Extended-release combination product to aid relaxation and reduce irritability

Abstract

The present invention relates to a prolonged-release combination product comprising, as active substances, at least magnesium and vitamin B6 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 and to reduce irritability.

Description

Title of the invention: Extended-release combination product to aid relaxation and reduce irritability technical field

[0001] The present invention relates to a prolonged-release combination product comprising, as active substances, at least magnesium and vitamin B6 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 and to reduce irritability.

[0002] BACKGROUND

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

[0004] The origin of stress can be multiple; it is due to 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 the kind of stress that, for example, helps the body to increase its performance or to adapt to a new situation.

[0006] - Chronic stress, which lasts for a certain period of time. It is due to more serious problems deep. Any stress lasting several weeks or months is classified as 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, allowing the body to manage and overcome the stressful situation. However, if stress persists, the body remains perpetually in a state of alert despite the absence of danger.

[0008] The continuous release of hormones and the 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 prolonged-release composition to help manage stress, promote relaxation and reduce irritability in adults or children, preferably in adults.

[0010] A number of products exist on the market to alleviate problems of relaxation or irritability. Among these products, one can cite, for example, the products marketed by Opella Healthcare under the trade name MagnéVieBô, based on magnesium in the form of anhydrous magnesium citrate and of Vitamin B6. This product contains lactose as an excipient and is therefore not suitable for everyone. Cooper's Mag2 24h product is a bilayer product; the first layer contains immediate-release vitamin B6 and vitamin B12, and the second layer contains delayed-release magnesium (in the form of magnesium oxide). The Formag product marketed by Pileje is based on magnesium (in the form of magnesium oxide), taurine, and vitamin B6.

[0011] None of the proposed products contain the specific association that is the subject of the present invention, in the same quantities and with a prolonged release of all the active ingredients.

[0012] These products, although containing magnesium in combination with vitamin B6, do not provide complete satisfaction in terms of calming, stress resistance, relaxation, and / or reducing irritability. The combination product of the present invention provides a calming effect for coping with stress and also reduces irritability. The product according to the present invention has no side effects or risk of addiction. The combination product according to the present invention helps to calm and relax and reduces irritability.

[0013] The combination product according to the invention has the advantage of having in a single dose (one tablet per day), at least 80% of the recommended daily intake of magnesium, 100% of the recommended daily intake of vitamin B6 as well as a prolonged release of at least 6 hours, all with ingredients of natural origin.

[0014] The product according to the present invention also has the advantage of preferably containing no allergens and of being preferably lactose-free, gluten-free, preservative-free, free of artificial colors or flavors, and suitable for vegetarian and vegan diets.

[0015] The product of the present invention has a galenic form suitable for children over 12 years of age and for adults, preferably in the form of a tablet. Summary of the invention

[0016] The present invention relates to a prolonged-release combination product, comprising at least: i. Magnesium, ii. Vitamin B6 iii. Hydroxypropylmethylcellulose having a viscosity between 10,000 mPas and 20,000 mPas In a physiologically acceptable environment.

[0017] The present invention relates to a prolonged-release combination product, including at least: i. Magnesium, ii. Vitamin B6 iii. Hydroxypropylmethylcellulose having a viscosity between 10,000 mPas and 20,000 mPas to help with stress management, relaxation, and / or reducing irritability.

[0018] The present invention also relates to a combination product comprising, as active substances, at least:

[0019] (i) Magnesium,

[0020] (ii) Vitamin B 6

[0021] Hydroxypropylmethylcellulose having a viscosity between 10,000 mPas and 20,000 mPas

[0022] for its use in the treatment or prevention of stress.

[0023] In certain embodiments, the combination product according to the invention comprises, in addition to magnesium and vitamin B6, as active substances: - Plants or plant extracts, such as, for example, orange blossom, lavender, marjoram, valerian, hops, gentian, rhodiola, lemon balm and / or passionflower, - Vitamins and minerals, such as vitamin D, B vitamins such as vitamin B12, and minerals such as calcium - Amino acids or amino acid derivatives, such as tryptophan

[0024] 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 the following active substances: - 200 to 600 mg, preferably 300 to 400 mg of magnesium - 0.5 to 4 mg, preferably 1 to 3 mg of vitamin B6 - 45 to 50 mg of hydroxypropylmethylcellulose with a viscosity between 10,000 mPas and 20,000 mPas in a physiologically acceptable medium

[0025] According to a particular embodiment of the invention, the combination product is characterized in that the ingredients (i), (ii), (iii) are in a medium suitable for oral administration. Preferably, the combination product is in the form of a tablet.

