WO2005023279A1

WO2005023279A1 - Anti-stress composition and inhaler therefor

Info

Publication number: WO2005023279A1
Application number: PCT/FR2004/002211
Authority: WO
Inventors: Denis Marin; Serge Sonie
Original assignee: Persee Medica
Priority date: 2003-08-28
Filing date: 2004-08-30
Publication date: 2005-03-17
Also published as: FR2859108A1; FR2859108B1

Abstract

The invention relates to an anti-stress composition comprising at least one compound selected from the following essential oils: mint, eucalyptus or rose. The invention also relates to a nasal and/or buccal inhaler provided with a container comprising the inventive anti-stress composition.

Description

ANTI-STRESS COMPOSITION AND ITS INHALER

The present invention relates to the field of anti-stress compositions. The present invention relates more particularly to an anti-stress composition intended for combating acute stress attacks, commonly known as "bursts of stress".

The objective of the present invention is in fact to produce an anti-stress composition to achieve the following physiological objectives on a patient under acute stress: • calm the subject by restoring long and deep breathing, • decrease the secretion of adrenaline to limit the impact of "hot flashes", flushing of the face, excessive sweating, heart palpitations, • relax the subject by reducing muscle contractions and allowing him to regain the fullness of his intellectual faculties .

Stress is a general, non-specific term, which includes any request (physical or psychological) outside of norms and limits and which signals a disparity between what is optimal and the reality of the moment. We can consider that there are episodes of life during which the subjects admit to being more stressed than others. Stress develops in three phases: • The alarm reaction characterized by an acceleration of the heart rate with short and rapid breathing, muscle tension, dryness in the throat, redness in the neck or face, excessive sweating, difficulty expressing and thinking calmly, difficulty concentrating. These signs are transient and correspond to a situation of acute stress. The signs felt are commonly called "bursts of stress", • The stage of resistance: the body and organs adapt well to aggression to resist over a period of short or medium duration. The mechanisms implemented by the body can be adapted, or on the contrary inappropriate with the adequate response. In case of prolonged maladjustment, intellectual performance decreases, the patient becomes depressed, becomes extremely nervous and aggressive, • The stage of exhaustion: the physical signs are very strong muscle tension, with frequent headaches and migraines, disturbed intestinal transit (spasms and pain), the appearance of ulcers.

The effects of stress are visible on our body, which reacts to this external aggression by changing our psychological behavior (sleep disturbances, headaches and diffuse pain, tension, intellectual overwork) and by modifying our physical appearance (excessive sweating, redness of the face, dermatitis and minor skin conditions ...). These changes do not occur simultaneously, the effects of short-term stress (acute stress) being rather managed by the sympathetic system.

In situations of acute stress, the psychic pressure generated by stress is the result of a psycho-physiological reaction to an emergency. Our organism will quickly mobilize, either to face external aggression or on the contrary, to give man the means of his escape. Stimulation by the nervous system central of the orthosympathetic system produces a rapid release of adrenaline. This mechanism is well known to the general public since the term "adrenaline rush" is part of popular expressions.

As examples of anti-stress compositions of the prior art, application JP 6065068 is already known containing β-carotene as active agent intended to act on the nervous system and deliver in liquid form.

Patent application JP 2000136143 describes an anti-stress composition comprising a plant belonging to the family of Ebenaceae while US patent 6265450 discloses an anti-stress composition, administered in liquid form or as a food supplement, comprising as active agent astaxanthin and / or one of its esters.

Patent application JP 7215879 discloses an anti-stress composition containing a mixture of nucleic acids, such as for example inosine or cytidine and thymidine in a particular molar ratio.

Patent application WO 0232234 describes an anti-stress composition, having a calming effect, regulator of stress hormones and immunostimulator, comprising a component consisting of a mixture of linoleic and linolenic acids, such as for example walnut oil, a component from the group of flavonoids, such as ginseng, and a component having sedative properties such as tryptophan.

Finally, US patent 20030012824 describes an anti-stress composition administered orally comprising at least minus an antacid compound and a compound that reduces anxiety in a particular relationship.

