Combination product to aid relaxation and reduce irritability

Abstract

The present invention relates to a combination product comprising, as active substances, at least gamma-aminobutyric acid (GABA), rhodiola, and lemon balm to aid relaxation and / or reduce irritability. The invention also relates to the use of a combination product as defined above for the treatment or prevention of stress.

Description

Title of the invention: Combination product to aid relaxation and reduce irritability Technical field

[0001] The present invention relates to a combination product comprising, as active substances, at least gamma-aminobutyric acid (GABA), rhodiola and lemon balm to aid relaxation and / or reduce irritability. The invention finally relates to the use of a combination product as previously defined for the treatment or prevention of stress and reducing irritability.

[0002] BACKGROUND

[0003] Stress is a normal reaction of the body to environmental constraints. If it is temporary, stress can be positive, but if it lasts too long, it can affect health.

[0004] Stress can have multiple origins, and is due to what we call stress factors or "stressors." It is a feeling of normal physical or emotional tension. There are two types of stress:

[0005] - Acute stress that disappears quickly. It is stress that, for example, helps the body to increase its performance or adapt to a new situation.

[0006] - Chronic stress, which lasts for a certain time. It is due to more deep. Any stress lasting several weeks or months is called chronic stress.

[0007] The body reacts to stress by releasing hormones that affect the brain, muscles, and heart rate. In the short term, these reactions are beneficial and protective for the body, allowing the human being to manage and overcome the stressful situation. However, if the stress persists, the human body remains in a state of constant alert despite the absence of danger.

[0008] The continuous release of hormones and activation of the brain, muscles and heart can then lead to health risks such as high blood pressure, heart problems, anxiety, depression, or skin problems.

[0009] The present invention relates to a composition for aiding stress management, relaxation and reducing irritability in adults or children, preferably in adults.

[0010] There are a number of products on the market to alleviate relaxation or irritability problems. Examples of these products include the products marketed by Sanofi under the trade name Stress Resist based on rhodiola, green tea, magnesium and vitamin B, or the product Euphytose Zen from Bayer, which contains rhodiola, bacopa and holy basil, or the Stress product marketed by Les Miraculeux based on GABA, Hawthorn, rhodiola and vitamin B6.

[0011] None of the products offered contain the combination that is the subject of the present invention.

[0012] These products, although containing gamma-aminobutyric acid (GABA) in combination with rhodiola, do not provide complete satisfaction in terms of calming, resistance to stress, relaxation, and / or help to reduce irritability. The combination product of the present invention provides a calming effect to cope with stress but also to reduce irritability. The product according to the present invention has no side effects or habituation. The combination product according to the present invention helps to help calm, relax and reduce irritability.

[0013] The product according to the present invention also has the advantage of preferably containing no allergens and of being, preferably, lactose-free or gluten-free.

[0014] The product of the present invention has a galenic suitable for children and adults, preferably in the form of a tablet. Summary of the invention

[0015] The present invention relates to a combination product, comprising as active substances, at least: i. gamma-aminobutyric acid, ii. rhodiola and iii. lemon balm to aid in stress management, relaxation, and / or reducing irritability.

[0016] The present invention also relates to a combination product, comprising as active substances, at least:

[0017] (i) gamma-aminobutyric acid,

[0018] (ii) rhodiola and

[0019] (iii) lemon balm

[0020] for its use in the treatment or prevention of stress.

[0021] In certain embodiments, the combination product according to the invention comprises, in addition to gamma-aminobutyric acid, rhodiola and lemon balm, as active substances: - Plants or plant extracts, such as orange blossom, lavender, marjoram, valerian, hops, gentian and / or passionflower, - Vitamins and minerals, such as vitamin D, B vitamins such as vitamin B6, magnesium and / or calcium - Amino acids or amino acid derivatives, such as for example tryptophan

[0022] In certain embodiments of the invention, the combination product according to the invention may be in the form of a single composition containing at least as active substances:

[0023] (i) GABA,

[0024] (ii) rhodiola, and

[0025] (iii) lemon balm

[0026] in a physiologically acceptable medium.

