WO2017153829A1

WO2017153829A1 - Saffron extract for treating sleep disorders

Info

Publication number: WO2017153829A1
Application number: PCT/IB2017/000121
Authority: WO
Inventors: Jacques D'ANTHENAISE; Estelle Enaud
Original assignee: Green Plants Extracts S.A.S.
Priority date: 2016-03-09
Filing date: 2017-02-16
Publication date: 2017-09-14
Also published as: FR3048615B1; FR3048615A1; EP3426277A1

Abstract

The invention relates to a saffron extract comprising crocins and crocetins, for use in the treatment of sleep disorders in humans. According to the invention, the saffron extract comprises at least 2% by weight of crocins relative to the total weight of dry matter of the extract.

Description

SAFRAN EXTRACT FOR THE TREATMENT OF THE DISORDERS OF

SLEEP

The present invention relates to a particular saffron extract for use in the treatment of sleep disorders in humans.

Sleep disorders, especially insomnia, are common pathologies that affect more and more people. In France, for example, about 30% of adults have frequent insomnia and 15% complain of chronic insomnia, with a higher prevalence among women.

Sleep disorders can have many origins, such as stress. Stressful life events often lead to ruminating at bedtime, which has been correlated with the perception of poor sleep, and depression and anxiety are seen as major causes of insomnia. .

In addition, reducing sleep time is a strong feature of our modern societies. Exposure to artificial lights such as telephones, laptops and televisions during the hours of darkness activates brain cells that promote wakefulness and suppresses the release of melatonin, the sleep hormone.

Certain medications, or the consumption of alcohol or caffeinated beverages also have a negative impact on sleepiness and quality of sleep.

Similarly, certain social habits that cause a shift in sleep schedules (exits, night work), jet lag, lack of physical activity are particularly unfavorable to falling asleep.

We know that sleep is a beneficial factor for health and mental balance. A full night of sleep allows the body to perform all the phases required for muscle repair, memory consolidation, the production of hormones regulating growth and appetite, while on the contrary, lack of sleep or poor sleep have negative effects on both health and mood.

The most obvious effects are observed on cognitive functions such as responsiveness, attention, alertness.

Creativity and innovation are also modes of reasoning particularly degraded by a debt of sleep.

The bad sleep also plays on the mood: irritability, anger, hostility. In addition, people who are lacking sleep feel less friendly, empathic and lose their ability to reap the emotional benefits of a positive experience.

Chronic insomnia is also considered a risk factor for anxiety and depressive disorders.

Regarding the immune system, chronic sleep deprivation induces chronic inflammation along with immunodeficiency with increased susceptibility to infection and reduced immune response to vaccination.

On the other hand, sleep participates in glucose homeostasis so that a reduction in the quality or quantity of sleep disturbs both glucose use and tolerance. Lack of sleep is associated with metabolic syndrome, type 2 diabetes, and an increased tendency to obesity. Increased blood pressure and cardiovascular risk are also long-term consequences of sleep deprivation.

Finally, sleep is a factor of beauty. The skin rehydrates during sleep making wrinkles and dark circles less visible. During the night there is cell and tissue repair, collagen is synthesized to restore elastic and resistant skin.

Given these findings, several products to fight against sleep disorders have been proposed. We can mention in particular substances of the barbiturate family, today abandoned because of too many serious side effects, or benzodiazepines. Naturally occurring products such as infusions or extracts of passionflower, hawthorn, valerian, chamomile, poppy, passionflower, hops, lemon balm or linden are also used for their sedative and anxiolytic properties.

All of these drug products and plant-derived actives act by binding to GABAA receptors. By positive allosteric effect, they increase the affinity of GABA receptors (GABA: gamma-aminobutyric acid) which is the main inhibitory neurotransmitter of the central nervous system. Thus, they increase the inhibitory activity of GABA making the nervous system less excitable and anxiolytic, sedative and myorelaxant effects are observed.

However, this mode of action causes side effects such as drowsiness (at unwanted moments), confusional states, falls ... but especially prolonged use leads to an addictive effect (the substance becomes less effective) , an addiction and a rebound effect (weaning is accompanied by a return of sleep disorders).