The anti - stress products and compositions disclosed in these documents act on stress according to a well known approach: • an indirect action: the products act on the medium and long term physiological and pathological consequences of stress, such as insomnia, depression , anxiety, pathological skin disorders (eczema, psoriasis ...); • an action restricted to a single pharmacological approach: the products act by a sedative effect whose objective is to calm the individual; an action on chronic and long-term stress: certain products act on one of the stress hormones (cortisol) which is released during chronic stress, it is a long-term effect which is felt after several weeks of treatment.

Surprisingly, none of the products responds to an action: • direct on bursts of stress by reducing adrenaline (hormone responsible for bursts of stress); • multi-approaches on intellectual and muscular relaxation, a decrease in body temperature; .on acute stress with an immediate effect. The present invention intends to remedy the drawbacks of the prior art by proposing an anti-stress composition making it possible to provide a rapid physiological response to a situation of acute stress by allowing the user to immediately relax. The anti-stress composition according to the invention will thus promote the decrease in the secretion of adrenaline in order to participate in the control of hot flushes, excessive sweating, redness of the face and heart palpitations and make it possible to establish a state of intellectual and physical relaxation, thanks to the properties of its essential oils. This object is achieved according to the invention thanks to an anti-stress composition characterized in that it comprises, as active agent, at least one essential oil chosen from the group comprising essential oil of mint, essential oil of eucalyptus or rose essential oil.

According to one embodiment of the invention, the anti-stress composition will comprise, as active agent, at least two essential oils chosen from the group comprising essential oil of mint, essential oil of eucalyptus or rose essential oil. In this case, preferably, the two essential oils constituting the composition will be the essential oil of mint and the essential oil of rose.

According to another embodiment of the invention, the composition will comprise essential oil of mint, essential oil of eucalyptus and essential oil of rose.

Advantageously, the essential oil of mint may consist of essential oil of Menthae piperi tae or peppermint. Advantageously, the essential oil of eucalyptus will comprise 1,8-cineole or eucalyptol up to at least 60% by mass. According to one embodiment of the invention, the composition will comprise, as the only essential oil, essential oil of mint.

Advantageously, the majority constituent of the essential oil of mint, both in weight and in molar percentage, will be menthol.

Advantageously, the essential oil of mint will comprise flavonoids whose majority constituent, both in mass and in molar proportion, is 1 Eriocitroside.

According to one possibility offered by the invention, the composition may comprise a solvent from the family of alcohols.

In this case, preferably, the solvent will be ethanol. As indicated previously, the essential oil (s) defined above is / are useful for the preparation of anti-stress compositions, in particular for promoting the decrease in the secretion of adrenaline to help control hot flashes, excessive sweating, redness of the face and heart palpitations and help establish a state of intellectual and physical relaxation. Thus, the invention relates to a method of treating or preventing stress in an individual (man or animal) consisting of administering to said individual an effective amount of a composition defined above.

The present invention also relates to a use of a composition containing at least mint essential oil and eucalyptus essential oil, as active agent, for the preparation of the anti-stress composition previously described. The present invention also relates to the use of a composition containing at least mint essential oil and rose essential oil, as active agent, for the preparation of the anti-stress composition described above. .

The present invention also relates to a device allowing the inhalation of a composition as described above. In light of the invention, it is obvious that a person skilled in the art will understand by the expression “device for inhalation” any form allowing inhalation of the essential oils constituting the composition. In particular, it may be a nasal and / or oral inhaler having a container comprising the anti-stress composition to be administered. It will be noted that the inhaler may also be used to deliver a certain amount of the anti-stress composition according to the invention to another part of the body, such as the forearm or the temples, to allow the volatile essential oils to diffuse. and thus be inhaled through the patient / wearer's respiratory system. It may also be a device in the form of ointment, solution, lotion, cream, milk, shampoo, soap, red lip, make-up, foundation, powder, sunscreen, deodorant, spray, etc.

The present invention also relates to a process for the preparation of an anti-stress composition as defined above.