[0026] When used for the therapeutic treatment of stress, the combination product according to the present invention is intended in particular for adults or children, preferably children over 12 years of age.

[0027] According to a preferred embodiment, magnesium is in the form of magnesium oxide. Description of the embodiments

[0028] i. In the present invention, the applicant has demonstrated that the combination of at least (i) magnesium, (ii) vitamin B6 and (iii) hydroxypropylmethylcellulose having a viscosity between 10,000 mPas and 20,000 mPas allows a prolonged release of magnesium and vitamin B6 to help manage stress and relaxation and / or reduce irritability over time.

[0029] Magnesium

[0030] The body does not produce magnesium and must obtain it from food. Magnesium is poorly absorbed by the body and cannot be stored. It is naturally released in feces or urine.

[0031] Magnesium supplementation may reduce anxiety in some people. Other disorders may result from a lack of magnesium, including depression, muscle spasms, cramps, insomnia, and osteoporosis.

[0032] Magnesium is involved in more than 400 biochemical reactions. In particular, it plays a role in the osmotic transport of glucose, the insulin-mediated transport of glucose, and in all stages of energy production. A major mechanism of biochemical activation, consisting of adding a phosphate group to a protein, magnesium is a cofactor of phosphorylation. It also plays a role in homeostasis, the mechanism that maintains internal balance (cell function, heart rate, urination, digestion, body temperature, etc.), and is an essential cofactor for the polymerization of nucleic acids.

[0033] The adult human body contains approximately 24 grams (1 mol) of magnesium, half of which is found in the bones and the other half in the soft tissues. Serum contains only about 0.3% of the body's magnesium, which is why serum concentrations are not useful for diagnosing magnesium deficiency.

[0034] The role of magnesium in the body:

[0035] -the formation of bones and teeth, with calcium and phosphorus

[0036] - promotes the fixation of calcium on bone

[0037] - action on growth

[0038] - the transmission of nerve impulses

[0039] - promotes brain plasticity and prevents memory decline

[0040] - muscle contraction, heart rate

[0041] - to contribute to immune defense mechanisms

[0042] - combats stress, sedative effect (muscle relaxant)

[0043] - at high concentration, combats constipation by osmotic action and sti- local motor stimulation

[0044] - combating calcium oxalate lithiasis

[0045] - anti-allergy

[0046] - anti-inflammatory

[0047] - antiplatelet agent (protective role against thrombosis)

[0048] - radioprotective

[0049] - thermal regulator

[0050] - catalysis of numerous metabolic reactions (enzymatic catalysis, syntheses glycogen and protein, phosphate transfer, etc.).

[0051] - fight against insomnia

[0052] - It is essential for the development and proliferation of T lymphocytes.

[0053] - It has a strong vasodilatory and bronchodilatory effect.

[0054] Signs of magnesium deficiency (hypomagnesemia):

[0055] Magnesium deficiency, which affects a majority of the population, is the leading cause of fatigue and anxiety. But it is also a significant factor in the following disorders: - stress (psychological, allergic, digestive, respiratory, oxidative, toxic, inflammatory...) - neuromuscular hyperexcitability: tetany attacks characterized by contracture of the upper limbs (obstetrician's hands) and face; - chronic manifestations include Chvostek's sign (= percussion of the mouth causes contraction of the upper lip) and Trousseau's sign (= a tourniquet on the arm causes contraction of the hand); - immunological disorders; - cardiovascular damage and, in extreme cases, heart attack; - muscle fatigue; - digestive disorders: diarrhea, nausea and anorexia; - irritability, nervousness, insomnia; - cramps, tremors; - myoclonus (= brief and involuntary muscle contractions, resulting in movement or not); - confusional syndrome; - epileptic seizures (= seizures of epilepsy) most often convulsive; - problems during gestation, for the mother and the fetus; - disruption of the body's thermal system (in the middle of summer, we have the sensation that it is terribly cold). - spasmophilia

[0056] According to a preferred embodiment of the present invention, the magnesium is in the form of magnesium oxide. Indeed, when used in this form, the magnesium is more concentrated and therefore allows for more space in the formula for adjusting the extended release. - According to a preferred embodiment of the present invention, magnesium is present in the composition according to the invention in a content of 200 to 600 mg, preferably 300 to 400 mg of magnesium per single composition.

