WO2017036488A1

WO2017036488A1 - Combination product for assisting with relaxation and sleep

Info

Publication number: WO2017036488A1
Application number: PCT/EP2015/001785
Authority: WO
Inventors: Marilyn GELTILHOMME; Tiphaine BRICOUT
Original assignee: Urgo Recherche Innovation Et Developpement; Hcp Healthcare Asia Pte. Ltd.
Priority date: 2015-09-04
Filing date: 2015-09-04
Publication date: 2017-03-09
Also published as: EP3349765A1; WO2017036488A8; FR3040628A1

Abstract

The invention relates to a combination product comprising, as active substances, at least lemon balm, linden, chamomile and magnesium or a bioequivalent compound thereof to assist with relaxation and/or sleep. The invention also relates to the use of such a combination product for the treatment of somnipathies.

Description

Combination product to help with relaxation and falling asleep

TECHNICAL AREA

The subject of the present invention is a combination product comprising, as active substances, at least lemon balm, linden, chamomile and magnesium, or a bioequivalent compound thereof, to aid relaxation and / or sleep. The invention finally relates to the use of a combination product as previously defined for the treatment of somnipathies.

BACKGROUND A sleep disorder (somnipathy) is a disorder related to the sleep habits of an individual. Some sleep disorders are serious enough to interfere with physical, mental and emotional functioning. A test commonly used for sleep disorders is polysomnography.

Sleep dysfunction can be caused by a variety of problems, from grinding of teeth (bruxism) to night terrors. When an individual has difficulty falling asleep without apparent cause, it is insomnia. In addition, sleep disorders can lead the individual to sleep enormously, a situation known as hypersomnia. Other conditions of the sleep disorder may be related to substantial abuse. Sleep disorders include:

- primary insomnia - chronic difficulty falling asleep and / or maintaining sleep when no other symptomatic cause can be perceived;

- bruxism, creaking or involuntary clanging of the teeth during sleep;

-Sleep phase delay syndrome, inability to fall asleep or to wake up for socially acceptable hours but not causing any problems in sleep maintenance, circadian rhythm disorder (similar symptom - hypernycthemeral syndrome);

hypopnoea, respiratory or cardiac abnormality during sleep; -narcolepsy, sudden sleep often spontaneous at any time of the day;

cataplexy, sudden weakness of the motor muscles that may result in a fall on the ground;

- nocturnal terror, pavor nocturnus, nocturnal disorder characterized by strong fear and anxiety;

sleepwalking, an activity that is physically and unconsciously engaged during sleep; Somniphobia, afraid to sleep; sleep apnea

Following the evolution of knowledge about sleep in the twentieth century, including the discovery of hypnology and sleep apnea, the medical importance of sleep is recognized. The clinical community is taking a closer look at sleep disorders, such as sleep apnea, and the role and quality of sleep under different conditions. During the 1970s in the United States, clinics and laboratories devoted themselves to the study of sleep accompanied by its troubles.

The impact of sleep disorders on the lives of individuals can be very important: a study in 2014 found that sleep perceived as being of poor quality is associated with an increased risk of suicide in the elderly ( mean age in the study, 74.9 years plus or minus 5.6 years).

Sleep medicine is now adapted in internal medicine, family medicine, pediatrics, otolaryngology, psychiatry and neurology.

The present invention relates to a composition for assisting relaxation and sleep, particularly in children.

Indeed, a study published in Paediatrica (vol 14 no. 3 2003) takes stock of children's sleep disorders. Up to 25% of small children and almost 50% of school-aged children have sleep disorders that have lasted for at least 6 months. The prevalence is 33% for adolescents. Hedger Archbold et al. have differentiated these disorders. Some sleep disorders are more common at a certain age and related to particular situations, others may occur at any age (for example: sleep apnea syndrome, sleep-related epilepsies. Sleep is not just a problem for parents. Disrupted sleep also involves risks for the cognitive development of the child with the occurrence of behavioral disorders. As with adults, there appears to be an association between obstructive sleep apnea and a higher prevalence of metabolic syndrome in children and adolescents.

