KR102331317B1 - Composition for improving premenstrual syndrome symptom comprising compounds isolated from Chrysanthemum zawadskii extract - Google Patents

Abstract

The present invention relates to a composition for preventing, improving or treating premenstrual syndrome comprising any one or more of chlorogenic acid, esculetin, and linarin compounds isolated from Guulcho extract, and specifically, the present compounds are a phenomenon occurring in premenstrual syndrome By effectively inhibiting the secretion of prolactin from the pituitary cells, it can be usefully used as a composition for preventing and improving or treating premenstrual syndrome occurring during the luteal phase of women.

Description

Composition for improving premenstrual syndrome symptom comprising compounds isolated from Chrysanthemum　zawadskii extract

The present specification relates to a composition for the improvement, prevention or treatment of premenstrual syndrome comprising chlorogenic acid, esculetin, and linarin, which are compounds isolated from Guulcho extract, as active ingredients.

As defined by the International Classification of Disease ([ICD]-10), minor psychological discomfort, bloating, weight gain, breast tenderness, muscle pain ( When one or more of the seven symptoms of muscular tension or aches), poor concentration, and change in appetite are satisfied, and these symptoms are confined to the luteal phase of the menstrual cycle, it is defined that premenstrual syndrome can be diagnosed. This is a symptom that appears from 4-7 days before menstruation to before menstruation, and the symptoms completely disappear with the onset of menstruation. Therefore, it is classified as a disease different from menstrual pain caused by the peeling of the endometrium during menstruation.

Although the cause of PMS has not been clearly identified, lifestyle habits such as hormonal imbalance and genetic predisposition, ovulation menstrual cycle, drug use, smoking, drinking and caffeine intake, eating pattern, contraceptive use, emotional state, and marital status and social factors, other factors such as age, height and weight, childbirth and menstrual history, and stress are also known to be related to PMS. It has been reported that it can induce the development of premenstrual syndrome. In particular, it has been reported that hormonal problems such as imbalance of progesterone and estrogen and decrease of serotonin due to the increase of prolactin play a very important role in the occurrence of PMS (Biqqs and Demuth, 2011; Imai et al., 2015; Schmidt et al., 2017).

Prolactin is a lactation-stimulating hormone secreted by coral cells of the anterior pituitary gland, and it is known that it is increased by estrogen and decreased by dopamine secreted by the hypothalamus. In the case of normal persons, the secretion of prolactin is higher than that of estrogen in the luteal phase, so the secretion of prolactin is stabilized. It has been reported to induce the syndrome (Halbreich et al., 1976). Based on this, Prefemin Tablet (Agnus castus fruit extract), which exhibits prolactin secretion inhibitory effect, is sold as a representative premenstrual syndrome treatment, and in clinical trials, it relieves symptoms such as irritability, depression, anger, headache, and breast pain. It is known that the improvement is about 50%.

However, there is no research on a method for preventing or treating PMS using chlorogenic acid, esculetin, and linarin, which are active ingredients isolated from Gujeolcho used as a traditional medicine in Korea, or from it.

Korean Patent Publication No. 10-2013-0076114 Korean Patent Publication No. 10-2010-0044433 Korean Patent Publication No. 10-2013-0092256

Accordingly, the present inventors recognized the importance of prevention and treatment for female premenstrual syndrome, and selected natural resources showing the efficacy of inhibiting prolactin secretion in pituitary cells using various natural materials. As a result, Guulcho extract had the effect of inhibiting the secretion of prolactin from pituitary cells, and chlorogenic acid, esculetin, and linarin, which are compounds isolated from Guulcho, have a very excellent inhibitory effect on prolactin secretion. The compounds isolated from the gujeolcho extract of the present invention have a very high potential for commercialization as a composition for the prevention and improvement of premenstrual syndrome, or treatment.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing, improving or treating premenstrual syndrome comprising a compound isolated from the extract of gujeolcho.

Another object of the present invention is to provide a health functional food composition for the prevention and improvement of premenstrual syndrome symptoms comprising a compound isolated from gujeolcho extract.

The object of the present invention is not limited to the object mentioned above. The objects of the present invention will become more apparent from the following description, and will be realized by means and combinations thereof described in the claims.

In order to achieve the above object, the present invention is a chlorogenic acid (chlorogenic acid), esculetin (esculetin), and linarin (linarin) compound isolated from the extract of gujeolcho premenstrual syndrome comprising any one or more as an active ingredient A pharmaceutical composition for prevention or treatment is provided.