[0027] In certain embodiments of the invention, the combination product according to the invention may be in the form of a single composition containing at least as active substances: - from 50 to 500 mg, preferably 100 to 300 mg, more preferably from 150 to 250 mg of GABA - from 5 to 300 mg, preferably 50 to 200 mg, more preferably from 100 to 150 mg of rhodiola - from 5 to 200 mg, preferably 50 to 150 mg, more preferably from 60 to 100 mg of lemon balm in a physiologically acceptable environment

[0028] According to a particular embodiment of the invention, the combination product is characterized in that the active ingredients (i), (ii), (iii), (iv) are in a medium suitable for oral administration. Preferably, the combination product is in the form of a tablet.

[0029] When used for the therapeutic treatment of stress, the combination product according to the present invention is intended in particular for adults or children.

[0030] Rhodiola and lemon balm may be present as ingredients (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.

[0031] The concentration of the rhodiola plant extract is preferably 1.5:1, which means that 1.5g of dry plant was used to produce 1g of plant extract.

[0032] The concentration of the lemon balm plant extract is preferably 4-6:1, meaning that 4 to 6 g of dry plant were used to produce 1 g of plant extract. Description of the embodiments

[0033] In the present invention, the applicant has demonstrated that the combination of at least (i) gamma-butyric acid (GABA), (ii) rhodiola and (iii) lemon balm has a synergistic effect to help manage stress and relaxation and / or reduce irritability.

[0034] By synergistic effect, it is understood according to the present invention that the combination of at least (i) GABA, (ii) rhodiola and (iii) lemon balm has an effect on aiding relaxation and / or reducing irritability, during the treatment which is greater than the cumulative effects of a treatment (a) comprising the administration of GABA, not associated with rhodiola and lemon balm, and conversely of a treatment (b) comprising the administration of rhodiola, not associated with GABA and lemon balm or of a treatment (c) comprising the administration of lemon balm, not associated with GABA and rhodiola.

[0035] Gamma-aminobutyric acid or GABA

[0036] Gamma-aminobutyric acid, or GABA, is the main inhibitory neurotransmitter in the central nervous system in mammals. It is a neuromodulator known to be inhibitory in adults but excitatory during human embryonic development. It plays an important role in adults by preventing prolonged excitation of neurons. It also has a neurotrophic role, meaning it promotes the growth of certain neurons.

[0037] The inhibitory effects of GABA counterbalance the excitatory effects of glutamate. An imbalance between these two neurotransmitters is involved in epilepsy and cerebral ischemia.

[0038] GABA is thought to be involved in at least 30% of brain synapses. The second inhibitory neurotransmitter is glycine, which is more specifically located in the spinal cord.

[0039] Two types of GABAminergic neurons are found: - short neurons which are intermeurons; they represent the majority of GABAminergic neurons; - long neurons such as Purkinje cells of the cerebellum or striatonigral neurons, involved in the modulation of nigrostriatal dopaminergic transmission. GABA-containing neurons have been detected in the ventral tegmental cortex (VTC) of the midbrain. GABA has been detected primarily in non-pyramidal neurons such as granule or stellate cells, in layers II to IV of the cortex. It has been postulated that GABAminergic interneurons exert a modulatory influence on the cell body and axon initial segment of pyramidal (glutaminergic) cells to maintain sustained activity in the maintenance of working memory.

[0040] GABA is synthesized from glutamic acid by an enzyme GD (Glutamate decarboxylase) or AGD (Glutamic Acid Decarboxylase) [GAD in English (Glutamic Acid Decarboxylase, or Glutamate Decarboxylase)] and is catabolized by another enzyme: GABA transaminase (GABA-T).