[0057] Vitamin B6

[0058] Vitamin B6 is a water-soluble vitamin that exists in several forms, with pyridoxal phosphate being its biologically active form, acting as a cofactor involved in several amino acid metabolism reactions, including transaminations, deaminations, and decarboxylations. Pyridoxal phosphate also plays a role in the hydrolysis of glycogen to glucose.

[0059] Vitamin B6 is known in seven different forms, which are interconvertible with each other except for the last one:

[0060] 1. pyridoxine (PN), the form in which vitamin B6 is administered in dietary supplement

[0061] 2. pyridoxine phosphate (PNP),

[0062] 3. pyridoxal (PL),

[0063] 4. Pyridoxal phosphate (PLP), biologically active form (distributed as vitamin supplement "P-5-P"),

[0064] 5. pyridoxamine (PM),

[0065] 6. pyridoxamine phosphate (PMP),

[0066] 7. 4-pyridoxic acid (PA), catabolite excreted via the urinary route.

[0067] Vitamin B6 participates in the conversion of tryptophan to vitamin B3, and in the metabolism of lipids and amino acids (decarboxylation and transamination). Pyridoxal phosphate enables the conversion of glycogen to glucose (Glucose-1-Phospate) by Glycogen phosphorylase.

[0068] Vitamin B6 also participates in the biosynthesis of serotonin.

[0069] It is present in significant quantities in poultry, livers (beef, lamb, veal), bananas, various types of cabbage, tomatoes, spinach, potatoes...

[0070] Combined with cystine, it is administered to facilitate the development of hair, nails, etc.

[0071] According to a preferred embodiment of the present invention, vitamin B6 is present in the composition according to the invention in a content of 0.5 to 4 mg, preferably 1 to 3 mg of vitamin B6 per single composition.

[0072] Hydroxypropylmethylcellulose or high viscosity hypromellose

[0073] Hypromellose (INN), short for hydroxypropylmethylcellulose (HPMC), is an inert, viscoelastic cellulose ether used as eye drops, as well as an excipient in oral medications, in commercial products, or as a food additive.

[0074] As a food additive, HPMC is an emulsifier, thickener and suspending agent, and an alternative to animal gelatin. In the Codex Alimentarius, its code (E) is E464.

[0075] HPMC is a solid powder, ranging in color from light off-white to beige. The compound forms water-soluble colloids. While supposedly non-toxic, this ingredient is flammable and can react vigorously with oxidizing agents.

[0076] Unlike methylcellulose, HPMC in aqueous solution exhibits thermal gelation: when the solution is heated to a critical temperature, it solidifies into a semi-flexible, non-fluid mass. Generally, this critical semi-freezing temperature is inversely proportional to both the concentration of the HPMC solution and the concentration of the methoxy group within the HPMC molecule (which in turn depends on both the degree of methoxy group substitution and the molar substitution). That is, the higher the methoxy group concentration, the lower the critical temperature. The lack of flexibility or viscosity of the resulting mass, however, is directly related to the methoxy group concentration (the higher the concentration, the more viscous or less flexible the resulting mass will be).

[0077] HPMC has been used as an excipient in oral tablets and capsule formulations, where, depending on the category, it functions as a delayed-release agent for a drug compound in the gastrointestinal tract. It is also used as a binder and as a component of tablet coatings.

[0078] HPMC: - viscosity; - the degree of substitution (DS); - molar substitution (MS); - the salt content; - humidity. In the context of the present invention, HPMC has a viscosity in 2% water at 20°C of between 1000mPas and 20000mPas.

[0079] Degree of substitution

[0080] A degree of substitution is the average level of methoxy substitution of the cellulose chain. Since there are a maximum of three possible substitution sites with each cellulose molecule, this average value is a real number between 0 and 3. However, the degree of substitution is often expressed as percentages.

[0081] Molar substitution

[0082] Molar substitution is the average level of hydroxypropoxy substitution of the cellulose chain. Since the hydroxypropoxy base can be attached to each of the side chains and does not require a base substitution site on the cellulose molecule, this number can be greater than 3. However, molar substitution is also often expressed as a percentage.