To overcome these disadvantages Aritake et al. [1] proposes to use a product of natural origin, namely: a saffron extract with an efficiency on both the quality of sleep and the time of falling asleep. According to [1], the saffron extract comprising crocins and crocetins is suitable for use in the treatment of sleep disorders. This extract helps to fight against all sleep disorders, including transient or chronic dyssomnias, transient or chronic parasomnias. It is particularly effective in the treatment of sleep disorders related to stress, anxiety, worries, jet lag or psychiatric or neurological origin. According to [1], administration of crocin or crocetin is by the oral route using a unit dose. The latter must be calculated according to the weight of a user which is bothersome and can be a source of undesirable errors. The present invention, which is based on this original observation, is primarily intended to provide a saffron extract comprising crocins and crocetins, for use in the treatment of sleep disorders in humans, aimed at least to reduce a previously mentioned limitation. For this purpose, said saffron extract comprises at least 2% of crocines by weight relative to the total weight of dry matter of the extract.

Thanks to this advantageous characteristic, it is possible to easily obtain a food supplement capsule comprising a daily dose with an adequate amount of extract.

Preferably, said saffron extract according to the invention can be used in the treatment of transient or chronic dyssomnias.

Advantageously, said saffron extract according to the invention can be used in the treatment of transient or chronic parasomnias.

Advantageously, said saffron extract according to the invention can be used in the treatment of sleep disorders related to stress, anxiety, preoccupation, jet lag or of psychiatric, neurological or other diseases.

Preferably, the saffron extract according to the invention comprises at least one compound chosen from picrocrocine, flavonoids, fibers and proteins.

Preferably, the saffron extract according to the invention has a crocetin / crocin ratio of less than 1/10.

Preferably, the saffron extract according to the invention is present as an extract of stigmas of category 1 saffron.

Preferably, the saffron extract according to the invention is obtained by hydroalcoholic extraction.

Preferably, the saffron extract according to the invention is obtained by a process comprising the implementation of the following steps: • multiple hydroalcoholic extraction,

• filtration and evaporation until complete elimination of alcohol,

• possibly drying on a suitable support.

In a variant of the invention, said saffron extract may be used in a composition.

In this variant, said saffron extract according to the invention can be used in aqueous form or in dry form, the composition comprising a suitable food carrier.

Preferably, this food carrier is chosen from: gum arabic, silica, maltodextrin, titanium dioxide, starch, lactose, glucose microcrystalline cellulose, salt or a mixture.

Preferably, said saffron extract according to the invention represents at least 0.1% by weight relative to the total weight of the composition.

Advantageously, said saffron extract according to the invention may also represent at least 1% by weight relative to the total weight of the composition.

Preferably, said composition is in liquid, pasty or solid form.

Other characteristics and advantages of the invention will emerge clearly from the description which is given hereinafter, by way of indication and in no way limitative, with reference to the appended drawings, in which:

FIG. 1 represents graphical representations of the results of a double-blind placebo-controlled clinical study carried out with the extract according to the invention, for the quality of the sleep, the time of falling asleep and the restful sleep,

• Figure 2 represents graphical representations of the results of a self-evaluation questionnaire of a double-blind clinical study against placebo performed with the extract according to the invention, for the quality of sleep, relaxation and memory.

The invention therefore relates to an extract of Saffron comprising crocins and crocetins, for use in the treatment of sleep disorders in humans.

Crocetin is a carotenoid diacid carboxylic acid that exists in free form (crocetin) or as a glycoside ester (crocin). This family of molecules is responsible for the garnet color of saffron and especially many biological properties such as beneficial actions on o lipid metabolism, atherosclerosis, insulin resistance, reduction of oxidative stress, reduction the lack effect (addiction).

By Saffron extract is meant any part of the plant or any molecule or mixture of molecules extracted from all or part of the plant. Preferentially, the extract is derived from whole or reduced Saffron stigmas in powder form, more preferably Stigma stigmas of category 1 with the highest crocin and crocetins content. The stigmas are preferably dried stigmas in order to protect them from mold and other bacteriological contamination which would affect the edibility of the product as well as its crocin / crocetins content.

