Dihydromyricetin derivative, composition, its use and method for the preparation of a dihydromyricetin derivative

Abstract

The invention relates to a dihydromyricetin derivative (1,2), wherein the dihydromyricetin derivative (1,2) is edible and water-soluble and, when completely dissolved in a liquid, is unpolymerized, and to a composition containing the dihydromyricetin derivative (1,2). Furthermore, the invention relates to the use of the dihydromyricetin derivative (1,2) or the composition as an anti-hangover additive for a food and / or a pharmaceutical product for the relief, prevention, and / or treatment of hangover symptoms caused by alcohol consumption and / or for accelerating the breakdown and metabolism of alcohol.The invention further relates to a process for producing a dihydromyricetin derivative (1, 2) that is edible and water-soluble and, when completely dissolved in a liquid, is unpolymerized, comprising modifying (3) dihydromyricetin to obtain the edible, water-soluble dihydromyricetin derivative (1, 2) that, when completely dissolved in a liquid, is unpolymerized. The invention further relates to a process for maintaining the long-term solubility of the DHM derivative in aqueous solutions and preventing crystallization by adding 35-45% vol alcohol as well as essential oils or flavorings. These additional components ensure that the DHM derivative remains dissolved and stable for extended periods, making the solution suitable for use in various products such as foods, dietary supplements, and pharmaceuticals.

Description

Technical field

[0001] The present invention relates to a dihydromyricetin derivative, a composition, its use, and a process for producing a dihydromyricetin derivative. In particular, the present invention relates to a water-soluble dihydromyricetin derivative, a composition containing the dihydromyricetin derivative, its use in food and / or pharmaceuticals, its use against alcohol-induced hangovers, and a process for producing and long-term stabilizing the dihydromyricetin derivative. The present invention therefore relates to a food supplement in powder or liquid form based on dihydromyricetin (DHM), a natural plant extract that has been technically developed to be water-soluble and to dissolve completely in liquids without polymerizing.This novel DHM derivative can be added to solid and liquid foods and pharmaceuticals to produce beneficial effects in humans and animals. Suitable applications include its use to alleviate and prevent hangovers caused by alcohol consumption. Furthermore, this novel DHM derivative is suitable as an additive for medical and therapeutic purposes, as well as for applications promoting well-being. Background of the invention

[0002] Alcohol consumption often leads to a variety of complaints the next day, including headaches, nausea, fatigue, and dehydration. These symptoms, often referred to as a "hangover," significantly impair quality of life. Existing anti-hangover products often do not provide sufficient relief or have drawbacks such as poor solubility and a tendency to polymerize. The approach of existing anti-hangover products is primarily focused on replenishing vitamins and minerals to support the liver after alcohol metabolism, rather than before or during the process.

[0003] Dihydromyricetin (DHM, 3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one), also known as ampelopsin, is a secondary plant compound and flavonoid that occurs naturally in several plants, particularly in the plant *Hovenia dulcis*. The active ingredient dihydromyricetin has been used for centuries for a variety of applications in humans and is highly regarded. Its anti-hangover effect is widely known and supported by numerous studies. DHM, as a plant extract, can be used as a flavoring agent (bittering agent) and, in higher concentrations, can alleviate alcohol poisoning. DHM binds to the GABAA receptor. Alcohol and presumably GHB (gamma-hydroxybutyric acid) also bind to this nerve cell receptor.

[0004] A liver-protective effect of DHM is assumed based on various studies in mice (Hase et al. 1997; Fang et al. 2007; Murakami et al. 2004). Shen et al. (Shen et al. 2012) report that at the cellular level, even 1 µM of DHM has effects on the GABAARs receptor. Extracts of the Japanese raisin tree have been approved by the Korean Food and Drug Administration since 2008 for liver regeneration in patients with alcohol abuse. Its effects have been known for over 500 years (Mitchell 2012).

[0005] DHM can support detoxification processes by inducing the enzymes responsible for breaking down and eliminating toxins, including alcohol and its metabolites. Dihydromyricetin accelerates alcohol breakdown in the liver by enhancing the activity of the enzymes alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). These enzymes are crucial for breaking down ethanol to acetaldehyde and ultimately to acetic acid, which is then further metabolized to carbon dioxide and water. By accelerating this process, DHM helps reduce the toxic effects of alcohol and acetaldehyde.

[0006] Shen et al. (Shen et al. 2012) reported that in animal experiments, with an ethanol dose of 4 g / kg body weight and without DHM, it took approximately 112 minutes to regain an upright posture (LORR - latency to lose righting reflex). In the presence of just 1 mg / kg body weight of DHM, this time was reduced to approximately 28 minutes. This demonstrates that even at this low dose of DHM, the breakdown of alcohol proceeds about four times faster.

[0007] Dihydromyricetin (DHM) acts as an antioxidant and anti-inflammatory agent, which can protect liver cells from damage caused by oxidative stress and inflammation. DHM can reduce oxidative stress by decreasing the production of reactive oxygen species (ROS) and increasing the activity of antioxidant enzymes such as glutathione peroxidase (GPx) and superoxide dismutase (SOD). These properties may help prevent liver damage caused by excessive alcohol consumption.