[0083] In the context of the present invention, the "methoxy" percentage of HPMC is between 19 and 24%. The "hydroxypropy" percentage is between 7 and 12%.

[0084] Humidity

[0085] Since all cellulose ethers are hygroscopic, they absorb moisture from their surroundings if left exposed outside their original packaging. Therefore, the moisture content must be checked and the weight adjusted to ensure that a sufficient quantity of dry active material is allocated for use. The moisture content is checked by weighing a sample of X grams on a laboratory balance and drying the sample in an oven at 105 °C for two hours, followed by weighing the sample again on the same balance.

[0086] According to a preferred embodiment of the present invention, hydroxypropylmethylcellulose is present in the composition according to the invention in a content of 45 to 50 mg of hydroxypropylmethylcellulose per single composition.

[0087] Physiologically acceptable environment

[0088] A physiologically acceptable medium is one that has no toxic or harmful 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, colorants, fillers, preservatives, diluents, wetting or suspending agents, etc. Such media may also allow for the immediate, modified, or delayed release of one or more of the active ingredients.

[0089] The physiologically acceptable medium may consist of water, fruit puree and / or juice, texturizers, emulsifiers, colors, preservatives, flavors, sugar or sugars.

[0090] By "fruit puree and / or juice" is meant a preparation more or less liquid, 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 resulting pulp and / or separation (in particular filtration) of the seeds, achenes and / or all or part of the pulp, and / or flash pasteurization.

[0091] The fruits can be chosen from: apple, banana, strawberry, peach, the 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 their mixtures, without this list being exhaustive.

[0092] By "texturizers" is meant compounds that modify the texture of the products in which they are incorporated. Examples of texturizers are: guar and locust bean gums; arabic, xanthan and gellan gums; carrageenans; starches (native or modified); microcrystalline cellulose; gelatin; pectin; alginates (E400 to E405); agar-agar; and mixtures thereof. The term "emulsifiers" refers to amphiphilic compounds characterized by their HLB (Hydrophile Lipophilic Balance) value, particularly those capable of stabilizing oil-in-water emulsions (especially useful when adding, for example, fat-soluble active ingredients such as fat-soluble vitamins). Examples of food emulsifiers include lecithin and its derivatives, found notably in egg yolks; mono- and diglycerides of fatty acids; and polysorbate 80.

[0093] The term "colorants" refers to compounds of natural or synthetic origin capable of imparting color to the composition on their own. Examples of food colorings are known in Europe under the codes El00 to El80. In the context of the present invention, the combination product is preferably free of artificial colorings.

[0094] By "preservatives" is meant compounds that inhibit the growth 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 contain any preservatives.

[0095] The term "flavorings" refers to compounds of natural or synthetic origin capable of altering the taste of the composition on their own. Examples of flavorings include 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. In the context of the present invention, the combination product is preferably free of artificial flavorings.

[0096]

[0097] For the purposes of this invention, sugar or sugars means any hydrate of sweetening carbon, 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.

[0098] Additional asset(s)

[0099] Any additional active ingredient with nutritional value and / or that aids relaxation or reduces irritability 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, and flavonoids.

[0100] Advantageously, such an additional active ingredient may be intended to enhance the desired effect as described above.

[0101] Of course, a person skilled in the art will take care to choose the additional assets and their quantity in such a way that the advantageous properties of the composition according to the invention are not, or substantially not, altered by the envisaged addition.

[0102] As an additional usable asset, one may cite:

[0103] - water-soluble vitamins and fat-soluble vitamins. Examples of 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 known as vitamin PP (Pellagra Preventive), vitamin B5 (pantothenic acid), 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 (a mixture of tocopherols and tocotrienols), and vitamin K (phylloquinone).

[0104] - antioxidants, such as curcuminoids; carotenoids, in particular selected among beta-carotene, astaxanthin, zeaxanthin, lutein, or compounds containing them such as goji berries; polyphenol compounds, flavonoids such as catechins; proanthocyanidins, anthocyanins, OPCs (oligomeric procyanidins); ubiquinones; coffee extracts containing polyphenols and / or diterpenes; chicory extracts; ginkgo biloba extracts; grape extracts rich in proanthocyanidins; chili pepper extracts; soy extracts; cocoa; pomegranate; Emblica; Coenzyme Q10; selenium,

[0105] - minerals, such as zinc, calcium, copper, iron, iodine, manganese, the selenium, chromium (III),

[0106] - amino acids, in particular sulfur-containing amino acids, such as precursors of glutathione, selenium amino acids, citrulline,

[0107] -phytosterols, resveratrol, hesperidin, neohesperidin, orthosilicic acid, monomethylsilanetriol, and mixtures thereof.