In addition, the present invention provides a health functional food composition for the prevention or improvement of premenstrual syndrome symptoms comprising as an active ingredient any one or more of chlorogenic acid, esculetin, and linarin compounds, which are compounds isolated from Guulcho extract.

In one aspect of the present invention, the composition provides a composition, characterized in that it inhibits the secretion of prolactin in women in the premenstrual luteal phase.

In one aspect of the present invention, the symptoms of the premenstrual syndrome are minor psychological discomfort, bloating (bloating), weight gain, breast tenderness, muscle pain (muscular tension or aches) , It provides a composition, characterized in that any one or more of poor concentration and change in appetite, wherein the premenstrual syndrome symptoms appear only in the luteal phase of the menstrual cycle.

Chlorogenic acid, esculetin, and linarin, which are active ingredients isolated from the Guulcho extract of the present invention, effectively inhibit the secretion of prolactin from the pituitary cells. Therefore, chlorogenic acid, esculetin, and linarin, which are compounds isolated from the Guulcho extract, can improve, prevent or treat diseases requiring inhibition of prolactin secretion, that is, premenstrual syndrome.

The effects of the present invention are not limited to the above-mentioned effects. It should be understood that the effects of the present invention include all effects that can be inferred from the following description.

1 shows the chromatographic results of Guulcho extract. (1, chlorogenic acid; 2, esculetin; 3, linarin)
Figure 2 shows the inhibitory effect of chlorogenic acid of the present invention on the secretion of prolactin in the pituitary cells.
Figure 3 shows the inhibitory effect of prolactin secretion in the pituitary cells of the esculetin of the present invention.
Figure 4 shows the inhibitory effect of prolactin secretion in pituitary cells of linarin of the present invention.

Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and amounts of ingredients used herein refer to a variety of measures that may occur in obtaining such values, among others, in which such numbers are inherently different. Since they are approximations reflecting uncertainty, it should be understood as being modified by the term "about" in all cases. Also, where the disclosure discloses numerical ranges, such ranges are continuous and inclusive of all values from the minimum to the maximum inclusive of the range, unless otherwise indicated. Furthermore, when such ranges refer to integers, all integers inclusive from the minimum to the maximum inclusive are included, unless otherwise indicated.

In this specification, when a range is described for a variable, the variable will be understood to include all values within the stated range including the stated endpoints of the range. For example, a range of “5 to 10” includes the values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood to include any value between integers that are appropriate for the scope of the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also for example, a range of "10% to 30%" includes values such as 10%, 11%, 12%, 13%, and all integers up to and including 30%, as well as 10% to 15%, 12% to It will be understood to include any subrange, such as 18%, 20% to 30%, etc., as well as any value between reasonable integers within the scope of the recited range, such as 10.5%, 15.5%, 25.5%, and the like.

Hereinafter, the present invention will be described in detail.

The present invention relates to a composition for preventing, ameliorating or treating premenstrual syndrome comprising a compound isolated from gujeolcho extract as an active ingredient. It can be usefully used as a composition for preventing and improving or treating female premenstrual syndrome by effectively inhibiting the secretion of prolactin from human pituitary cells.

Gujeolcho (Chrysanthemi Zawadskii Herba) is a perennial herb belonging to the Asteraceae family, and the whole plant is used as an herbal medicine. The main components of Gujeolcho are linarin and chlorogenic acid, which are flavonoid compounds, hydroxycoumarin, scopoletin and esculetin, which are coumarin compounds, angeloylcumambrin B and cumambrin A, which are sesquiterpene lactone compounds, and chamazulene, an essential oil component. Action, antipyretic action and hepatoprotective action, sesquiterpene lactone has been reported to have various pharmacological activities such as antitumor activity, cancer cell cytotoxicity, allelopathy, antibacterial action and insecticidal action, as well as protective action, analgesic action, and antioxidant action of gastrointestinal cells. . Gujeolcho of this material is a herbal medicine used in oriental medicine for menstrual irregularities, but irregular menstruation is a disease that generally shows no menstruation or irregular menstruation, which includes rare ovulation and anovulation. Therefore, menstruation must occur, and it is a disease clearly distinguished from premenstrual syndrome, which shows breast tenderness and psychological symptoms in the luteal phase before menstruation. In addition, none of the literature published to date has revealed that the gujeolcho extract and its main components are effective in preventing, improving, or treating female premenstrual syndrome due to suppression of prolactin secretion.