The duration and organization of sleep are subject to changes during development. Basic knowledge helps distinguish true sleep disorders from variations in the norm. As an indication the approximate values of sleep duration in 24 hours are: 16 hours for the newborn term, 13 hours for the child of 2 years, 11 hours to 5 years, 10 hours to 9 years and about 9 hours for a 14 year old. Young adults still need about 8 hours, a fact often forgotten. The variability of these values is quite important and corresponds to the distribution of genetic traits in the population. Individual sleep needs are more easily established during weekends and holidays when the body is allowed to sleep for as long as needed.

During the night, three states are observed: wakefulness, REM sleep (rapid eye movement sleep) and non-REM sleep (slow sleep). A sleep cycle includes a passage through the three states. In deep sleep can come different parasomnias (non-REM parasomnias): for example nocturnal terrors of small children, which are replaced by somnambulism at the bigger child. Since sleep cycles with deep phases occur in the first half of the night, it is usual to observe these parasomnias during the first hours after falling asleep.

There are a number of products on the market to overcome the problems of falling asleep or relaxation. Among these products, mention may be made, for example, of Passiflora, a homeopathic preparation of Boiron which contains: Passiflora incarnata, Ignatia amara, Coffea cruda, Nyckterinia, Tellurium metallicum, Phosphoricum acidum, Palladium metallicum, Magnesium metallicum. Quietness, which is also a homeopathic preparation of Boiron, which contains: Chamomilla vulgaris, Gelsemium, Hyoscyamus niger, Kalium bromatum, Passiflora incarnata, Stramonium. The product Pédiakid Sleep of Ineldea is based on magnesium, manganese, phosphorus, orange blossom extract, lavender extract, chamomile extract, melissa extract, extract of marjoram, hawthorn extract. The product Pédiakid Nervesse d'Ineldea contains hydroglycerinated extracts of plants (hops, lemon balm, orange blossom, passionflower, gentian), magnesium, vitamin B6, and phosphate. Euphytocalm from Bayer contains a dry extract of lemon balm and magnesium. None of the products proposed contains the association object of the present invention.

These products, although containing lemon balm or chamomile and / or magnesium, do not provide complete satisfaction in terms of appeasement, relaxation and / or help with falling asleep. In addition, the taste and galenic are not necessarily suitable for children. In particular, chamomile, has a bitter taste that is not appreciated by all individuals.

The combination product of the present invention provides a soothing effect to facilitate falling asleep, especially for children, and help them to naturally recover a restful sleep, without nocturnal awakening. The product of the present invention has a good taste. It has no side effects or addiction. The combination product of the present invention helps to help you fall asleep, soothes, relaxes and helps maintain a healthy sleep. It also contributes to the proper functioning of the nervous system.

The product according to the present invention also has the advantage of preferably containing no artificial dyes, allergens and preferably being lactose or gluten-free. The product of the present invention has a galenic adapted to the child, preferably in the form of a syrup.

SUMMARY OF THE INVENTION

The present invention relates to a combination product comprising as active substances at least: (i) melissa,

(ii) linden tree,

(iii) chamomile, and

(iv) magnesium or a bioequivalent compound of lemon balm, linden, chamomile and / or magnesium to aid relaxation and / or sleep.

The present invention also relates to a combination product comprising as active substances at least: (i) melissa,

(ii) linden tree,

(iii) chamomile, and

(iv) magnesium or a bioequivalent compound of lemon balm, linden, chamomile and / or magnesium for use in the treatment of somnipathies.