[0041] The metabolisms of GABA and glutamate (or glutamic acid) are closely linked. Glutamate itself comes from glutamine and alpha-ketoglutarate, from the Krebs cycle. Glutamate is then decarboxylated into GABA under the influence of glutamate decarboxylase (GAD) and its cofactor, pyridoxal phosphate, derived from vitamin B6.

[0042] GABA molecules are stored in synaptic vesicles, via VGat transporters (vesicular GABA transporter), formed by transmembrane proteins. The arrival of an action potential in the end of the axon opens the voltage-sensitive calcium channels. The influx of Ca++ causes, by exocytosis, the release of GABA into the synaptic cleft.

[0043] GABA released into the cleft can follow several pathways: - either be captured by postsynaptic GABAminergic receptors and contribute to the transduction of the neuronal signal; - either be recycled indirectly by a glial cell; - or be recycled directly by a GABAminergic neuron.

[0044] GABA therefore exerts its effect on its receptors or is recaptured by specific membrane transporters. Four types of high-affinity transporters for GABA have been described: GAT-1 to GAT-4. Transporters GAT-1 and -4 are more expressed in neurons, GAT-2 in glial cells and GAT-2 and 3 in the kidneys and liver. - In the context of the present invention, GABA is present in the composition in an amount of 50 to 500 mg, preferably 100 to 300 mg, more preferably 150 to 250 mg of GABA.

[0045] Rhodiola

[0046] Rhodiola rosea, rhodiola, rhodiola, golden root or arctic root (Rhodiola rosea, synonym Lignum rhodium or Sedum roseum) is a species of plant in the Crassulaceae family. It grows in cold regions such as the Arctic, the mountains of Central Asia, the Rocky Mountains, and the mountainous regions of Europe, such as the Alps, the Pyrenees, and the Carpathians, Scandinavia, Iceland, the United Kingdom and Ireland. This perennial plant grows up to 2,280 meters above sea level.

[0047] Rhodiola rosea can improve depressive states. Pilot studies conducted on patients show improvement in physical and mental performance, and can reduce fatigue.

[0048] The hypothesis is that the effects of Rhodiola rosea would modify the levels of serotonin and dopamine thanks to the inhibition that monoamine oxidase causes and its influences on opioid peptides, such as beta-endorphins, although these specific neurochemical mechanisms have not been clearly defined by scientific studies.

[0049] Rhodiola is classified as an adaptogen, which therefore differs from stimulants such as nicotine and amphetamine. The adaptogenic factor has less effectiveness and different physiological effects than stimulants.

[0050] Rhodiola rosea extracts have an anti-fatigue effect that increases mental performance, particularly the ability to concentrate in healthy subjects and in patients with 'burnout' and fatigue syndrome. Rhodiola reduces fatigue symptoms and improves attention after four weeks of taking it.

[0051] In the context of the present invention, rhodiola is present in the composition in an amount of 5 to 300 mg, preferably 50 to 200 mg, more preferably 100 to 150 mg of rhodiola.

[0052] Rhodiola is preferably in the form of a plant extract. This extract is preferably derived from the root of rhodiola. The quantities of rhodiola represent in plant equivalent from 7.5 to 450 mg, preferably 75 to 300 mg, more preferably from 150 to 225 mg of rhodiola.

[0053] Lemon balm

[0054] Lemon balm or lemon balm (Melissa officinalis) is a perennial herbaceous plant of the Lamiaceae family. Its name comes from the Greek melissophullon, which means "bee leaf." It is also called lemon balm or simply lemongrass, not to be confused with lemongrass (Cymbopogon citratus) used in Asian cuisine. It is a plant native to the eastern Mediterranean basin, which has spread throughout Europe since ancient times. Lemon balm, or lemon balm, has been cultivated in gardens since ancient times. Originally from Europe, it was introduced to North America. The stems and leaves are still used as a tonic and mild stimulant. The taste is astringent and the aroma light. Alcohol is obtained by distillation of its fresh leaves: lemon balm water has antispasmodic properties. Lemon balm can also be consumed in the form of herbal teas.