[0008] DHM can have a concentration-enhancing, relaxing, performance-enhancing, mood-lifting, balancing, sleep-promoting, and well-being-enhancing effect. This opens up further areas of application for medical, therapeutic, and supportive benefits in humans and animals.

[0009] Enriching solid and liquid foods with DHM to achieve an anti-hangover and alcohol-metabolizing effect, or to benefit from its other beneficial properties, is necessary to obtain satisfactory results. However, in its natural form, DHM is not water-soluble, which limits its use in liquid supplements or medications. State of the art:

[0010] Most well-known anti-hangover drinks and foods contain vitamins, electrolytes, and green tea extracts as active ingredients. These can support the liver and provide it with the raw materials needed for alcohol metabolism; however, the burden on the liver remains significantly elevated. Satisfactory support for the liver in the alcohol detoxification process is often not achieved.

[0011] Dihydromyricetin, or DHM, has various biological effects, particularly regarding liver function and alcohol metabolism. It has been used for centuries in Asian countries as a popular anti-hangover remedy.

[0012] DHM is poorly absorbed into the bloodstream after oral administration, with a bioavailability of approximately 4%, as demonstrated in studies in rats (Martinez-Coria et al. 2019). At an oral dose of 20 mg / kg body weight, the maximum plasma concentration is reached after 2.67 hours (Liu et al. 2017).

[0013] In its natural form, DHM is not very soluble in water (approx. 0.7 g / L), which severely limits its use in liquid foods and pharmaceuticals and makes it impossible in the pharmacologically effective concentration range.

[0014] The derivatives already listed under patent law for making DHM water-soluble have significant deficiencies and potentially harmful characteristics.

[0015] Triethylammonium DHM (TDHM) and piperinidinium DHM (PDHM) are unsuitable for use in liquid foods and pharmaceuticals due to the sensory and toxicological properties of triethanolammonium and piperidine, as they release triethylamine (triethanolammonium) and piperidine in aqueous media. Both exhibit unsuitable sensory properties and are not authorized in the European Union according to Annex II of Regulation (EC) No. 1333 / 2008. Beta-cyclodextrin (E 459) is permitted according to Annex II of Regulation (EC) No. 1333 / 2008 only in foodstuffs in the form of compressed tablets and coated tablets, but not in liquid foods such as beverages. Furthermore, TDHM and PDHM exist unpolymerized for a short time after dissolving in aqueous media, but then precipitate as insoluble DHM. Object of the invention

[0016] It is an object of the invention to provide a substance, a composition, and a process for producing the substance, wherein the substance and the composition are water-soluble and bioavailable, as well as being addable to solid and liquid foods and pharmaceuticals, and / or effective as an anti-hangover agent. Furthermore, crystallization of the substance in aqueous solution is to be prevented, and long-term solubility of the substance is to be ensured. Description of the invention

[0017] The problem is solved by a dihydromyricetin derivative having the features of claim 1, a composition having the features of claim 5, a use having the features of claim 9, and a method having the features of claims 10 and 12. Advantageous further developments and modifications are specified in the dependent claims.

[0018] This invention generates a water-soluble derivative or modification of DHM that exhibits solubility in water-based beverages or pharmaceuticals without subsequent polymerization, while the modification has no effect on the physiological action and positively influences bioavailability. The present invention further discloses manufacturing processes for water-soluble DHM derivatives suitable for use in food and pharmaceuticals.

[0019] Furthermore, the invention provides a method for maintaining the long-term solubility of the DHM derivative in aqueous solution and preventing crystallization by adding 35-45% vol alcohol and optionally essential oils or flavorings. This additional component(s) ensures that the DHM derivative remains dissolved and stable over extended periods, making the solution suitable for use in various products such as foods, dietary supplements, and pharmaceuticals.

[0020] The invention therefore fulfills a long-standing need for a water-soluble dihydromyricetin (DHM) through the technical advancement of the DHM derivative, which can be added to solid and liquid foods and pharmaceuticals, dissolving in a liquid without polymerizing or remaining unpolymerized. Adding the water-soluble DHM derivative to beverages, for example, offers its use as an anti-hangover remedy. Adding 35-45% vol alcohol, as well as essential oils or flavorings, to the liquid prevents crystallization and maintains long-term solubility. DHM has been known for many years as an effective and suitable agent against the symptoms of alcohol consumption and can contribute to a faster reduction in blood alcohol levels, as has already been scientifically confirmed in experiments with mice.Furthermore, DHM can improve concentration, liver function, sleep quality, and well-being, and counteract inflammation. The water solubility of DHM, now achieved through technological advancements, offers diverse applications for humans and animals and significant societal benefits.

[0021] The invention provides a dietary supplement in powder or liquid form based on dihydromyricetin (DHM), a natural plant extract. Through technical development, DHM is made water-soluble and dissolves completely in liquid without polymerizing. This novel DHM derivative or modification can be added to solid and liquid foods and pharmaceuticals to produce beneficial effects in humans or animals. Suitable applications include its use to alleviate and / or prevent hangovers caused by alcohol consumption. Furthermore, this novel DHM derivative is suitable as an additive for medical, therapeutic, and wellness-promoting applications.