Accordingly, the present invention provides a chlorogenic acid compound represented by the following formula (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient for preventing, improving or treating premenstrual syndrome A composition is provided.

[Formula 1]

Chlorogenic acid of the present invention is a compound of polyphenol, one of ester compounds of quinic acid and caffeic acid, and is mostly present in fruits or leaves of dicotyledonous plants. The chemical name of the chlorogenic acid is (1S,3R,4R,5R)-3-{[(2Z)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy}-1,4,5-trihydroxycyclohexanecarboxylic acid It can be isolated from a naturally occurring, commercially available one (eg, SIGMA-ALDRICH), or synthesized by a method known in the art. Chlorogenic acid has been known in the past for its inhibitory effect on the production of lipid peroxide, cholesterol biosynthesis inhibitory effect, antioxidant activity, and anticancer activity, but its prevention, improvement or therapeutic effect on premenstrual syndrome in women during the luteal phase has not been revealed.

In addition, the present invention provides an esculetin compound represented by the following Chemical Formula 2, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient to prevent, improve or improve premenstrual syndrome. A therapeutic composition is provided.

[Formula 2]

The esculetin of the present invention is a coumarin derivative and is widely present in plants including Gujeolcho, plum, lemon, and wormwood. The esculetin is also called 6,7-Dihydroxycoumarin, it can be isolated from a naturally occurring, commercially available one (eg, SIGMA-ALDRICH), or synthesized by a method known in the art. can Esculetin is known in the prior art for platelet aggregation, antioxidant, inhibitory effect on breast cancer and lung cancer, bone loss inhibitory effect, anti-aging effect, etc., but the prevention, improvement or treatment effect for premenstrual syndrome in women's luteal phase has been found. none.

In addition, the present invention is a linarin compound represented by the following formula (3), an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, as an active ingredient, prevention, improvement or treatment of premenstrual syndrome comprising A composition is provided.

[Formula 3]

Linalin of the present invention is a flavonoid-based compound and is known to exist in large amounts in Gujeolcho. The lininin may be isolated from a naturally occurring, commercially available one (eg, SIGMA-ALDRICH), or may be synthesized by a method known in the art. Linalin has been known in the past for its analgesic and antipyretic action, osteoporosis improvement effect, liver damage relief effect, antidiabetic effect, and dementia prevention effect, but the prevention, improvement or treatment effect for premenstrual syndrome in the luteal phase of women has been revealed. none.

Accordingly, the present invention provides a pharmaceutical composition for the prevention and treatment of premenstrual syndrome comprising any one or more of chlorogenic acid, esculetin, and linarin isolated or synthesized from the Guulcho extract as an active ingredient. In a preferred embodiment, the active ingredient is preferably an active ingredient separated from the Gujeolcho extract.

In addition, the present invention provides a health functional food composition for preventing and improving premenstrual syndrome comprising as an active ingredient any one or more of chlorogenic acid, esculetin, and linarin isolated or synthesized from the Guulcho extract. In a preferred embodiment, the active ingredient is preferably an active ingredient separated from the Gujeolcho extract.

Various aspects of the present invention are described below.

One aspect of the present invention provides a composition for the improvement, prevention or treatment of premenstrual syndrome, comprising chlorogenic acid isolated from gujeolcho extract as an active ingredient.

Another aspect of the present invention provides a composition for improving, preventing, or treating premenstrual syndrome, comprising esculetin isolated from the Guolcho extract as an active ingredient.

Another aspect of the present invention provides a composition for improving, preventing or treating premenstrual syndrome, comprising linarin isolated from the Guulcho extract as an active ingredient.

One aspect of the present invention is a chlorogenic acid compound represented by the following Chemical Formula 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; Esculetin compound represented by the following formula (2), its optical isomer, its pharmaceutically acceptable salt, its hydrate or its solvate; and a Linarin compound represented by the following Chemical Formula 3, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; It provides a composition for improving, preventing or treating premenstrual syndrome, comprising any one or more of them as an active ingredient.

[Formula 1]

[Formula 2]

[Formula 3]

In one aspect of the present invention, the active ingredient is a chlorogenic acid compound represented by Chemical Formula 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, improvement of premenstrual syndrome, A composition for prevention or treatment is provided.