In certain embodiments, the combination product according to the invention comprises, in addition to lemon balm, linden, chamomile and / or magnesium, as active substances:

(i) Plants or extracts of plants, such as, for example, orange blossom, lavender, hawthorn, marjoram, hops, gentian, valerian, passionflower and / or rhodiola,

(ii) Vitamins and minerals, such as for example vitamin D, vitamins of group B, such as vitamin B6 and / or calcium

In some embodiments, the combination product of the invention is characterized in that lemon balm, linden and chamomile are in the form of plant extracts and are administered in a daily dose of 0.5 to 5 g. per day, preferably 1 to 3 g / day of melissa of 50 to 500 mg / day, preferably 50 to 200 mg / day of linden of 10 to 200 mg / day, preferably 20 to 80 mg / day of chamomile. Embodiments, the combination product of the invention is characterized in that the magnesium is administered at a daily dose of 10 to 200 mg / day, preferably 20 to 80 mg / day. In some embodiments of the invention, the combination product according to the invention may be in the form of a single (or combined) composition containing at least as active substances:

(i) lemon balm, (ii) linden tree,

(iii) chamomile, and

(iv) magnesium in a physiologically acceptable medium.

According to a particular embodiment of the invention, the combination product is characterized in that the active ingredients (i), (ii), (iii), (iv) or a bioequivalent compound thereof are in a medium adapted to oral administration. Preferably, the suitable medium is a liquid medium. Preferably, the combination product is a syrup or capsule containing said syrup.

When used for the therapeutic treatment of sleep disorders, the combination product according to the present invention is especially intended for children.

Melissa, linden and chamomile may be present as ingredients (i), (ii) or (iii) in a combination product of the invention in more or less purified form, in particular in the form of a plant extract. .

Magnesium may be present as an ingredient (iv) in a combination product of the invention in more or less purified form. It may also be in free form or in the form of derivatives. The acceptable magnesium derivatives according to the invention include in particular the complexed, protected forms or salts.

The various embodiments of the invention are particularly described in the detailed description below. These embodiments may be taken separately or in combination with each other. DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the applicant has demonstrated that the combination of at least (i) lemon balm, (ii) linden, (iii) chamomile and (iv) magnesium, has a synergistic effect to help According to the present invention, the synergistic effect is understood to mean that the combination of at least (i) lemon balm, (ii) linden, (iii) chamomile and (iv) magnesium has an effect on the aid for relaxation and / or sleep, during treatment which is superior to the cumulative effects of a treatment (a) comprising the administration of lemon balm, not associated with linden, to chamomile and magnesium, and conversely a treatment (b) including the administration of lime, not associated with lemon balm, chamomile and magnesium or a treatment (c) including the administration of chamomile, not associated with lemon balm, lime blossom or magnesium or a treatment (d) magnesium, not associated with lemon balm, chamomile and linden.

Melissa Melissa or Melissa officinalis (Melissa offcinalis) is a perennial herb of the Lamiaceae family. Its name comes from the Greek melissophullon which means "bee leaf". It is also known as lemon balm or simply lemongrass, not to be confused with lemongrass (Cymbopogon citratus) used in Asian cooking. It is a plant native to the eastern Mediterranean basin, which has spread throughout Europe since ancient times. Lemon balm, or lemongrass balm, has been cultivated in gardens since ancient times. Originally from Europe, it was introduced in North America. The stems and leaves are still used as a tonic and mild stimulant. The taste is astringent and the aroma is light. The alcohol is obtained by distillation of its fresh leaves: melissa water has antispasmodic properties. Lemon balm can also be consumed as herbal teas.

Melissa is most often used for its soothing and relaxing virtues. In fact, it regulates nerve impulses, which has a beneficial effect on tachycardia, but also reduces spasms of the stomach and colon (it also has antifungal properties). In infusion, lemon balm has a slightly sedative effect, and further promotes sweating, so it is recommended in cases of insomnia, or hot weather in infants and the elderly. The linden

The lime tree is a wild and ornamental tree whose fragrant flowers and bracts are used in soothing and calming infusions. The common linden flowers contain mucilage, essential oils (38%, including farnesol) tannins, glucosides, gums, sugars, manganese and vitamin C. In mother tincture as infusion, they are recommended in many cases of nervous disorders (fatigue, anxiety attacks, neurasthenia), migraines, influenza, and insomnia. These flowers are antidepressants, euphoria and sedatives. They would also be antispasmodic, diaphoretic and make the blood more fluid and promote circulation.

