EP1879621A2

EP1879621A2 - Active composition for treatment or prevention of problems related to a disturbance of the biological clock

Info

Publication number: EP1879621A2
Application number: EP06764621A
Authority: EP
Inventors: Jean-Christophe Anton
Original assignee: Persee Medica SAS
Current assignee: Persee Medica SAS
Priority date: 2005-05-13
Filing date: 2006-05-12
Publication date: 2008-01-23
Also published as: NO20076426L; US20090069425A1; WO2006120360A2; WO2006120360A3; EA200702479A1; CA2608060A1; FR2885528A1

Abstract

The invention relates to an active composition for treatment or prevention of problems caused by a disturbance of the biological clock in humans and comprising polyunsaturated fatty acids and flavanoids as active ingredients.

Description

COMPOSITION USEFUL FOR TREATING OR PREVENTING DISORDERS ASSOCIATED WITH ORGANIC CLOCK DISRUPTION

The present invention relates to the field of treatment and prevention of disorders caused by disruption of the biological clock in humans and possibly in animals. More particularly, the invention is concerned with subjects whose sleep-wake cycle is disrupted, with main manifestations difficulty of falling asleep, poor quality of sleep, awakening difficult, significant fatigue during the day and consequently memory problems, difficulties in concentration and orientation in space.

Biological rhythms have been observed in humans, in the animal and plant world, at all levels of organization: ecosystem, population, individuals, organ systems, isolated organs, tissues, cells and subcellular fractions. From this research came Chronobiology, which aims to study and quantify the mechanisms of the biological temporal structure. The biological clock is closely related to wake - wake rhythms and consequently to sleep.

The dominant biological clock of the organism is located at the level of supra - chiasmatic nuclei. She is responsible for the construction and distribution of oscillations to pacemakers. The lack of scientific work leads to interest (by exclusion) in the dominant biological clock that controls the circadian rhythm.

The oscillations produced by the biological clock give rise to the production of hormones. The best known and studied to date is melatonin. The "hormonal" nature of the biological clock gives rise to strong interindividual variabilities. Indeed, many factors such as age, sex, weight, height and ethnicity influence hormonal status. Other external factors (environment) also play a role. In physiological conditions, the biological clock can be desynchronized by external factors (time difference, night work) and by internal factors (aging, illness, depression, surgery ...). In this context, melatonin plays the role of synchronizer of the biological clock.

Other studies confirm the importance of melatonin. A recent study shows that aging induces a decrease in melatonin synthesis. This decrease, however, would seem to be counterbalanced by compensatory regulatory mechanisms (increased expression of melatoninergic receptors). The action of melatonin on aging is therefore still a controversial topic and scientific evidence is lacking. In contrast, desynchronization of the biological clock by a decrease in melatonin concentrations in some patients is a phenomenon studied and validated.

Melatonin is synthesized from serotonin. Its main degradation occurs in the liver under the influence of enzymes controlled by cytochrome CYP1A2. Three melatonin receptors have been cloned to date, but unlike other receptor families, it is still impossible to link a physiological function or behavior to a specific receptor. The melatonin synthesis shown in Figure 1 follows a main physiological pathway under the influence of two hormones (AA-NAT and HIOMT). Several ways of approach are possible to compensate a melatonin deficiency: to bring or to favor the production of melatonin precursors, to bring directly from the melatonin or promote its production, decrease the degradation of melatonin.

The biological clock intimately controls the rhythms and the alternation between wakefulness and awakening. Under certain conditions, the biological clock can be out of sync with external factors (jet lag, night work) and internal factors (aging, illness, depression, surgery ...). The first manifestation of this desynchronization takes place on the sleep and is translated more particularly by a slumber of poor quality, difficulties of falling asleep and a diminished vigilance during the day.

The present invention aims to provide a composition capable of effectively opposing disorders caused by a disturbance of the biological clock. More particularly, the composition according to the invention comprises an original combination of natural assets that promote the synthesis of melatonin from its precursors and increase its bioavailability by acting on its metabolism. The combined action of these different assets promotes the rebalancing of the biological clock. In addition, certain active ingredients contained in the composition of the invention also play a direct role in sleep thanks to their sedative properties.

This object is achieved by means of a nutritional or pharmaceutical supplementation composition comprising, as active agents, polyunsaturated fatty acids and flavonoids.

This association is remarkable in that it exerts a physiological action at the different stages of the metabolic pathway of synthesis and degradation of melatonin. It promotes the synthesis of melatonin from its precursors and increases its bioavailability by acting on its metabolism. The polyunsaturated fatty acids of the composition of the invention are preferably alpha-linolenic acid [C ₁₈ : 3n-3] and linoleic acid [C ₁₈ : 2n-6]. Advantageously, the alpha-linolenic and linoleic acids of the composition are present in the form of one or more vegetable oils, such as hemp and soybean oils.