[0022] To achieve a minimum effect, 2 g of DHM must be ingested orally so that 0.08 g of physiologically active DHM are available in the body. To increase hydrophilicity for use in water-based beverages, foods, or pharmaceuticals, modifications to DHM are made in such a way that physiological efficacy is maintained. In principle, both chemical and physical modifications are possible.

[0023] The invention relates to a dihydromyricetin derivative that is edible and water-soluble and, when completely dissolved in a liquid, is unpolymerized or monomeric. The dihydromyricetin derivative or dihydromyricetin modification is edible and safe for use in food and pharmaceuticals. Therefore, it is suitable for use as an anti-hangover remedy and / or as an additive in food and pharmaceuticals. When the dihydromyricetin derivative is dissolved in a liquid, it remains in its monomeric form; that is, it does not polymerize but is unpolymerized. Nuclear magnetic resonance spectroscopy (NMR) is used as a measurement method to verify the presence of the monomer—that is, the unpolymerized DHM—in solution. This analytical technique, recognized as a primary measurement method, allows for the observation of the monomer by means of NMR spectroscopy. 1¹H NMR can analyze every position in the molecule where a proton is anchored. Changes in the DHM molecule, such as those caused by polymerization, become visible in the NMR spectrum. Furthermore, the increasing polymerization of dissolved DHM is characterized by a change in color, which can be used as an additional measurement method to verify the presence of the DHM monomer in solution. Polymerization leads to an expansion of the π-electron system, resulting in an increasing shift in the spectral wavelength with a color change from RAL 1xxx (yellow) to RAL 8xxx (brown). Visual verification (VIS) is performed by an expert accredited by the German Accreditation Body (DAkkS). When completely dissolved in liquid, preferably water, the dihydromyricetin derivative remains unpolymerized in the liquid for several hours, preferably several days, and more preferably several weeks.

[0024] In general, the solubility of a substance indicates the extent to which the pure substance can be dissolved in a solvent until saturation occurs. The term "water-soluble" indicates that the dihydromyricetin derivative dissolves in water as the solvent. Quantitative solubility represents the saturation concentration of the dihydromyricetin derivative in water at a specific temperature, although the solubility in water is not necessarily limited. The water solubility of the dihydromyricetin derivative is > 20 g / 100 ml water at 25°C ± 5°C. A measurement method for determining water solubility is carried out by precisely weighing the solid DHM derivative using an analytical balance and conducting dissolution tests with varying amounts in different aqueous solutions.

[0025] The phrase "dihydromyricetin derivative that is unpolymerized when completely dissolved in a liquid" means that the dihydromyricetin derivative, when completely dissolved in a liquid, does not form a polymer but exists as a monomer. That is, it does not polymerize when dissolved in the liquid. The liquid may contain one or more solvents. Preferably, the liquid contains or consists of water. It is important that the dihydromyricetin derivative is unpolymerized because it is inactivated upon polymerization. The inventors have found that the dihydromyricetin derivative, when completely dissolved in a liquid, remains unpolymerized over time, which has been verified using various aqueous systems over time experiments.

[0026] The dihydromyricetin derivative is preferably available as a powder. For its production, dihydromyricetin (DHM) is extracted, for example, from the plant Hovenia dulcis and subsequently converted into the dihydromyricetin derivative. DHM is insoluble in aqueous beverages. Through the technical development of specific processes, the DHM is modified into the dihydromyricetin derivative, making it water-soluble so that it dissolves completely in liquids without polymerizing. This also increases its bioavailability when taken orally. Therefore, it can be added to solid and liquid foods and pharmaceuticals.

[0027] In a preferred embodiment, the dihydromyricetin derivative is selected from the group consisting of dihydromyricetin salt, dihydromyricetin ester, dihydromyricetin oxidation product, dihydromyricetin reduction product, dihydromyricetin glycation product, dihydromyricetin glycosylation product, dihydromyricetin addition product, dihydromyricetin substitution product, dihydromyricetin ether, dihydromyricetin ring-cleavage product, dihydromyricetin alkylation product, or dihydromyricetin arylation product. Chemical modifications such as oxidation, reduction (in particular chemical and / or enzymatic reduction), glycation (in particular glycation and / or glycosylation), addition, substitution (in particular ether formation), ring cleavage, alkylation of at least one hydroxyl group, arylation of at least one hydroxyl group, and esterification are also considered.Treatment with acids or halogenations leads to improved hydrophilicity but also to a change in the physiological effect of DHM. Any chemical covalent modification of a molecule results in a change in its physiological effect. The biochemical processes involved are diverse and described in the scientific literature.