[0055] Lemon balm is most often used for its calming and relaxing properties. 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 also promotes sweating, which is why it is recommended in cases of insomnia, or in cases of high heat in infants and the elderly.

[0056] In the context of the present invention, lemon balm is present in the composition in an amount of 5 to 200 mg, preferably 50 to 150 mg, more preferably 60 to 100 mg of lemon balm.

[0057] . Its quantities of lemon balm represent in plant equivalent from 30 to 1200 mg, of preferably 300 to 900 mg, more preferably 360 to 600 mg of lemon balm.

[0058] Lemon balm is preferably present in the form of a plant extract.

[0059] Physiologically acceptable medium

[0060] A physiologically acceptable medium is a medium having no toxic or detrimental effects 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 depending on its therapeutic or cosmetic purpose, such as, but not limited to, flavorings, colorants, fillers, preservatives, diluents, wetting or suspending agents, etc. Such media may also allow immediate, modified or delayed release of one or other of the active ingredients.

[0061] The physiologically acceptable medium may be composed of water, fruit puree and / or juice, texturizers, emulsifiers, colorants, preservatives, flavorings, sugar or sugars.

[0062] By "fruit puree and / or juice" is meant a more or less liquid preparation, in particular depending on the nature of the fruit and / or the fineness of the grinding, prepared by grinding, pressing or other extraction process of one or more fruits and possibly 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 pasteurization.

[0063] The fruits can be chosen from: apple, banana, strawberry, peach, raspberry, blackberry, mango, kiwi, blueberry, blackcurrant, redcurrant, orange, cherry, fig, pear, apricot, coconut, passion fruit, guava, papaya, melon, lychee, pineapple, lemon, mandarin, mirabelle plum, grapefruit, grape, rhubarb and mixtures thereof, without this list being exhaustive.

[0064] By "texturants" is meant compounds that modify the texture of the products in which they are incorporated. Examples of texturants are: guar and carob flours; arabic, xanthan and gellan gums; carrageenans; starches (native or modified); microcrystalline cellulose; gelatin; pectin; alginates (E400 to E405); agar-agar; and mixtures thereof. By "emulsifiers" we mean amphiphilic compounds characterized by their HLB (Hydrophilic Lipophilic Balance) value, particularly capable of stabilizing oil-in-water emulsions (particularly interesting if one wishes to add, for example, liposoluble active ingredients such as liposoluble 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.

[0065] By "colorants" is meant compounds of natural or synthetic origin capable of conferring a coloring to the composition on their own. Examples of food colorings are known in Europe under the codes El00 to El80.

[0066] 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.

[0067] By "flavors" is meant compounds of natural or synthetic origin capable of modifying the taste of the composition on their own. Examples of flavors are apricot, pineapple, banana, blackcurrant, cherry, lemon, lime, strawberry, raspberry, passion fruit, mandarin, mint, orange, pistachio, pear, licorice, rose, anise, blueberry, cinnamon, ginger, grapefruit, apple, kiwi, lychee, melon, coconut, peach, redcurrant, guava, grenadine, mango, blackberry, papaya, vanillin, natural vanilla extract, essential oils and mixtures thereof.

[0068] By sugar or sugars is meant, within the meaning of the present invention, any sweetening carbohydrate, preferably glucose syrup, sucrose, glucose, fructose, invert sugar, honey, maltose, polyol or mixtures thereof. In the context of the present invention, the sugar used is a polyol, preferably sorbitol.

[0069] Additional asset(s)

[0070] Any additional active ingredient of nutritional interest and / or helping with relaxation or reducing irritability may also be added to the combination products of the invention in pharmaceutical or cosmetic form. The combination product may comprise, for example, vitamins, mineral salts, essential amino acids, essential fatty acids, trace elements, various plant extracts, fibers, antioxidants, flavonoids.