Chamomile or Matricaria recutita

Wild Chamomile, Chamomile Chamomile, Chamomile, (Matricaria recutita) is an annual herbaceous plant of the family Asteraceae and genus Matricaria. It is sometimes called German Chamomile or True Chamomile or Truncated Matricaria.

It is a medicinal plant used since ancient Greek-Latin, simply called "chamomile" in herbalism.

Matricaria recutita differs from the other two medicinal chamomiles in that it is an annual plant, consisting of a single upright erect stem. A number of chamomile chamomile activities have been demonstrated by in vitro and in vivo studies:

-Anti-inflammatory: this property can be attributed to chamazulene, its precursor matricin, (-) - a-bisabolol and its oxide. Good anti-inflammatory activity has been clearly established on rat paw induced edema, induced arthritis and radio-induced erythema26. (-) - a-bisabolol is resistant to gastric ulceration induced by various agents (ethanol, stress, indomethacin, in rats, orally). A wound on the rat's tongue treated with a chamomile ointment heals faster (because it promotes epithelialization with a higher percentage of collagen fibers). -Spasmolytic: the hydro-alcoholic extract of the flowers is spasmolytic. This activity could be due to apigenol which is more active than papaverine on isolated guinea pig ileum

-Antibacterial, antifungal: the essential oil of feverfew Chamomile is weakly antibacterial and antifungal. It stimulates biliary secretion in cats and dogs. -Sedative: observations in humans have reported a sedative action of Chamomile chamomile.

The chamomile feverfew is used as the Roman chamomile: it is known as tonic, stomachic, antispasmodic and analgesic.

Magnesium Magnesium is an alkaline earth metal. The recommended daily intake is estimated at 300 mg of magnesium a day (double for athletes or pregnant women) or 6 mg per kg of body weight.

The body does not produce magnesium and must draw it from the diet. Excessive consumption of magnesium is eliminated in the urine, magnesium does not accumulate.

Some disorders may be due to a lack of magnesium: depression, anxiety, diabetes, muscle spasms, cramps, cardiovascular disorders, high blood pressure, insomnia and osteoporosis.

Magnesium, in the form of hydrate, hydrated oxide, carbonate (MgCOs), chloride (MgCl ₂ ), is used in medicine.

Magnesium is used for the formation of bones and teeth, with calcium and phosphorus, promotes the fixation of calcium on the bone, an action on growth, the transmission of nerve impulses, promotes brain plasticity and avoids memory decline, muscle contraction, heart rate, contributes to the immune defense mechanisms, fight against stress, sedative effect (muscle relaxant), high concentration, fight against constipation by osmotic action and local motor stimulation, fight against oxalic calcium lithiasis, antiallergic, anti-inflammatory, platelet antiaggregant (protective role against thromboses), protective radio, thermal regulator, catalysis of numerous metabolic reactions (enzymatic catalysis, glycogen and protein synthesis, phosphate transfer, etc.).

Physiologically acceptable medium A physiologically acceptable medium is a medium having no toxic or detrimental effect under the conditions of use and inert with respect to the active ingredients of the combination product. Such a medium may for example comprise different adjuvants according to its therapeutic or cosmetic purpose, such as, but not limited to, flavors, dyes, fillers, preservatives, diluents, wetting or suspending agents, etc. Such media may also allow immediate, modified or delayed release of either active ingredient.