[0028] Preferably, the dihydromyricetin derivative is selected from the group consisting of a dihydromyricetin salt with an inorganic cation and a dihydromyricetin ester. One way to modify a hydroxyl group of dihydromyricetin (DHM) is esterification with an acid such as acetic acid, citric acid, boric acid, ascorbic acid, phosphoric acid, sulfuric acid, maleic acid, or malonic acid. The dihydromyricetin derivative is therefore preferably a dihydromyricetin ester, which is a reaction product of the esterification of dihydromyricetin with acetic acid, citric acid, boric acid, ascorbic acid, phosphoric acid, sulfuric acid, maleic acid, or malonic acid. During esterification, it is assumed that the ester bond is hydrolyzed in the gastrointestinal tract. This can result in a difference in bioavailability and / or toxicology compared to unmodified DHM. Esterification requires several production steps and can increase manufacturing costs.

[0029] The preferred dihydromyricetin derivative is the dihydromyricetin salt (XDHM), whose cation is inorganic. This modification of DHM involves the exchange of a proton for a cation. This can be achieved, for example, by reacting DHM with a proton-equimolar cation source such as NaOH, KOH, ammonium chloride, sodium carbonate, potassium carbonate, ammonium carbonate, magnesium carbonate, magnesium chloride, calcium carbonate, or calcium chloride.

[0030] Preferably, the inorganic dihydromyricetin salt is selected from the group consisting of - SDHM or sodium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one, - PotDHM or potassium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one, - ADHM or ammonium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one, - CaDHM or calcium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one, - MgDHM or Magnesium (2R,3R)-3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one.

[0031] In the production of SDHM, PotDHM, ADHM, CaDHM and MgDHM, a proton of a hydroxy group on the trihydroxy-phenyl residue of DHM is exchanged for a cation that is safe for food and drugs, thereby not altering the physiological effect of the DHM, but achieving very good water solubility.

[0032] The following reaction equation is preferably used as a basis for the proton exchange:

[0033] Alternatively, the following reaction equation is preferred for the proton exchange:

[0034] The production process of DHM to XDHM (e.g., SDHM) is preferably as follows: DHM is completely dissolved in ethanol, then a cation source such as baking soda is added for salt conversion. Only when DHM has been converted to XDHM can it separate from the ethanol. The starting material DHM is soluble in ethanol, while XDHM is insoluble. Therefore, DHM and XDHM separate completely in the ethanol. After the conversion of DHM to XDHM, the mixture is filtered, and the crystals separated by filtration are washed to obtain dry XDHM. Residual DHM remains in the ethanol and does not mix with the dry XDHM.

[0035] The invention further relates to a composition containing the dihydromyricetin derivative. The composition can be in solid or liquid form. The term "edible" means that the DHM derivative and / or the composition is non-toxic to humans and animals in any consistency, i.e., liquid or solid.

[0036] In a preferred embodiment, the composition further contains a stabilizer, a preservative, an essential oil, and / or an acid. These additions further prevent polymerization of the DHM in the long term. The dihydromyricetin derivative or the composition is stabilized.

[0037] The preservative is preferably selected from the group of naturally occurring preservatives such as sugar, vinegar (also as acetate), salt, oil or ethanol, and food-approved preservatives such as additives like sorbic acid (also as sorbate), benzoic acid (also as benzoate), sulfur dioxide, nitrite, hexamethylenetetramine, boric acid and natamycin, and mixtures thereof.

[0038] The acid is an acid approved for use in food, such as citric acid (also as monohydrate), phosphoric acid, and mixtures thereof.

[0039] The essential oil is preferably one or more essential oils such as those from citrus fruits, spices and herbs, including medicinal herbs, consisting of hydrocarbons, alcohols and / or terpenes.

[0040] To keep the dihydromyricetin derivative preferably XDHM (X = sodium, potassium, ammonium, calcium, and magnesium) stable in solution in a beverage, a preferred embodiment incorporates physical modifications in the form of stabilization of the dihydromyricetin derivative preferably XDHM for use in aqueous foods and pharmaceuticals using food-safe solvents and / or additives. The following stabilizers are preferred: - Propylene glycol (1,2-propanediol, E 1520, max. 1 g / kg in the final food) - Triethyl citrate (E 1505, max. 1 g / kg in beverages) - Citric acid (E 330, quantum satis) - Phosphoric acid (E338) or sodium phosphate (E339) or potassium phosphate (E340) or other sources of phosphoric acid (0.5 - 20 g / kg) - (Hydroxypropyl)methylcellulose (E 464, quantum satis for food additives or carriers) - Sodium carboxymethylcellulose (E 466, quantum satis) - Polysorbate 80 (E 433, no limit value specified) - Gum arabic (E 414, 1 g / L in energy drinks and fruit juice-based beverages). Preferably, the composition contains citric acid monohydrate. Citric acid monohydrate is a safe and approved food additive. At a concentration of 600 mg / 50 ml of liquid (equivalent to 5 cl of beverage), citric acid monohydrate prevents the polymerization of the dihydromyricetin derivative over the long term.

[0041] To stabilize the DHM derivative XDHM, particularly SDHM, in aqueous solution, the addition of 35-45% vol alcohol is suitable. Tests have shown that XDHM, especially SDHM, remains stable and non-crystallized in beverages and general aqueous solutions when 35-45% vol alcohol is added. For example, 2.5 g of SDHM in 250 ml of beverage with the addition of 35-45% vol alcohol proved stable, and any amount of XDHM can be stable and non-crystallized with a corresponding addition of 35-45% vol alcohol. Examples of suitable beverages include multivitamin juice, blackcurrant nectar, strawberry-flavored berry drinks, grapefruit juice, cola, herbal liqueur, gin, and whisky.