The invention will be better understood using the description, given below for purely explanatory purposes, of an embodiment of the invention, with reference to the appended figures: FIG. 1 illustrates a table showing four different compositions comprising peppermint essential oil and eucalyptus essential oil mixed in ethanol; FIG. 2 illustrates a table showing the electroencephalogram activity (ECG), in microvolts per second (μv / s), at rest of the temporal muscle for the four compositions present in the table in FIG. 1.

As we have seen previously, the anti-stress composition according to the invention may comprise only a single essential oil chosen from essential oil of mint, rose or eucalyptus. This composition may also include two of these essential oils or the three essential oils. The anti-stress composition may be mixed or dissolved in a suitable solvent, conventionally an alcohol such as ethanol. There is a strong rational or pharmacological interest in combining the essential oils of peppermint, eucalyptus and rose in order to reduce the physiological manifestations of a situation of acute stress. Indeed, taken separately, these assets show properties pharmacological interesting which are useful in order to decrease the level of adrenaline, to appease the respiration, to decrease the muscular tension and to reduce the body temperature and to have an effect of mental relaxation according to the following main functions:

The essential oil of mint will ideally be menthae piper ± tae, commonly known as peppermint. The mint leaf contains many compounds such as triterpenes, carotenoids, phenol acids (up to 7%) and flavonoids. The latter are represented by lipophilic polysubstituted flavones (genins), by heterosides of particularly abundant flavones and flavonols. Some clones contain more than 17% of flavonoids, the majority compound always being eriocitroside. The majority constituent of the essential oil is always menthol which represents 30-40%, sometimes more than 50%. Mint essential oil is antispasmodic. It lifts the morphine-induced Oddi sphincter contraction (guinea pig) and non-competitively inhibits intestinal smooth muscle contractions induced by various agonists or by depolarization (guinea pig ileum, rabbit jejunum and other models) and this by direct action on calcium channels.

A placebo-controlled clinical study has shown that a preparation of 10% essential oil of mint in ethanol, applied to the forearms and temples, was able to significantly reduce the intensity of pain from 15 first minutes (p <0.01). This study highlights the analgesic properties of peppermint essential oil.

The relaxing and anti-spasmodic action of the essential oil of mint decreases the basal metabolism of the organism, this allowing a better regulation of the body temperature, element particularly important in situation of acute stress or appear "bursts of stress" accompanied by excessive sweating.

It should be noted that the essential oil of Ae therol eum Menthae Piperi tae is the subject of a monograph by the World Health Organization (WHO).

Concerning the essential oil of eucalyptus, 1,8-cineole (or eucalyptol) is the majority constituent (70-80%); the other constituents are mainly terpene. The leaf also contains a dozen oxygenated heterocycles with an acylphloroglucinol-mono or sesquiterpene structure as well as phenolic compounds, banal phenol acids and flavonoids. Eucalyptus essential oil has antiseptic properties established in vitro and unequivocally on many germs. Cineole, easily absorbed by the digestive tract as well as by the cutaneous or rectal route, is eliminated via the pulmonary and renal routes. Eucalyptus essential oil has expectorant, stimulating properties of the bronchial and mucolytic epithelium. Eucalyptus essential oil, like menthol, decongests the upper airways in case of rhinitis.

The composition of rose essential oil is variable and contains compounds such as nerol, geraniol, lemon grass, linalool, esters, rose oxide, damascenone.

Figure 2 illustrates different anti-stress compositions comprising a mixture of essential oils of Menthae piperi tae and eucalyptus solubilized in 90% ethanol (purity of ethanol). A study was carried out on 32 healthy subjects in order to measure the effect of essential oils on the psychological and neurophysiological parameters of these subjects. These four different preparations were applied to the forearm and temples with a soaked tampon. The effectiveness of the various preparations was measured by comparing the initial values of the parameters (that is to say before the application) with the final values.