According to a particular embodiment, the composition comprises a weight ratio alpha-linolenic acid [C ₁₈ : 3n-3] / linoleic acid [C ₁₈ : 2n-6] ranging from 0.01 to 10, in particular from 0.1 to 1 and in particular from 0.2 to 0.8, or even from 0.25 to 0.5.

Alpha-linolenic and linoleic acids will increase serotonin synthesis in the brain and improve its bioavailability by causing its release at the platelet level. At the same time, linoleic acid, by increasing cyclic AMP concentrations, will stimulate the two enzymes AA-NAT (responsible for the conversion of serotonin to N-acetyl-serotonin) and HIOMT (responsible for the conversion of N-acetyl-serotonin). acetyl serotonin to melatonin). Thus, polyunsaturated fatty acids may promote increased melatonin concentrations by affecting the availability of the precursor (serotonin) and its metabolism to melatonin (stimulation of the enzymes responsible for the conversion).

The flavonoids of the composition of the invention are those contained in an extract of Humulus lupulus (hops). They have cytochrome CYP1A2 inhibition properties, which are responsible for the metabolism of melatonin. Inhibition of the enzyme responsible for the degradation of melatonin to its inactive metabolite is in the direction of enhancing the activity of the hormone by simply increasing its concentration and bioavailability for its receptors. Other substances present in the extract such as humulone and lupulone also have sedative properties in humans.

In particular, the composition comprises a weight ratio of linoleic acid and linolenic acid / dry extract of hop cone powder ranging from 1 to 20, in particular from 5 to 15, and in particular from 8 to 12.

A composition according to the invention is prepared by incorporating a dry extract of hop cones (female inflorescences of Humulus lupulus) to vegetable oils rich in polyunsaturated fatty acids. Thus, the amount of extract and oil in the composition is such that it allows a daily intake of: - Humulus lupulus (dry extract of powder of hop cones): 20 to 1000 mg and preferably of the order 100 mg;

Vegetable oil (s) rich in polyunsaturated fatty acids (hemp and soya oils): 400 to 3000 mg and preferably of the order of 866 mg, which corresponds to:

. approximately 300 to 2600 mg and preferably of the order of 540 mg of linoleic acid,

. approximately 60 to 600 mg and preferably of the order of 160 mg of alpha-linolenic acid.

This daily intake can be achieved using two doses of a composition according to the invention.

By way of a preferred example, a composition according to the invention comprises from: 10 to 500 mg and preferably of the order of 50 mg of Humulus lupulus extract, and

- 200 to 1500 mg and preferably 433 mg of vegetable oil (s) rich (s) polyunsaturated fatty acids (hemp and soya oils), which corresponds to: about 150 to 1300 mg and of preferably of the order of 370 mg of linoleic acid, . approximately 30 to 300 mg and preferably of the order of 80 mg of alpha-linolenic acid.

The composition of the invention may further comprise one or more other substances capable of completing or potentiating the action of the above assets. There may be mentioned for example: piperine and piperidine, or extracts of plants containing them, active agents known in disorders of the biological clock such as melatonin, N-acetyl serotonin, serotonin, tryptophan, active agents for stimulating ¹ arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) to give melatonin, sedative active agents, such as valerian, anti-depressant and hypnotic active agents , soothing or relaxing,

- vitamins and minerals,

- tonic active ingredients to combat the fatigue of the day, such as ginseng,

- Active ingredients to strengthen the immune system weakened by disorders of the biological clock ..., excipients adapted to the various galenic forms under which the compositions of the invention may be presented and promoting for example the bioavailability of the active ingredients or increasing their efficiency.

The compositions of the invention may be in any type of solid forms (tablet, capsule, soft capsule, cachet, sachet, powder, granule, etc.) and liquid (solution, syrup, drops, emulsion, etc.). As indicated above, the composition of the invention is intended for the treatment and / or prevention of disorders caused by a disturbance of the biological clock in humans and possibly in animals. The combination of polyunsaturated fatty acids and flavonoids described above is therefore particularly useful for the preparation of a medicament for synchronizing the biological clock of subjects having, for example, a poor quality of sleep. The composition of the invention is indicated in subjects whose sleep-wake cycle is disrupted, with the main manifestations of sleep disorders, difficulty falling asleep, poor sleep quality, difficult awakening, significant fatigue during sleep. day and consequently memory problems, difficulties of concentration and orientation in space.