[0071] Advantageously, such an additional active ingredient may be intended to reinforce the desired effect as described above.

[0072] Of course, those skilled in the art will take care to choose the additional active ingredients and their quantity in such a way that the advantageous properties of the composition in accordance with the invention are not, or not substantially, altered by the envisaged addition.

[0073] As additional usable assets, we can cite:

[0074] - water-soluble vitamins and fat-soluble vitamins. Examples of Water-soluble vitamins present in the syrupy product prepared according to the invention include: vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid) also called vitamin PP (Pellagra Preventive), 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 fat-soluble vitamins present in the product syrupy 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).

[0075] - antioxidants, such as curcuminoids; carotenoids, in particular chosen among beta-carotene, astaxanthin, zeaxanthin, lutein or compounds containing them 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 pepper extracts; soybean extracts; cocoa; pomegranate; Emblica; Coenzyme Q10; selenium,

[0076] - minerals, such as zinc, calcium, copper, iron, iodine, manganese, selenium, chromium (III),

[0077] - amino acids, in particular sulfur-containing amino acids, such as precursors of glutathione, selenium amino acids, citrulline,

[0078] -phytosterols, resveratrol, hesperidin, neohesperidin, ortho-silicic acid, monomethylsilanetriol, and mixtures thereof.

[0079] 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 or magnesium.

[0080] Preferably, a combination product according to the invention is administered orally. Forms suitable for oral administration are, for example, tablets, capsules, lozenges, powders, granules, lyophilisates, oral solutions and syrups. Tablets, powders, granules, lyophilisates, oral solutions and syrups constitute the currently preferred pharmaceutical or cosmetic form suitable for oral administration. In the case of the preparation of a solid composition in the form of tablets, the main active ingredients (i), (ii) or (iii) may, for example, be mixed with a physiologically acceptable vehicle such as gelatin, starch, magnesium stearate, talc, gum arabic or the like. The tablets may be of various types, with immediate, controlled or delayed release and optionally in effervescent or orodispersible form.

[0081] A tablet preparation is obtained by mixing the active ingredient (i), (ii) or (iii) in powder form and compressing the resulting mixture to obtain tablets.

[0082] Example 1 of composition according to the invention (Table 1) Compounds Unit quantity (in mg) GABA 200 Rhodiola (root dry extract), 1.5:1 144 Lemon balm (leaf dry extract), 4-6:1 76 Microcrystalline cellulose 317 Magnesium stearate 6 Coating: Hydroxypropylmethylcellulose 4.2 Microcrystalline cellulose 1.75 Magnesium salt of fatty acid 1.05

[0083] Manufacturing process:

[0084] This composition is obtained by mixing the different compounds according to the methods conventionally used for this type of preparation. The composition is preferably in the form of tablets.

Claims

Claims

1. Combination product comprising as active substances, at least: (i) gamma-butyric acid, (ii) rhodiola, and (iii) lemon balm

2. Combination product according to claim 1, characterized in that it is in the form of a single composition containing at least: (i) gamma-butyric acid, (ii) rhodiola, and (iii) lemon balm in a physiologically acceptable medium.

3. Combination product according to one of the preceding claims, characterized in that gamma-butyric acid, rhodiola and lemon balm are present in an amount: - from 50 to 500 mg, preferably 100 to 300 mg, more preferably 150 to 250 mg of GABA - from 5 to 300 mg, preferably 50 to 200 mg, more preferably 100 to 150 mg of rhodiola - from 5 to 200 mg, preferably 50 to 150 mg, more preferably 60 to 100 mg of lemon balm per single composition

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

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

6. Combination product according to one of the preceding claims, characterized in that the rhodiola and lemon balm are in the form of a plant extract.

7. Product according to claim 6 for its use in the treatment of stress.