According to the invention, the Saffron extract comprises at least 2% of crocines by weight relative to the total weight of solids, in particular between 2 and 50%, more preferably between 10 and 15%. Indeed, this concentration makes it possible to obtain the daily dose with a quantity of extract that is adequate to be formulated in a capsule of dietary supplement. Preferably, the extract has a crocetin / crocin ratio of less than 1/5 and even more preferably less than 1/10. Such a ratio makes it possible to ensure that the crocins are stable in the extract and that they have not undergone hydrolysis during extraction.

The Safran extract may also comprise other constituents. Preferably, the Safran extract also comprises at least one compound selected from picrocrocine, flavonoids, fibers, proteins. It may also contain other organic molecules. These constituents together improve the effect of the extract because there is a synergy between these different constituents. The use of the totum is therefore preferred.

According to a suitable embodiment, the extract of Safran, measured by UV spectrophotometric analysis, has a minimum extinction coefficient: E ^1% = 5 for the wavelength of 440 nm and preferably E ^1% 3oonm> 13. Such an extract is particularly effective in the context of the invention.

The saffron extract according to the invention can be obtained by any suitable method. Preferably, it is obtained by hydroalcoholic extraction, in particular by a process comprising the implementation of the following steps:

Multiple hydroalcoholic extraction, with a solvent preferably containing 20 to 80% alcohol (by volume); the extraction lasts preferably 30min to 4h and may be repeated 1 to 5 times;

• filtration and evaporation under vacuum until complete elimination of alcohol.

Various types of filtrations can be used: by gravity, by overpressure, or under vacuum. The filter is preferably made of a compatible material for food contact. The evaporation under vacuum is preferably carried out at a moderate temperature (30 to 50 ° C) under reduced pressure (100 to 300 mbar).

Optionally, the drying on a suitable foodstuff can be carried out by atomization, lyophilization, steaming or fluidized bed.

The Safran extract according to the invention may be in aqueous (liquid) or dry (solid) form. It can be used alone or in a composition. By composition within the meaning of the invention is meant a mixture of Safran extract according to the invention with at least one other constituent. The composition may especially be a composition comprising a suitable food carrier. For foodstuff within the meaning of the invention is meant the substances used to dissolve, dilute, disperse the saffron extract without affecting the quality in order to facilitate its handling, its application, its dosage or its use. The food carrier is preferably chosen from: gum arabic, silica, maltodextrin, titanium dioxide, starch, lactose, microcrystalline cellulose, glucose, salt or a mixture of at least two of these elements .

The composition may contain other elements such as:

Dyes, essential oils, flavors or any other additive known to those skilled in the food industry,

• other plant extracts, vitamins and minerals, or other active substances acting on sleep, relaxation.

The composition comprising the extract of Safran according to the invention may be in liquid form (for example syrup, emulsion, oral solution), pasty (for example cream or gel) or solid (for example powder, cachet, tablet, dragee or capsule).

Preferably, the saffron extract according to the invention represents at least 0.1% by weight relative to the total weight of the composition, still more preferably at least 1% by weight relative to the total weight of the composition.

The Safran extract according to the invention can be used alone or with other active ingredients such as, for example, pharmaceutical active ingredients, rhodiola extracts, vitamin B6 or magnesium. These active ingredients can be introduced into a composition containing Safran extract or administered separately.

The Safran extract according to the invention, alone or in a composition, is useful in the treatment of sleep disorders in humans, in particular: • in the treatment of transient or chronic dyssomnias

• in the treatment of transient or chronic parasomnias.

Indeed, the use of the extract of saffron according to the invention makes it possible to reduce the time necessary for falling asleep, reduces nocturnal awakenings 5 and thus leads to an awakening in shape

The Safran extract according to the invention is particularly useful in the treatment of sleep disorders related to stress, anxiety, anxiety, jet lag, psychiatric, neurological or other diseases.

To effectively fight against sleep disorders, the extract according to the invention is preferably used in a composition for daily administration of 0.5 mg to 100 mg of Saffron extract.

The invention is now illustrated by non-limiting examples of active principle and composition according to the invention as well as by the results of a randomized double-blind placebo-controlled clinical trial.