Sleep disorders include:

Dyssomnias: insomnia of psychological origin (inability to sleep at night), altitude insomnia, insomnia of external origin (extrinsic), sleep disorders related to alcohol or drugs, narcolepsy,

Parasomnias: sleep disturbances associated with nocturnal awakenings but without significant disruption of sleep or impaired alertness during the day. Parasomnia includes sleepwalking, nocturnal terrors, sleep disturbances associated with REM sleep, nocturnal bruxism, and

Sleep disorders of psychiatric origin, neurological or related to other diseases.

The invention also relates to the use of a combination of polyunsaturated fatty acids and flavonoids as an agent for combating disorders caused by a disturbance of the biological clock. in a composition, especially in a nutritional or pharmaceutical supplementation composition or for the preparation of a composition intended to combat disorders caused by a disturbance of the biological clock.

The subject of the invention is also the use of a combination of polyunsaturated fatty acids and flavonoids as regulating agent for the biological clock in a composition or for the preparation of a composition intended to regulate the biological clock.

Other advantages and characteristics of the invention will become apparent from the following examples concerning the preparation of a composition according to the invention and a study carried out on 33 patients.

This study shows that a composition of the invention, designated hereinafter HB1, is effective on sleep disorders with a very significant improvement in the total score of the ISI (Insomnia Severity Index) scale. The subjects participating in the study saw their sleep greatly improved on all the different items measured. This improvement is greater than 40% after one month of taking HBl on the overall score, with a significant improvement in sleep quality (43%), sleep satisfaction (44%) and a decrease in interference with sleep problems. sleep in the daily life of patients (37%). The results are consolidated and increased after one more month of taking the product.

Reference will be made hereinafter to the appended drawings in which:

- Figure 2 shows the evolution of the criteria (OJ versus J30). - Figure 3 shows the evolution of the criteria (OJ versus J30 versus J60, item TOTAL on the left axis, other items on the right axis).

By "of the order of X" or "about X" is meant within the meaning of the present application a range of values from X minus 15% to X plus 15%, in particular from X minus 10% to X plus 10% , in particular X minus 5% at X plus 5%, or even X minus 2% at X plus 2%.

Example 1 Preparation of a Composition According to the Invention (HB1)

A composition according to the invention is prepared by incorporating a dry extract of hop cones (female inflorescences of Humulus lupulus) to vegetable oils rich in polyunsaturated fatty acids. Thus, the amount of extract and oil in the composition is such that it allows a daily intake of: - Humulus lupulus (dry extract of hop cone powder): 100 mg;

- Vegetable oils of hemp and soy (high in polyunsaturated fatty acids): 866 mg.

Example 2: Study of the properties of HBl on sleep.

1) Analysis of insomnia.

The main criterion for this study is the measurement of sleep improvement in subjects having difficulty falling asleep, poor quality of sleep and consequently reduced vigilance during the day. The efficacy of HBl was assessed using a questionnaire to qualify and quantify insomnia according to the ISI (Insomnia Severity Index) scale. Insomnia means a decrease in the quality and duration of sleep, or recovery. Insomnia is a very common complaint that causes significant social and economic costs. The prevalence of insomnia is 27% on an occasional basis and 9% chronically. Insomnia is associated with many symptoms that disrupt the daily functioning of the individual.

The evaluation of insomnia can be made by subjective methods (clinical interview, questionnaire, sleep diary) and objective (polysonographic recording, actigraphy). The clinical interview provides information on the nature, history and severity of sleep difficulties as well as the possible causes of these difficulties. Although essential, this type of evaluation requires a great deal of time from the clinician and some experience to conduct the interview well. The use of a sleep diary or daily diary completed by the patient can collect useful information on sleep patterns. The administration of questionnaires can also facilitate the evaluation of insomnia while minimizing time and cost factors. These help to identify and detect sleep disorders, the amount and severity and impact of insomnia. Questionnaires provide quick and comprehensive information on the patient's subjective perception of sleep difficulties. As such, the Insomnia Severity Index (Sleep Impairment Rating Scale (SIRS)) provides a global index of deterioration or improvement in sleep. The patient considers the severity of his difficulties of falling asleep, the nocturnal awakenings and his premature awakenings, the degree of satisfaction vis-à-vis his sleep, the degree of interference with its daily functioning, the appearance of the deterioration related to its sleep problem and the level of anxiety caused by these difficulties. Sometimes the clinician and a significant person in the patient's entourage can complete these questionnaires in order to obtain additional indexes that more accurately measure the severity of the problem. This questionnaire is very useful in clinical and research since it allows to quickly obtain a subjective index of the patient's distress in the face of his sleep disorders. Moreover, it turns out to be a sensitive instrument to changes following a treatment of insomnia. The ISI scale questionnaire is reported in Tables 1 to 5 below:

Table 1: Please rate from 0 to 4 (for the last two weeks) the severity of your insomnia problems?