Indeed, essential oils have the advantageous property of being extremely volatile. So, when applied to the forearm or temples, volatile assets are naturally inhaled by the subject and play a physiological and therapeutic role on receptors located in the respiratory system. Each preparation was applied over a large area of the forearm and on the temples for 3 minutes. This operation was repeated three times: immediately after taking the initial values, 15 minutes and 30 minutes after. The final measurement was carried out 45 minutes after the initial measurement. The time intervals were arbitrarily determined based on preliminary research. All the measurements were taken between 3 p.m. and 6 p.m. to limit the influence of circadian rhythms as much as possible.

The study shows that the combination of essential oils of peppermint and eucalyptus produces a relaxing muscle effect, increases cognitive performance and induces a state of mental serenity in healthy subjects. As shown in Figure 2, the composition PI (combination of essential oils of mint, eucalyptus and ethanol solvent) showed the greatest decrease in ECG activity of the temporal muscle (30.6%, p <0.001 ). Only preparation P2 shows a similar effect with a decrease of around 28.8% (p <0.001), preparations P3 and P4 producing no statistically significant effects. The effect of the preparation PI is greater than the effects of the preparations P3 (p <0.05) and P4 (p <0.001).

Concerning the main criterion "mood", the dimension "performance-related activity", made up of the "activity" and "concentration" items, was increased by 78% (p <0.001) for PI preparation. The effect of the preparation PI was also significantly superior to that of other preparations for this same criterion. The dimension "emotional irritation", formed by the criteria "excitability", "sensitivity" and "annoyance" was reduced statistically significantly by 14% (p <0.05). This reduction is also significant (13.4%, p <0.01) for preparation P2. The other preparations did not show any effects. The study shows that the effects of the combination of essential oils are statistically superior to other preparations and to a placebo group on the criteria "relaxation of the pericranial muscle" and "activity linked to performance".

Regarding rose essential oil, several preparations of various essential oils (pepper, grapefruit, tarragon, fennel, patchouli and rose) were tested on 43 healthy subjects by inhalation. The objective was to measure changes in blood pressure and plasma levels of catecholamines. These effects were compared to the inhalation of the solvent used to make the preparations (control). Certain essential oils have shown an increase in the activity of the sympathetic system. Others, on the contrary, have shown a reduction of almost 40% of this activity (rose essential oil).

Each essential oil was dissolved at a concentration of 2% in an odorless solvent (TriEthyl aCetate, TEC). For inhalation, 20 μl of each solution was placed on a piece of absorbent cotton, which was placed using an appropriate device under the subject's nose. Subjects inhaled for a period of 3 minutes for tests measuring variations in blood pressure and 7 minutes for measuring variations in catecholamines. The stimulation and inhibition effects of the sympathetic system show very clear differences between the essential oils analyzed. Thus, pepper essential oil induces a marked increase in the amplitude of the systolic blood pressure (SBP-LH) compared to the rest period before inhalation. For rose essential oil, the amplitude SBP-LH is on the contrary greatly reduced. These results have been converted into variations of "relative sympathetic activity". All the essential oils analyzed show, compared to the control, either an increase in relative sympathetic activity (pepper, tarragon, fennel, grapefruit), or a decrease (rose, patchouli). There are no variations for the solvent compared to a piece of unimpregnated cotton.

Changes in the plasma concentration of certain catecholamines have been measured (adrenaline, noradrenaline, dopamine). In this case too, important differences exist between essential oils. Some are capable of increasing the concentrations of catecholamines (pepper and grapefruit), others of decreasing these same concentrations (pink). For all of the essential oils studied, only rose essential oil statistically significantly decreases the plasma concentration of adrenaline. The decrease in the adrenaline concentration is 30% after inhalation of oil rose essential (p <0.01). For the other essential oils, the variations are not statistically significant. These results confirm that the inhalation of essential oils is likely to modify certain components of the sympathetic system.

The invention has been tested on subjects experiencing acute stress, that is to say experiencing stress bursts. A total of 27 subjects participated in the study, the majority of women (81%) aged 43 years on average (16 - 81 years). All have used the invention for a period greater than or equal to 10 days.