[0108] Preferably, a combination product according to the invention is administered orally. Suitable oral dosage forms include, for example, tablets, capsules, lozenges, powders, granules, lyophilized powders, oral solutions, and syrups. Tablets, powders, granules, lyophilized powders, oral solutions, and syrups constitute the currently preferred pharmaceutical or cosmetic dosage form suitable for oral administration. In the case of preparing a solid composition in tablet form, the main ingredients (i), (ii), or (iii) may, for example, be mixed with a physiologically acceptable vehicle such as gelatin, starch, magnesium stearate, talc, acacia gum, or similar substances.

[0109] A tablet preparation is obtained by mixing the ingredients (i), (ii) or (iii) in powder form and compressing the resulting mixture in order to obtain tablets.

[0110] Example 1 of composition according to the invention (Table 1) Ingredients Unit Quantity (in mg) Vitamin B6 2.681 Magnesium Oxide 501.253 Hydroxypropylmethylcellulose (Tylopur Xtend Nutra 15T by Shin-Etsu) 45 Sorbitol 206.066 Magnesium Stearate 20

[0111] Manufacturing process:

[0112] This composition is obtained by mixing the different compounds according to the processes conventionally used for this type of preparation. The composition is preferably in tablet form.

[0113] Comparative Examples 2 to 7 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Compounds Unit Quantity (in mg) Vitamin B6 2.681 2.681 2.681 2.681 2.681 2.681 Magnesium Oxide 497.512 501.253 501.253 501.253 501.253 501.253 Microcrystalline Cellulose (Vivapur by JRS) 50.000 Hydroxypropyl methylcellulose (Tylopur Xtend Nutra 15T from Shin-Etsu) 251,066 125,533 85,000 60,000 55,000 Sorbitol 204,807 125,533 166,066 191,066 196,066 Magnesium stearate 20 20 20 20 20 20

[0114] Example 8: Disaggregation test

[0115] The disintegration test is carried out with the Copley Scientific DTG 1000 Disintegration Tester.

[0116] The apparatus is equipped with a basket containing 6 tubes and an 800 mL beaker. A tablet is placed horizontally in each tube and covered with a float supplied with the apparatus. The basket is immersed at regular time intervals (30 times per minute) in a beaker containing 800 mL of a hydrochloric acid solution at pH 3.5 maintained at 37°C using a water bath.

[0117] The objective of this test is to demonstrate the prolonged release of magnesium and vitamin B6 tablets in an acidic medium.

[0118] The test is launched for a duration of 8h30.

[0119] The tablet according to example 1 is completely disintegrated after 6 hours and 30 minutes, the tablet according to example 2 is completely disintegrated after 30 minutes. The tablets of examples 3 to 7 take more than 8 hours to disintegrate.

[0120] Too short a disintegration time (such as example 2) does not allow for a prolonged release of magnesium and vitamin B6. If the time exceeds 8 hours, there is a risk that the tablet will not disintegrate completely and will not release all of the magnesium and vitamin B6 it contains.

Claims

Claims

1. A prolonged-release combination product comprising at least: (i) Magnesium, (ii) Vitamin B 6 (iii) Hydroxypropylmethylcellulose having a viscosity of between 10,000 mPas and 20,000 mPas

2. Combination product according to claim 1, characterized in that it is in the form of a single composition containing at least: (i) Magnesium, (ii) Vitamin B 6 (iii) Hydroxypropylmethylcellulose having a viscosity of between 10,000 mPas and 20,000 mPas in a physiologically acceptable medium.

3. Combination product according to one of the preceding claims, characterized in that the magnesium, vitamin B6 and hydroxypropylcellulose are present in an amount: - from 200 to 600 mg, preferably 300 to 400 mg of magnesium - from 0.5 to 4 mg, preferably 1 to 3 mg of vitamin B6 - from 45 to 50 mg of hydroxypropylmethylcellulose having a viscosity of between 10,000 mPas and 20,000 mPas 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.

6. Product according to one of the preceding claims for its use in the treatment of stress.