Table 2: How satisfied are you with your sleep?

Table 3: How much do you consider your sleep problems interfering with your life daily (eg, fatigue during the day, work capacity, managing daily tasks, concentration, mood memory?

Table 4: To what degree do you think that your sleep problems are noticeable on your life?

Table 5: How much does your sleep problem distress and distress you?

The evaluation is done by a system of adding the scores of the different questions according to the formula:

Total score = score question + Ib + Ic + 2 + 3 + 4 + 5

A total score of 0 to 7 is considered to be a total absence of insomnia, 8 to 14 latent insomnia, 15 to 21 moderate insomnia, and 22 to 28 severe insomnia.

2) Operating mode

2.1) Inclusion visit (OJ)

During the inclusion visit, the medical assessor proposes the study to patients who are part of his clientele. Inclusion criteria must be met, ie a healthy voluntary female or male subject aged between 16 and 50, whose biological clock is out of sync (the sleep-wake cycle is disrupted), with the main manifestations being difficulty falling asleep, poor quality of sleep, a difficult awakening due to a late sleep or on the contrary an early awakening, decreased vigilance during the day characterized by significant fatigue, memory problems, difficulties in concentration and orientation in space.

In proposing the study, the medical assessor must ensure that the subject faces in his professional or family life a disturbance of his sleep resulting in a situation of insomnia and that the subject is ready to accept the study.

The patient fills the scale according to the intensity of the different questions. To validate the inclusion, the evaluating physician must calculate the total score that corresponds to the sum of the answers to the questions. If the score is ≥ 15, it continues to include the subject.

The subject receives two capsules each evening, approximately two hours before bedtime, for a period of 30 days. 2.2) Intermediate visit

At the second appointment, the patient completes the second part of the result book. The patient takes two capsules each evening, approximately two hours before bedtime, for a further period of 30 days. 2.3) End-of-study visit

At the third appointment, the patient completes the third part of the result book. The experimental doctor collects all the result books for analysis. 3) Results

3.1) Inclusion visit analysis (OJ)

42 patients were included in the study. The average age of the subjects is 48 years, and the subjects participating in the study were mostly women (more than 80%). The inclusion criteria were met, namely healthy volunteers of both sexes, aged 16 at age 50, experiencing sleep disturbances and diminished alertness during the day.

The questionnaire was built in five parts and had to be completed by the doctor during the interrogation of the subject. The first item concerned insomnia problems, including difficulty falling asleep, difficulty staying asleep and waking up too early. All of these three questions were grouped together in subtotal called "quality of sleep". The second item was the degree of sleep satisfaction, the third was interference with sleep problems during the day (fatigue during the day, work capacity, management of daily tasks, concentration, memory, mood), the fourth to the influence of sleep problems on the quality of life and finally the fifth to the distressing and depressing nature of sleep problems. The questionnaire was consistent with the study protocol.

Of the 42 patients included in the OJ, 9 patients did not show up at the intermediate visit on day 30 and the end-of-study visit on day 60. These patients were excluded from the study, and it was from a total of 33 patients that the analysis of the results could be performed. There were no apparent reasons for leaving the study of these patients. Some patients contacted by telephone mentioned that the product was active and that they did not see the need to consult again.

At inclusion, the main results (Table 6a) indicate that the sum average of all items (19) is greater than the set limit (≥ 15) required to validate inclusion. Depending on the items, there are significant disparities between patients with relatively high variance scores. However, when measuring the sum of several items such as the items "difficulty falling asleep, staying asleep, waking up too early" (corresponding to the item "Quality of sleep "), the measure of variance is lower and translates a better homogeneity of patients (Table 6b)

Table 6a

Table 6b

Total Average Variance

Total 626 19.0 3.97

Quality of sleep 237 7.2 1.97

In general, the included patients mainly have difficulty staying asleep (average score of 2.5) and waking up problems too early (average score of 2.5). The value of these scores corresponds to a perception of the problem at moderate to severe intensity. The satisfaction of sleep is evaluated as clearly insufficient by the patients who notice the strong interference of the problems of sleep on their daily life, on their quality of life. The poor quality of sleep "angers and depresses" heavily these patients. 3.2) Intermediate visit analysis (J30) Tables 7a and 7b below show a strong improvement of all the items in the patients after one month of taking the HB1 product (see Figure 2). The average change in the total score of all the items is -38%, ie the overall average has improved and has changed from a value of 19 at OJ to a value of 11.8 at J30. This change places the overall score of the patient group below the limit value at inclusion (15). It clearly shows the improvement in sleep provided by the HBl product. More specifically, there are differences in improvements between the different criteria. The criterion that evolves most favorably is "the difficulty to stay asleep", a criterion that reflects the frequency and intensity of insomnia.