The physiologically acceptable medium may be water, mash and / or fruit juice, texturizers, emulsifiers, colorants, preservatives, flavorings, sugar or sugars. By "mash and / or fruit juice" is meant a more or less liquid preparation, in particular according to the nature of the fruit and / or the fineness of the grinding, prepared by grinding, pressing or other extraction process of one or several fruits and optionally the concentration of the ground material obtained and / or separation (in particular filtration) of the seeds, achenes and / or all or part of the pulp, and / or flash pasteurisation. The fruits can be chosen from: apple, banana, strawberry, peach, raspberry, blackberry, mango, kiwi, blueberry, blackcurrant, currant, orange, cherry, fig, pear, apricot, coconut, passion fruit, guava, papaya, melon, lychee, pineapple, lemon, mandarin, mirabelle plum, grapefruit, grape, rhubarb and their mixtures, without this list being exhaustive. "Texturizers" means compounds that modify the texture of the products in which they are incorporated. Examples of texturants are: guar and carob flour; gum arabic, xanthan and gellan; carrageenans; starches (native or modified); microcrystalline cellulose; gelatin; pectin; alginates (E400 to E405); agar-agar; and their mixtures. By "emulsifiers" is meant amphiphilic compounds characterized by their HLB value (Hydrophilic Lipophilic Balance), in particular capable of stabilizing oil-in-water emulsions (particularly advantageous if it is desired to add, for example, liposoluble active agents such as fat-soluble vitamins.) Examples of food emulsifiers are lecithin and its derivatives present in particular. in egg yolk, mono- and diglycerides of fatty acids, and polysorbate 80.

By "dyes" is meant compounds of natural or synthetic origin capable of conferring on their own a coloration to the composition. Examples of food colorants are known in Europe under the codes El 00 to El 80.

By "preservatives" is meant compounds inhibiting the proliferation of microorganisms, in particular yeasts and / or molds and / or bacteria, in particular Staphylococcus aureus, in the composition. Examples of food preservatives are sorbic acid and its salts (E200 to E203: benzoic acid and its salts (E210 to E219), sulfites and derivatives (E220 to E228), natamycin, nisin, and mixtures thereof Preferably, the composition according to the invention does not comprise any preservative. "Aromas" means compounds of natural or synthetic origin which alone are capable of modifying the taste of the composition. apricot, pineapple, banana, blackcurrant, cherry, lemon, lime, strawberry, raspberry, passion fruit, mandarin, mint, orange, pistachio, pear, licorice, rose, anise, bilberry, cinnamon, ginger, grapefruit, apple, kiwi, lychee, melon, coconut, peach, currant, guava, grenadine, mango, blackberry, papaya, vanillin, natural vanilla extract, essential oils and their mixtures.

Preferably the flavor used in the present invention is the vanilla aroma combined with the banana flavor. For the purposes of the present invention, sugar or sugar is understood to mean any sweetening carbohydrate, preferably glucose syrup, sucrose, glucose, fructose, invert sugar, honey, maltose, or mixtures thereof. In the context of the present invention, the sugars used are a mixture of glucose syrup, sucrose and honey.

Additional asset (s) Any additional active ingredient of nutritional interest and / or aiding in relaxation or asleep may also be added to the combination products of the invention in pharmaceutical or cosmetic form. The combination product may include, by way of example, vitamins, mineral salts, essential amino acids, essential fatty acids, trace elements, various plant extracts, fibers, antioxidants, flavonoids.

Advantageously, such additional asset may be intended to enhance the desired effect as described above.

Of course, those skilled in the art will take care to choose the additional assets and their amount so that the advantageous properties of the composition according to the invention are not, or not substantially impaired by the addition envisaged.

As additional assets that can be used, mention may be made of:

- water-soluble vitamins and fat-soluble vitamins. Examples of water-soluble vitamins present in the syrupy product prepared according to the invention are in particular: vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid) also called vitamin PP (preventive pellagra), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B8 or H (biotin), vitamin B9 (folic acid), vitamin B12 (cobalamin) and vitamin C (ascorbic acid). Examples of liposoluble vitamins present in the syrupy product prepared according to the invention are in particular: vitamin A (retinol), vitamin D3 (cholecalciferol), vitamin E (mixture of tocopherols and tocotrienols) and vitamin K (phylloquinone) .