[0042] Preferably, the composition further contains a dispersion medium, a solubilizing agent, a pH modifier, an emulsifier, and / or a dispersing agent. This allows the dihydromyricetin derivative to be further physically modified. Using the dispersion medium, colloidalization can occur. Dissolving the dihydromyricetin derivative with solubilizing agents, e.g., ethanol, propylene glycol, and optionally gold or humic acids, further increases the solubility of the dihydromyricetin derivative in the liquid. pH modification of the composition or of the dihydromyricetin derivative, such as...Adding baking powder (sodium bicarbonate / baking soda, NaHCO3 or potassium bicarbonate, KHCO3) and an acidifying agent often containing phosphate, such as disodium dihydrogen diphosphate (E 450a) or calcium dihydrogen phosphate (E 341a), or a phosphate-free alternative like cream of tartar or sodium carbonate (Na2CO3), can have a stabilizing effect and / or increase the solubility of the dihydromyricetin derivative in the liquid. Emulsifiers also have a stabilizing effect on the dihydromyricetin derivative in the liquid.

[0043] The invention further relates to a use of the dihydromyricetin derivative or the composition - as an anti-hangover additive for a food and / or a medicine to relieve, prevent and / or treat "hangover" symptoms caused by alcohol consumption and / or - to accelerate the breakdown, support the liver and metabolism of alcohol and / or - as an additive for a food and / or a medicinal product to enhance health and well-being, promote concentration and sleep, treat illnesses, prevent illnesses, reduce inflammation, improve health, and / or for administration to humans and animals. As explained above, when the dihydromyricetin derivative or the composition containing dihydromyricetin derivatives is ingested, DHM is released in the body, which, as described above, prevents, relieves, and / or treats hangover symptoms. Its use is primarily intended for humans.

[0044] The foodstuff and / or medicinal product is solid and / or liquid. It can have any consistency. The term "foodstuff" includes solid foods and beverages.

[0045] The invention further relates to a process for producing a dihydromyricetin derivative that is edible and water-soluble and, when completely dissolved in a liquid, is unpolymerized, wherein the process comprises modifying dihydromyricetin to the dihydromyricetin derivative that is edible and water-soluble and, when completely dissolved in a liquid, is unpolymerized or monomeric.

[0046] In a preferred embodiment, the modification of the dihydromyricetin to the dihydromyricetin derivative, which is water-soluble and, when completely dissolved in a liquid, unpolymerized, is carried out by proton exchange, esterification, oxidation, chemical and / or enzymatic reduction, glycation, preferably glycation and / or glycosylation, addition, substitution, preferably ether formation, ring cleavage, alkylation of at least one hydroxy group or arylation of at least one hydroxy group.

[0047] Preferably, the modification involves proton exchange or esterification. The DHM salts or esters underlying the invention have good water solubility, in particular > 20 g / 100 ml. The production process is simple to carry out, the reaction conditions are mild, and it can be performed at room temperature without the need for complex equipment. The cations or acids of the esters are toxicologically safe for use in liquid foods and pharmaceuticals and can therefore be used safely in these product groups.

[0048] Preferably, the modification involves proton exchange. Preferably, a proton from one of the hydroxyl groups is exchanged, resulting in the formation of a dihydromyricetin salt with an inorganic cation as the dihydromyricetin derivative.

[0049] For this process, dihydromyricetin, a solvent such as alcohol (e.g., ethanol or methanol), and a single proton equimolar sodium source (e.g., NaOH or Na₂CO₃), a potassium source (e.g., KOH or K₂CO₃), or an ammonium source (e.g., NH₄Cl or (NH₄)₂CO₃) are preferably used. The sodium-, potassium-, or ammonium-containing powder is added to the alcohol and dissolved using ultrasound. The dihydromyricetin is added and stirred for a predetermined period. After the predetermined period, the resulting solid is filtered off, washed with alcohol if necessary, and then dried to obtain the dihydromyricetin derivative. Instead of the proton equimolar sodium, potassium, or ammonium source, a proton equimolar calcium or magnesium source (e.g., calcium carbonate, magnesium carbonate, calcium chloride, or magnesium chloride) can be used for proton exchange.

[0050] In a preferred embodiment, the process further includes a stabilization step of the resulting dihydromyricetin derivative. To ensure long-term solubility in liquid foods and pharmaceuticals and to prevent polymerization, i.e., inactivation, a stabilizer, e.g., in the form of an acidifying agent, is preferably added to the dihydromyricetin derivative. The stabilizer is, for example, propylene glycol, triethyl citrate, citric acid, phosphoric acid, sodium phosphate, potassium phosphate, or other phosphoric acid sources, (hydroxypropyl)methylcellulose, sodium carboxymethylcellulose, polysorbate 80, and / or gum arabic. Optionally, in addition to adding the stabilizer, the stabilization process includes the use of ultrasound, stirring, and dispersion, e.g., with Ultraturrax (IKA-Werke GmbH & Co. KG, Staufen, Germany).