Example 1 Saffron Extract on a Liquid Base

An example of Safran extract on a liquid base particularly adapted according to the invention is an extract obtained by a process implementing the following steps:

0 · stigmas of Safran, 10 kg, of category 1 according to the standard ISO 3632 (E ^1% 257 nm = 79, E ^1% 33o nm = 37, E ^1% 44o nm = 204) are infused in a mixture ethanol / water (30/70, v / v) for 24 h at 45 ° C,

The liquid phase is recovered by filtration and then the volume of the filtrate is reduced by evaporation under vacuum (50 ° C., 200 mbar).

The resulting extract is composed of 5.8 kg of dry matter, including 606 g of crocin as determined by spectrophotometric analysis according to ISO 3632. Example 2 Saffron Extract on a Liquid Base

A second example of saffron extract on a liquid base particularly adapted according to the invention is an extract obtained by a process implementing the following steps: · stigmas of Safran, 16 kg, category 1 according to the ISO 3632 standard (E ^1% 25 nm ₀ = 77; 33o nm E ^1% = 34; E ^1% 440 nm = 204) are infused into a ethanol / water mixture (80/20; v / v) for 15 h at 45 ° C,

The resulting extract is composed of 9 kg of dry matter including 968 g of crocin as determined by HPLC analysis.

Example 3 Saffron Extract on a Solid Base

An example of Safran extract on a solid base particularly adapted according to the invention is an extract obtained by a method implementing the following steps:

• Safflowers of Safran, 16 kg, category 1 according to ISO 3632 (E ^1% 25o nm = 77, E ^1% 33 ₀ nm = 34, E ^1% 44o nm = 204) are infused in an ethanol / water (80/20, v / v) for 15h at 45 ° C,

The extract is then spray-dried in the presence of maltodextrins acting as a carrier for easy manipulation and dosage of the plant extract. The extract produced contains 2.5% crocins, with a relative humidity of 2.7%.

Example 4 Safran Extract on a Solid Base

A second example of Saffron extract on a solid base particularly adapted according to the invention is an extract obtained by a method implementing the following steps: • stigma of Safran, 16 kg, category 1 according to the ISO 3632 standard (E ^1% 25o nm = 77, E ^1% 33o nm = 34, E ^1% ₄₄₀ nm = 204) are infused in an ethanol / water mixture (20/80, v / v) for 14 h at 45 ° C,

The liquid phase is recovered by filtration and then the volume of the filtrate is reduced by evaporation under vacuum (50 ° C., 200mbar).

The extract is then dried by lyophilization in the presence of maltodextrins. The extract produced contains 10.65% Crocin as determined by HPLC analysis.

Example 5 Composition Comprising Saffron Extract in Liquid Form

An exemplary composition for a "shot" type drink comprising a Safran extract particularly adapted according to the invention is a composition in liquid form comprising the following constituents:

· 30 μl of liquid saffron obtained as in example 2,

• 150 ml of mango juice.

Example 6 Composition Comprising a Saffron Extract in Capsule Form

An example of a composition comprising a Safran extract that is particularly suitable according to the invention is a solid-form composition in the form of capsules comprising the following constituents:

Constituents Quantity

Magnesium 317 mg

Stigma extract of 30 mg

saffron of example 3

600 pg

Of which crocin

Vitamin B6 1, 4 mg

Zinc 10 mg

Melatonin 1 mg

Vitamin B9 200 pg

Vitamin B12 2.5 pg

Example 7 Composition Comprising an Saffron Extract in the Form of a Tablet

An example of a composition in tablet form comprising a Safran extract particularly adapted according to the invention is a composition in the form of capsules comprising the following constituents:

30 mg of the extract obtained as in Example 3,

• 220 mg of carboxymethylcellulose as a filler,

• in a hydroxypropylcellulose tunic.

Clinical study demonstrating the effectiveness of the extract according to the invention

A randomized, double-blind, placebo-controlled clinical trial was conducted. Subjects took the extract from Example 3, in the composition (tablet of Example 7) or placebo once a day for 6 weeks.

The volunteers (15 for the placebo, 15 for the extract according to the invention) included in the study are subjects under moderate stress for more than one month.