antioxidants, such as curcuminoids; carotenoids, especially chosen from beta. -carotene, astaxanthin, zeaxanthin, lutein or compounds containing it such as goji berries; polyphenol compounds, flavonoids such as catechins; proanthocyanidins, anthocyanins, OPCs (procyanidolic oligomers); ubiquinones; coffee extracts containing polyphenols and / or diterpenes; chicory extracts; ginkgo biloba extracts; grape extracts rich in proanthocyanidins; chili extracts; soy extracts; Cocoa ; the grenade ; the Emblica; CoenzymeQ10; selenium, - minerals, such as zinc, calcium, copper, iron, iodine, manganese, selenium, chromium (III), amino acids, especially sulfur-containing amino acids, such as glutathione precursors, the amino acids of selenium, citrulline,

phytosterols, resveratrol, hesperidin, neohesperidin, orthosilicic acid, monomethylsilanetriol, and mixtures thereof. In a particularly advantageous embodiment of the invention, the combination of active ingredients comprises, as additional active ingredient, a fat-soluble vitamin, in particular vitamin D3, minerals such as potassium.

Preferably, a combination product according to the invention is administered orally. Suitable forms for the oral route are, for example, tablets, capsules, lozenges, powders, granules, lyophilisates, oral solutes and syrups. Tablets, powders, granules, lyophilisates, oral solutes and syrups constitute the pharmaceutical or cosmetic form suitable for the currently preferred oral route. In the case of the preparation of a solid composition in the form of tablets, it is possible for example to mix the main active ingredients (i), (ii), (iii) or (iv) with a physiologically acceptable vehicle such as gelatin, starch, magnesium stearate, talc, gum arabic or analogies. The tablets may be varied in nature, immediate release, controlled or delayed and optionally in effervescent or orodispersible form. A capsule preparation is obtained by mixing the active ingredient (i), (ii), (iii) or (iv) with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

Example of composition according to the invention

Percent Compound (%)

Melissa (dry extract of leaf) 2.479

Linden (dry extract of inflorescence) 0.826

Chamomile (dry extract of flower) 0.413

Water 28.650

Potassium sorbate 0.029

Sodium Benzoate 0.029

Citric acid 0.172

Liquid extract 28.879

Glucose syrup 18.182

Sucrose 13,636

Banana puree 9.091

Honey of flowers 4.545

Vitamin D3 0.011

Potassium sorbate 0.066

Sodium benzoate 0.066

Citric acid monohydrate 1.224

Vanilla flavor 0.457

Banana flavor 0.457

Magnesium Glycerophosphate 4.263

Acacia xanthan gum 0.545

QSP 100 purified water

Claims

1. Combination product comprising as active substances at least:

i. melissa,

ii. linden tree,

iii. chamomile, and

iv. magnesium

or a bioequivalent compound of lemon balm, lime blossom or chamomile to aid relaxation and / or sleep.

Combination product according to Claim 1, characterized in that the active substances consist of:

i. from 0.5 to 5 g / day, preferably 1 to 3 g / day of melissa ii. from 50 to 500 mg / day, preferably from 50 to 200 mg / day of linden iii, from 10 to 200 mg / day, preferably from 20 to 80 mg / day of iv camomile. 10 to 200 mg / day, preferably 20 to 80 mg / day of magnesium

3. Combination product according to one of claims 1 or 2, characterized in that it is in the form of a single composition containing at least:

i. melissa,

ii. linden tree,

iii. chamomile, and

iv. magnesium

in a physiologically acceptable medium.

4. Combination product according to one of the preceding claims characterized in that the physiologically acceptable medium is suitable for oral administration.

5. Combination product according to one of the preceding claims characterized in that it is in the form of a syrup or a capsule comprising a syrup.

6. Combination product according to one of the preceding claims characterized in that the lemon balm, linden and chamomile are in the form of plant extracts

7. Combination product according to at least one of the preceding claims, for the treatment of subjects with somnipathy.

8. Use of a product according to claim 7 to aid relaxation and / or sleep