.

"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.

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.

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.

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. %.

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.

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.

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.

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)

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.

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:

(1) meaningful shortening of sleep latency;

(2) meaningful reduction of number of intermittent awakening;

(3) meaningful increase of sleeping efficiency; and

(4) meaningful improvement in terms of tension and fatigue based on POMS.

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.

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).

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.

By providing effects such as sleep improvement and stress mitigation, the present invention can also improve menopause, PMS (premenstrual syndrome), physical vitality and appetite.

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).

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 autonomic 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.

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.

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.

Claim 1 of 24 Claims

1. A method for regulating autonomic nerve activity by increasing an ECG R--R interval in a person in need thereof, comprising administering by inhalation a composition comprising a sesquiterpene alcohol selected from the group consisting of cedrol, cedrenol, globulol and a mixture thereof to said person in an amount effective for regulating autonomic nerve activity, wherein said composition has no odor above a detectable threshold.

 

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