[0051] The invention further relates to a method for maintaining the long-term solubility of the DHM derivative, preferably XDHM, particularly SDHM, in aqueous solution and for preventing crystallization by adding 35-45% vol alcohol and optionally essential oils or flavorings. This additional component(s) ensures that SDHM remains dissolved and stable over extended periods, making the solution suitable for use in various products such as foods, dietary supplements, and pharmaceuticals. The alcohol is preferably ethanol. Essential oils are preferred, and flavorings are preferred.

[0052] Preferably, a dispersion medium, a solubility enhancer, a pH modifier, an emulsifier, and / or a dispersing agent are added to the DHM. This allows the dihydromyricetin derivative to be further physically modified. Physical modification includes colloid formation, also using ultrasound; dissolving with solubilizers, e.g., ethanol, propylene glycol, also using ultrasound and possibly gold, humic acids; pH modification of the solution or the starting material, e.g., with baking soda (sodium bicarbonate / baking soda, NaHCO3 or potassium bicarbonate, KHCO3) and an often phosphate-containing acidifying agent such as disodium dihydrogen diphosphate (E 450a) or calcium dihydrogen phosphate (E 341a) or a phosphate-free alternative such as cream of tartar or sodium carbonate (Na2CO3); emulsification with, e.g., approved emulsifiers; stirring, also in combination with the methods mentioned above; and dispersion.with Ultraturrax, as well as (re-)sublimation.

[0053] The invention is explained in more detail below by means of figures and examples.

[0054] It shows a schematic representation, not to scale: Fig. 1 a schematic representation of a chemical structure of a dihydromyricetin derivative according to the invention; Fig. 2 a schematic representation of a chemical structure of another dihydromyricetin derivative according to the invention; Fig. 3 a flowchart of a method according to the invention; and Fig. 4 a flowchart of another method according to the invention.

[0055] Fig. Figure 1 shows a schematic representation of a chemical structure of a dihydromyricetin derivative according to the invention. A dihydromyricetin derivative 1 in the form of a dihydromyricetin salt is shown, in which the cation X + N / a + , K + or NH4+ is.

[0056] Fig. Figure 2 shows a schematic representation of the chemical structure of another dihydromyricetin derivative according to the invention. Shown is a dihydromyricetin derivative 2 in the form of a dihydromyricetin salt, in which the cation X + Approx ++ or Mg ++ is.

[0057] Fig. Figure 3 shows a flowchart of a process according to the invention. The process includes a step 3 modifying dihydromyricetin to obtain the water-soluble dihydromyricetin derivative, which, when completely dissolved in a liquid, is unpolymerized.

[0058] Fig. Figure 4 shows a flowchart of another method according to the invention. The method corresponds to the one in Figure 4. Fig. The 3 methods shown differ in that the Modify 3 step is followed by a Stabilise 4 step of the dihydromyricetin derivative obtained in step 3. Examples Example 1: Synthesis of SDHM, PotDHM, ADHM

[0059] For the synthesis or preparation of SDHM, PotDHM, and ADHM, 100 g of dihydromyricetin (0.312256 mol, powder, purity typically >95%), 1000 ml of ethanol (purity 90–100%, preferably 95–100%), and a single proton equimolar sodium, potassium, or ammonium source are used (e.g., 12.49 g NaOH, 17.52 g KOH, or 16.70 g NH₄Cl). Alternatively, another alcohol such as methanol with the same specifications can be used. Other sodium, potassium, or ammonium sources such as sodium carbonate (Na₂CO₃, 16.55 g), potassium carbonate (K₂CO₃, 24.58 g), or ammonium carbonate ((NH₄)₂CO₃, 15.00 g) can also be used. The sodium-potassium or ammonium-containing powder is added to ethanol (or alternatively another alcohol such as methanol) and dissolved using ultrasound. The DHM is added and stirred for 30 minutes. After a 2-hour settling period, the mixture is filtered and the solid is washed with half the amount of alcohol (e.g., 500 ml ethanol).The solid is dried in a drying oven for 4 hours at 60°C-80°C to obtain the DHM derivative in the form of the DHM salt.

[0060] The yield of the prepared DHM derivative is ≥85%. The preservation of the DHM salt is confirmed by HPLC (high-performance liquid chromatography)-DAD (diode array detector) using the addition of ethanol. Example 2: Synthesis of CaDHM, MgDHM

[0061] For the synthesis of CaDHM and MgDHM, 100 g each of dihydromyricetin (0.312256 mol, powder, purity typically >95%), 1000 ml of ethanol (purity 90–100%, preferably 95–100%), and a proton-equimolar calcium or magnesium source such as calcium carbonate (CaCO3, 15.63 g) or magnesium carbonate (MgCO3, 13.16 g) are used. Alternatively, another alcohol such as methanol with the same specifications can be used. Other calcium or magnesium sources such as calcium chloride (CaCl2, 17.33 g) or magnesium chloride (MgCl2, 14.87 g) can also be used. The calcium- or magnesium-containing powder is added to the ethanol (or alternatively, another alcohol such as methanol) and dissolved using ultrasound. The DHM is added and stirred for 30 minutes. After standing for 2 hours, the mixture is filtered and the solid is washed with half the amount of alcohol (e.g. 500 ml ethanol).The solid is dried in a drying oven for 4 hours at 60°C-80°C to obtain the DHM derivative in the form of the DHM salt.

