GABA, rhodiola and lemon balm-based combination product to help with 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 help with relaxation and / or reduce irritability. The invention further relates to the use of a combination product as defined above for the treatment or prevention of stress.

Description

COMBINATION PRODUCT BASED ON GABA, RHODIOLA AND LEMON BALM TO AID RELAXATION AND REDUCE IRRITABILITY

[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 stress. If it is temporary, stress can be positive, but if it lasts too long, it can affect health.

[0004] Stress can have multiple causes, and is caused by what are called stressors or "stressors." It is a normal feeling of physical or emotional tension. There are two types of stress:

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

[0006] - Chronic stress, which lasts for a certain period of time. It is due to deeper problems. Any stress lasting several weeks or months is considered 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 perpetual state of 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 address relaxation or irritability issues. Examples include the products marketed by Sanofi under the trade name Stress Resist, which contains rhodiola, green tea, magnesium, and vitamin B, or the product Euphytose Zen from Bayer, which contains rhodiola, bacopa, and holy basil, or the product Stress marketed by Les Miraculeux, which contains 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, stress resistance, relaxation, and / or helping 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 is without side effects or habituation. The combination product according to the present invention helps to help calm, relax and reduces 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.

[0015] The present invention relates to a combination product, comprising as active substances, at least: gamma-aminobutyric acid, rhodiola and lemon balm to help with 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, for example, orange blossom, lavender, marjoram, valerian, hops, gentian and / or passionflower,Vitamins and minerals, such as, for example, vitamin D, B vitamins, such as vitamin B6, magnesium and / or calciumAmino 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 environment.

[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 GABAfrom 5 to 300 mg, preferably 50 to 200 mg, more preferably from 100 to 150 mg of rhodiolafrom 5 to 200 mg, preferably 50 to 150 mg, more preferably from 60 to 100 mg of lemon balmin a physiologically acceptable medium

[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 rhodiola plant extract is preferably 1.5:1, meaning that 1.5g of dry plant was used to produce 1g of plant extract.

[0032] The concentration of lemon balm plant extract is preferably 4-6:1, which means that 4 to 6 g of dry plant was used to produce 1 g of plant extract.

[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 primary inhibitory neurotransmitter in the mammalian central nervous system. 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 counteract the excitatory effects of glutamate. An imbalance between these two neurotransmitters is implicated 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 interneurons; they represent the majority of GABAminergic neurons; long neurons, such as Purkinje cells in the cerebellum or striatonigral neurons, involved in the modulation of nigrostriatal dopaminergic transmission. GABA-containing neurons have been detected in the ventral tegmental area (VTA) of the midbrain. GABA has been detected mainly 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 the initial segment of the axons of pyramidal (glutaminergic) cells to maintain their 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, which is produced by 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 (vesicular GABA transporters), formed by transmembrane proteins. The arrival of an action potential at the axon terminal opens voltage-sensitive calcium channels. The influx of Ca++ causes the release of GABA into the synaptic cleft by exocytosis.

[0043] GABA released into the cleft can follow several pathways: either be captured by postsynaptic GABAminergic receptors and contribute to neuronal signal transduction; or 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 conditions. Pilot studies on patients show improvements in physical and mental performance, and can reduce fatigue.

[0048] The hypothesis is that the effects of Rhodiola rosea modify the levels of serotonin and dopamine through the inhibition of monoamine oxidase and its influence 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 differs from stimulants like 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 significantly reduces symptoms of fatigue and improves attention after four weeks of use.

[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 presented in the form of a plant extract. This extract is preferably derived from the root of the rhodiola plant. 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, meaning "bee leaf." It is also called lemon balm or simply lemongrass, not to be confused with lemongrass (Cymbopogon citratus), which is used in Asian cuisine. It is a plant native to the eastern Mediterranean basin and 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 is light. Alcohol is obtained by distilling 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 stomach and colon spasms (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, preferably 300 to 900 mg, more preferably from 360 to 600 mg of lemon balm.

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

[0059] Physiologically acceptable environment

[0060] A physiologically acceptable medium is a medium that has no toxic or detrimental effects under the conditions of use and is inert with respect to the active ingredients of the combination product. Such a medium may, for example, include various adjuvants depending on its therapeutic or cosmetic purpose, such as, but not limited to, flavorings, colorings, 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, colorings, 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] Fruits may 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] Texturizers are compounds that modify the texture of the products in which they are incorporated. Examples of texturizers are: guar and carob flours; gums arabic, xanthan and gellan; 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, fat-soluble active ingredients 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.

[0065] By "colorants" we mean compounds of natural or synthetic origin that are capable of conferring a color on the composition on their own. Examples of food colorings are known in Europe under the codes E100 to E180.

[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] “Flavorings” means compounds of natural or synthetic origin that are capable of altering the taste of the composition on their own. Examples of flavorings 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] For the purposes of the present invention, sugar or sugars means 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 include, 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 syrupy product prepared according to the invention include: 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 from 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; CoenzymeQ10; 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 glutathione precursors, selenium amino acids, citrulline,

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

[0079] In a particularly advantageous embodiment of the invention, the combination of active ingredients comprises, as an 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)CompoundsUnit quantity (in mg)GABA200Rhodiole (dry root extract), 1.5:1144Lemon balm (dry leaf extract), 4-6:176Microcrystalline cellulose317Magnesium stearate6Coating:Hydroxypropylmethylcellulose4.2Microcrystalline cellulose1.75Magnesium salt of fatty acid1.05

[0083] Manufacturing process:

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

Claims

Combination product comprising as active substances, at least: (i) gamma-aminobutyric acid, (ii) rhodiola, and (iii) lemon balm, characterized in that gamma-aminobutyric acid, rhodiola and lemon balm are present in an amount: - from 150 to 250 mg of GABA - from 100 to 150 mg of rhodiola - from 60 to 100 mg of lemon balm per single composition Combination product according to claim 1, characterized in that it is in the form of a single composition containing at least: (i) gamma-aminobutyric acid, (ii) rhodiola, and (iii) lemon balm in a physiologically acceptable medium. Combination product according to one of the preceding claims, characterized in that the physiologically acceptable medium is in a form suitable for oral administration. Combination product according to one of the preceding claims, characterized in that it is in the form of a tablet or a capsule. 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. Product according to claim 6 for use in the treatment of stress.