* Student test: period n / period n-1

Table 7b

* Student test: period n / period n-1

The other criteria are all less than or equal to 2, which means a rating at a level considered low or average compared to the different situations. As expected, all these variations are statistically significant (Student's test). 3.3) Analysis end-of-study visit (J60) Tables 8a and 8b below show a marked improvement on J60 compared to OJ, which confirms the values obtained on D30. This improvement shows a positive trend compared to J30, without the values being statistically significant except for the criterion "Interference of sleep problems on the quality of life" (Figure 3)

Student test: period n / period n-1

Table 8b

Student test: period n / period n-1 The interpretation of the data shows that the second month of treatment confirms the positive effects obtained during the first month. The effectiveness of HB1 is then enhanced and maintained.

Claims

1) Composition comprising as active agents polyunsaturated fatty acids and flavonoids.

2) Composition according to claim 1, characterized in that the polyunsaturated fatty acids are alpha-linolenic acid [C ₁₈ : 3n-3] and linoleic acid [C ₁₈ : 2n-6].

3) Composition according to one of claims 1 or 2, characterized in that the alpha-linolenic and linoleic acids are present in the composition in the form of vegetable oils rich in polyunsaturated fatty acids, such as hemp oil and lemon oil. 'Soya oil.

4) Composition according to one of claims 1 to 3, characterized in that the flavonoids are in the form of an extract of Humulus lupulus.

5) Composition according to any one of the preceding claims, characterized in that the amount of extract and oil in the composition is such that it allows a daily intake of: - Humulus lupulus (dry extract of powder cones hops): 20 to 1000 mg and preferably of the order of 100 mg;

. approximately 60 to 600 mg and preferably of the order of 160 mg of alpha-linolenic acid. 6) Composition according to any one of the preceding claims, characterized in that it comprises:

10 to 500 mg and preferably of the order of 50 mg of Humulus lupulus extract, and

- 200 to 1500 mg and preferably 433 mg of vegetable oil (s) rich (s) polyunsaturated fatty acids, including hemp and soybean oils, which corresponds to:

. approximately 150 to 1300 mg and preferably of the order of 370 mg of linoleic acid,

. approximately 30 to 300 mg and preferably of the order of 80 mg of alpha-linolenic acid.

7) Use of polyunsaturated fatty acids and flavonoids for the preparation of a pharmaceutical composition intended for the treatment and / or prevention of disorders caused by a disturbance of the biological clock, in particular dyssomnias, parasomnias and / or disorders sleep of psychiatric origin, neurological or related to other diseases, in humans and possibly in animals.

8) Use of an extract of Humulus lupulus and one or more vegetable oils rich in polyunsaturated fatty acids for the preparation of a pharmaceutical composition for treating or preventing disorders caused by a disturbance of the biological clock, in particularly dyssomnias, parasomnias and / or sleep disorders of psychiatric, neurological or other diseases, in humans and possibly in animals.

9) Use according to claim 7 or 8, characterized in that said disorders are selected from a difficulty of falling asleep, a poor quality of sleep, awakening difficult, significant fatigue during the day and as a result memory problems, difficulties of concentration and orientation in space.

10) Use according to any one of claims 7 to 9, characterized in that said composition comprises an amount of Humulus lupulus extract and one or more vegetable oil (s) rich in acids polyunsaturated fat able to provide a daily intake of:

Humulus lupulus: 20 to 1000 mg and preferably of the order of 100 mg;

Vegetable oil (s) rich in polyunsaturated fatty acids, in particular hemp and soybean oils: 400 to 3000 mg and preferably of the order of 866 mg, which corresponds to:

11) Use of a combination of polyunsaturated fatty acids and flavonoids as an agent for combating disorders caused by a disturbance of the biological clock, including sleep disorders, in particular dyssomnias, parasomnias and / or sleep disorders of psychiatric, neurological or other disease-related origin in a composition, or for the preparation of a composition for combating disorders caused by a disturbance of the biological clock, in particular dyssomnias, parasomnias and / or sleep disorders of psychiatric, neurological or other diseases.

12) Use of a combination of polyunsaturated fatty acids and flavonoids as a regulating the biological clock in a composition or for preparing a composition for regulating the biological clock.