[0062] The yield of the prepared DHM derivative is ≥85%. The preservation of the DHM salt is confirmed by HPLC (high-performance liquid chromatography)-DAD (diode array detector) using the addition of ethanol. Example 3: Production of a composition

[0063] SDHM, as prepared in Example 1, was added to a beverage containing 35-45% vol alcohol. The beverages used were multivitamin juice, blackcurrant nectar, strawberry-flavored berry fruit, grapefruit drink, cola, herbal liqueur, gin, and whiskey. All non-alcoholic beverages were prepared by adding 3 ml of the beverage and 2 ml of ethanol, as well as 80 mg of citric acid monohydrate to every 5 ml of beverage. Then, 250 mg of SDHM was added and dissolved. SDHM dissolved in all beverages, demonstrating long-term solubility.

[0064] A stability test was performed. The target concentration is 2 g of DHM derivative in 50 ml of beverage, which, with a molecular weight of 320.25 g / ml, corresponds to 0.0062451 mol. SDHM has a molecular weight of 342.25 g / mol. 0.0062451 mol of SDHM corresponds to 2.137 g of SDHM. Since SDHM is present with a purity of 85%, 2.51 g of SDHM must be dissolved in 50 ml of beverage. Before adding SDHM, 600–800 mg of citric acid monohydrate are dissolved in 50 ml of the beverage. After preparing 50 ml of the beverage, it is stored in the dark and analyzed at regular intervals using 1H-NMR, which confirmed the stability of the DHM derivative.

[0065] The efficacy of the manufactured DHM derivatives as an anti-hangover additive for a food and / or a medicinal product for the relief, prevention, and / or treatment of hangover symptoms caused by alcohol consumption and / or for accelerating the breakdown and metabolism of alcohol was determined through studies on test subjects. These are summarized in Table 1 below. Table 1: Name of the DHM derivative Amount of DHM derivative ingested Amount of alcohol consumed Time of ingestion before alcohol in minutes Time of ingestion after alcohol consumption in minutes SDHM 1.5 0.751 White wine (Chardonnay) - 30 SDHM 1.5 1.51 beers - 30 SDHM 1.5 2 liters of beer - 30 SDHM 1.5 1 liter of rosé wine 20 - SDHM 1.5 0.5l red wine, 0.5l beer - 30 SDHM 1.7 6x Ramazotti 2cl each 20 - SDHM 1.7 2 Pina Colada 20 - SDHM 1.7 1x Whiskey Sour, 2x Gin & Tonics 20 - SDHM 2.0 2x Gin and Tonic, 2x Aperol Spritz - 30 SDHM 2.0 1 liter of white wine, 2 Aperol Spritz 20 - SDHM 2.0 1 liter of white wine, 1 x Ramazotti 2 cl 30 - SDHM 2.0 2 liters of beer, 1 x Ramazotti 2cl 30 - SDHM 2.4 1 liter of white wine, 8 x Jägermeister 2cl shots, 4 x Rum and Coke - 30 SDHM 2.4 5x Whiskey Sour - 30 SDHM 2.4 II wine, 5xwhiskey sour, 1 beer - 30 SDHM 2.4 2x AperolSpritz, 0.751 white wine, 1xRamazotti 2cl 20 - SDHM 2.4 4x Rum and Coke, 2x Ramazotti 2cl 30 - SDHM 2.4 8x WhiskeySour, 0.51 white wine, 2xRamazotti 2cl 20 - SDHM 2.4 1.0l white wine, 0.51l red wine 30 - SDHM 2.4 1.5 liters of beer, 4 rum and cokes, 1 Hugo cocktail 30 - SDHM 2.4 3x Mojito, 2x Pina Colada - 30 SDHM 2.4 3x Mojito, 0.75l white wine 20 -

[0066] The test subjects described a reduction in "hangover" symptoms through alcohol consumption. Main features of the invention 1. Dihydromyricetin (DHM): A natural extract known for its ability to alleviate the symptoms of a hangover after alcohol consumption by supporting the breakdown of alcohol in the body and improving liver function. 2. Technical Development: Modification processes that make DHM water-soluble in liquid foods and pharmaceuticals and prevent it from polymerizing in liquids. In the synthesis of DHM to XDHM, preferably SDHM, PotDHM, ADHM, CaDHM, and MgDHM, a proton of a hydroxyl group on the trihydroxyphenyl residue is exchanged for a food- and drug-safe cation. This does not alter the physiological effect of DHM but achieves very good water solubility. The addition of, for example, citric acid monohydrate further inhibits polymerization in the long term. 3. Long-term solubility: To maintain the long-term solubility of the DHM derivative in aqueous solutions and to prevent crystallization, 35-45% vol alcohol, as well as optionally essential oils or flavorings, are added. These additional components ensure that the DHM derivative, like SDHM, remains dissolved and stable over extended periods, making the solution suitable for use in various products such as food, dietary supplements, and pharmaceuticals. 4. Powder form: The modified DHM is provided in powder form, which can be easily dissolved in liquid foods or medications, allowing for broad use and enabling faster, more convenient, and more effective administration with improved bioavailability. It can also be marketed as a dietary supplement. Advantages of the invention