Efficacy was assessed using two types of questionnaires: • An assessment questionnaire that includes 25 questions on aspects of cognition, depression, anxiety, somatization, eating behaviors and sleep. These questions are noted and the average scores of the score were compared by t-test, a self-assessment questionnaire that includes 9 questions whose answer consists in placing a cursor on a line of ten centimeters. The cursor position is measured and the average positions are compared using a t-test.

The results of the study show a very good efficacy on the treatment of sleep disorders, namely:

• an improvement in sleep quality and a reduction in the perceived time required for falling asleep were quickly observed,

• Subjects also gradually felt less tired when they woke up (Figure 1). The overall score for these three aspects of the questionnaire

The assessment group increased for all participants in the group treated according to the invention.

The beneficial effects of the extract according to the invention on sleep are confirmed by the self-evaluation questionnaire (FIG. 2). These benefits are seen from the first week of treatment and are significant from day 21.

Finally, the memory of the subjects of the group treated according to the invention is better than that of the placebo group (FIG. 2). A slight improvement of the cognitive aspects was also observed by the evaluation questionnaire (average evolution of the cognition score after 6 weeks: -0.40 for 25 placebo, 0.73 for the extract according to the invention, p = 0.1 17) .

The saffron extracts according to the invention thus show a remarkable effect on sleep.

While pharmaceutical anxiolytics and sleeping pills have side effects such as vertigo, locomotor and cognitive disorders, the extract according to the invention is well tolerated and shows no adverse effect. In contrast, compared to placebo, the extract according to the invention tends to improve cognitive functions.

The subjects of the group treated with the extract according to the invention were satisfied with the product for 73% of them against 6% for the placebo.

Bibliography

1. K. Aritake, N. Ito, Y. Shoyama, Y. Urade "Crocin, a Carotenoid Pigment of Saffron, Promoted Non-Rapid Eye Movement Sleep," Sleep Medicine, vol. 16, 2015, XP029353129, ISSN: 1389-945, DOI:

10.1016 / J.SLEEP.2015.02.1406

Claims

claims

1. Saffron extract comprising crocins and crocetins, for use in the treatment of sleep disorders in humans, characterized in that it comprises at least 2% of crocines by weight relative to the total weight of materials dry extract.

Saffron extract for use according to claim 1 in the treatment of transient or chronic dyssomnias.

Saffron extract for use according to claim 1 in the treatment of transient or chronic parasomnias.

4. Saffron extract for use according to claim 1, in the treatment of sleep disorders related to stress, anxiety, anxiety, jet lag or of psychiatric, neurological or other diseases.

5. Saffron extract for use according to any one of claims 1 to 4, characterized in that it also comprises at least one compound selected from picrocrocine, flavonoids, fibers, proteins.

6. Saffron extract for use according to any one of claims 1 to 5, characterized in that it has a crocetin / crocin ratio less than 1/10.

7. Saffron extract for use according to any one of claims 1 to 6, characterized in that it is an extract of stigma stigma category 1.

8. Saffron extract for use according to any one of claims 1 to 7, characterized in that it is obtained by hydroalcoholic extraction.

9. Saffron extract for use according to any one of claims 1 to 8, characterized in that it is obtained by a process comprising the implementation of the following steps: • multiple hydroalcoholic extraction,

• filtration and evaporation until complete elimination of alcohol,

• possibly drying on a suitable support.

Saffron extract for use according to any one of claims 1 to 9 in a composition.

1. Saffron extract for use according to claim 10, in aqueous form or in dry form, the composition comprising a suitable food carrier.

12. Saffron extract for use according to claim 11, characterized in that the food carrier is chosen from: gum arabic, silica, maltodextrin, titanium dioxide, starch, lactose, microcrystalline cellulose of glucose, salt or a mixture.

13. Saffron extract for use according to any one of claims 10 to 12, characterized in that it represents at least 0.1% by weight relative to the total weight of the composition.

14. Saffron extract for use according to any one of claims 10 to 13, characterized in that it represents at least 1% by weight relative to the total weight of the composition.

15. Saffron extract for use according to one of claims 10 to 14, characterized in that the composition is in liquid, pasty or solid form.