The results show that at the first visit, the subjects were highly stressed with a total score on the Covi scale of 12.3 (10 - 15). For each of the three items, the average score is greater than 4, confirming the trend of the total score (grouping the three items). Thus, for the speech, behavior and somatic complaint items, the inclusion scores are 4.0 / 4.2 and 4.1 respectively. The sensation of hot flashes in these same subjects is severe and is felt to a significant extent. The population selected to participate in the study is therefore perfectly suited to the objectives of the study.

After using the invention during a burst of stress, all of the results evolve very favorably towards an improvement in the patient's state of acute stress. First, the total score goes from 12.3 to 8.1; or an improvement in the subjects' state of stress by 34%. Thus, the use of the invention allows reduce the state of acute stress in subjects by bringing this threshold below score 10 on the Covi scale (qualifying threshold). On the items taken separately, the speech item improved by 32% (p <0.001), behavior by 32% (p <0.001) and somatic complaints by 39% (p <0.001). The strongest improvement on this last criterion shows the perfect adequacy of the invention with its characteristics and claims since hot flashes are more precisely characterized by somatic complaints such as hot flashes, redness of the face, tremors and significant sweating.

Obtaining the various essential oils for the anti-stress composition according to the invention can be carried out according to at least one of the techniques well known to those skilled in the art, namely for example steam distillation, distillation under vacuum, extraction with carbon dioxide or by solvents. Steam distillation is considered to be the most effective and common method. The plant material is placed in a still or essencier resembling a huge pressure cooker. The plant material does not come into contact with water. Thereafter, the steam is passed under pressure. Thanks to the effect of heat, the vacuoles of the plant material containing the essence molecules burst and the essence evaporates easily. Both the essential oil vapor and the water vapor pass through a water-cooled pipe. The vapors become liquid and the essential oil separates from the water by floating on it.

Vacuum distillation is a very recent process. It is first a question of creating the vacuum inside a Hermetically sealed still by reducing air pressure. Subsequently, it can be distilled at lower temperatures and ensure better preservation of essential oils.

Carbon dioxide extraction is a very recent method. When liquefied under pressure, carbon dioxide extracts the essential oil from the plant. Subsequently, the liquid obtained is filtered and then subjected to a decomposition during which the carbon dioxide gas will return to the gaseous state. So only the pure essential oil remains.

Solvent extraction is a classic method. In a barrel which contains the vegetable matter, one mixes there a hydrocarbon which will cause the dissolution of the essential oil. The solution is then filtered and concentrated by distillation (concrete essence). The majority of the oil is then collected by carrying out a second extraction, by evaporation of the pure alcohol, one then obtains an "absolute essence".

Once one or more essential oil (s) are obtained, they are mixed to obtain a composition with or without a common solvent, generally ethanol. In the case where the anti-stress composition comprises only one essential oil, the latter may or may not be present in / with a solvent. The invention is described in the foregoing by way of example. It is understood that a person skilled in the art is able to carry out different variants of the invention without going beyond the scope of the patent.

Claims

1. Use of a composition containing at least mint essential oil and rose essential oil, as active agents, for the preparation of an anti-stress composition.

2. Use according to claim 1, characterized in that said composition comprises essential oil of mint, essential oil of eucalyptus and essential oil of rose.

3. Use according to claim 1 or claim 2, characterized in that the essential oil of mint consists of essential oil of Menthae piperitae or peppermint.

4. Use according to claim 2 or claim 3, characterized in that the essential oil of eucalyptus comprises 1,8-cineole or eucalyptol up to at least 60% by mass.

5. Use according to any one of the preceding claims, characterized in that the majority constituent of the mint essential oil, both by weight and in molar percentage, is menthol.

6. Use according to any one of the preceding claims, characterized in that the essential oil of mint comprises flavonoids whose majority constituent, both in mass and in molar proportion, is 1 eriocitroside.

7. Device for inhaling a composition as defined according to any one of claims 1 to 6.

8. Nasal and / or oral inhaler having a container comprising a composition as defined according to any one of claims 1 to 6.