[0067] The modification of DHM according to the invention into a water-soluble DHM derivative such as SDHM, PotDHM, ADHM, CaDHM and MgDHM, generally XDHM, offers several advantages over the existing water-insoluble DHM: • Effectiveness: The use of water-soluble and optionally stabilized DHM improves the absorption of the active ingredient in the body, leading to a more effective mode of action. • Ease of use: The water-soluble DHM in powder form allows for simple and flexible application. The powder can be dissolved in various liquids without leaving residues, lumps, or crystals. This makes it easy to take the effective DHM orally. • Range of applications: The water-soluble DHM can be easily added to liquid foods and pharmaceuticals. This opens up new areas of application for DHM. • Use as an anti-hangover powder: Water-soluble DHM such as SDHM, PotDHM, ADHM, CaDHM and MgDHM, generally XDHM, can be mixed into drinks as an anti-hangover powder to help those affected by alcohol consumption in relieving, preventing, treating and regenerating so-called "hangover" symptoms. • Safety and naturalness: The product is based on a natural active ingredient that has been known for its health benefits for centuries. No risks are known when taken in moderation. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited non-patent literature

[0000] Martinez-Coria et al. 2019

[0012]

Claims

[1] Dihydromyricetin derivative (1,2) wherein the dihydromyricetin derivative (1,2) is edible and water-soluble and is unpolymerized when completely dissolved in a liquid. [2] Dihydromyricetin derivative (1,2) according to claim 1, wherein the dihydromyricetin derivative (1,2) is selected from the group consisting of dihydromyricetin salt, dihydromyricetin ester, dihydromyricetin oxide, dihydromyricetin reduction product, dihydromyricetin glycation product, dihydromyricetin glycosylation product, dihydromyricetin addition product, dihydromyricetin substitution product, dihydromyricetin ether, dihydromyricetin ring gap product or dihydromyricetin alkylation product or dihydromyricetin arylation product. [3] Dihydromyricetin derivative (1,2) according to claim 2, wherein the dihydromyricetin derivative (1,2) is selected from the group consisting of a dihydromyricetin salt, wherein the cation is inorganic, and dihydromyricetin esters. [4] Dihydromyricetin derivative (1,2) according to claim 3, wherein the dihydromyricetin derivative (1,2) is the dihydromyricetin salt, wherein the cation is inorganic, wherein the dihydromyricetin salt is preferably selected from the group consisting of sodium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one, potassium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one), ammonium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one), calcium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one), magnesium (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one). [5] Composition containing the dihydromyricetin derivative according to any one of the preceding claims. [6] Composition according to claim 5, further comprising a stabilizer, a preservative, an essential oil and / or an acid, preferably citric acid monohydrate, and / or further comprising a dispersion medium, a solubility enhancer, a pH modifier, an emulsifier and / or a dispersing agent. [7] Composition according to claim 5 or 6, further comprising water, 35-45% vol alcohol and optionally essential oils or flavorings. [8] Use of the dihydromyricetin derivative according to any one of claims 1 to 4 or the composition according to any one of claims 5 to 7 as an anti-hangover additive for a food and / or a medicinal product for the relief, prevention and / or treatment of hangover symptoms caused by alcohol consumption and / or for accelerating the breakdown, support of the liver and metabolism of alcohol and / or as an additive for a food and / or a medicinal product to increase health and well-being, promote concentration, promote sleep, reduce inflammation, improve health and / or for administration to humans and animals. [9] Use according to claim 8, wherein the food and / or the drug is solid and / or liquid. [10] Method for producing a dihydromyricetin derivative (1,2) that is edible and water-soluble and, when completely dissolved in a liquid, is unpolymerized, comprising modifying (3) dihydromyricetin to obtain the edible water-soluble dihydromyricetin derivative (1,2) which, when completely dissolved in a liquid, is unpolymerized. [11] The method of claim 10, wherein the modification of the dihydromyricetin to the water-soluble dihydromyricetin derivative (1,2), which is unpolymerized when completely dissolved in a liquid, is carried out by proton exchange, esterification, oxidation, chemical and / or enzymatic reduction, glycation, preferably glycation and / or glycosylation, addition, substitution, preferably ether formation, ring cleavage, alkylation of at least one hydroxy group or arylation of at least one hydroxy group, and / or wherein the dihydromyricetin derivative (1,2) obtained after modification is stabilized. [12] Method for maintaining the long-term solubility of the DHM derivative according to any one of claims 1 to 4 in aqueous solution and for preventing crystallization by adding 35-45% vol alcohol and optionally essential oils or flavorings.