In one aspect of the present invention, the active ingredient is a chlorogenic acid compound represented by Formula 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; Esculetin compound represented by Formula 2, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a Linarin compound represented by Formula 3, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; It provides a composition for improving, preventing or treating premenstrual syndrome, which includes all of them.

As used herein, "isomers" are in particular optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers or mixtures thereof), as well as conformational isomers ( includes conformation isomers (i.e. isomers that differ only in the angle of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (e.g. cis-trans isomers) do.

As used herein, "essentially pure", for example, when used in reference to an enantiomer or diastereomer, contains at least about 90%, preferably about 95%, of a specific compound exemplified by enantiomer or diastereomer. or more, more preferably about 97% or more, or about 98% or more, even more preferably about 99% or more, even more preferably about 99.5% or more (w/w).

As used herein, "pharmaceutically acceptable" is approved by the government or equivalent regulatory body for use in animals, more specifically humans, by avoiding significant toxic effects when used in conventional medical dosages. means that it is available for, or has been approved for, or recognized as being listed in a pharmacopoeia or other general pharmacopoeia.

As used herein, "pharmaceutically acceptable salt" refers to a salt according to an aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. The salts are formed by (1) inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid , 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, acid addition salts formed with organic acids such as tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) salts formed when an acidic proton present in the parent compound is substituted.

As used herein, the term “hydrate” refers to a compound to which water is bonded, and is a broad concept including inclusion compounds that do not have a chemical bonding force between water and the compound.

As used herein, the term “solvate” refers to a higher-order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent.

The compounds of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

Acid addition salts according to the invention can be prepared by conventional methods, for example, by dissolving the compound of the invention in an aqueous solution of an excess of acid, and dissolving the salt in a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using

It can also be prepared by heating the same amount of the compound represented by the formulas 1, 2, and 3 and an acid or alcohol in water, and then evaporating the mixture to dryness or suction filtration of the precipitated salt.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-dissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. Also, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

In one aspect of the present invention, the compound represented by Formula 1, the compound represented by Formula 2, and the compound represented by Formula 3 are each independently isolated from or synthesized from the Guulcho extract, premenstrual syndrome It provides a composition for improvement, prevention or treatment of

The gujeolcho extract may be one obtained by extracting gujeolcho by a conventional extraction method, and may be an extract having a powdered form by drying the extract under reduced pressure and freeze-drying. The malt extract may be obtained by extracting malt by a conventional extraction method, and may be an extract having a powdered form by drying the extract under reduced pressure and freeze-drying. In addition, the aloe extract may be extracted by a conventional extraction method, the extract may be an extract having a powdered form by drying the extract under reduced pressure and freeze-drying, and freeze-dried immediately after peeling the skin of aloe. It may be a powder.

The composition for preventing, improving or treating premenstrual syndrome having the above composition of the present invention is obtained by extracting Gujeolcho, malt, and aloe each or together using an extraction solvent that is water, alcohol, alcohol, or a mixture thereof according to a conventional method. The extract can be obtained and used, and if necessary, the extraction process can be repeated, and the extract extracted 2 to 5 times can be used. In addition, the powdery dry extract obtained by freeze-drying the extract can be prepared and used in the composition for preventing and improving or treating the premenstrual syndrome.

The content of alcohol in the extraction solvent is 0 to 95% by weight of alcohol, preferably 30 to 70% by weight, more preferably 70% by weight of Gujeolcho, 50% by weight of malt, and 30% by weight of aloe. Keeping it is good in terms of extraction efficiency. Such alcohol can be applied as long as it is generally used in the art, and preferably, an alcohol having 1 to 5 carbon atoms, the alcohol may be one or more selected from methanol, ethanol, isopropanol, propanol and butanol. More preferably, the alcohol may be ethanol, alcohol, or the like.

The extraction method is a method commonly known in the art, for example, a method using an extraction device such as supercritical extraction, subcritical extraction, high temperature extraction, high pressure extraction or ultrasonic extraction, or an adsorption resin including XAD and HP-20. How to use, etc. can be used.

In addition, the extract is concentrated under reduced pressure using a vacuum rotary evaporator or the like to obtain an extract. In addition, the obtained extract can also be dried under reduced pressure, vacuum drying, boiling drying, spray drying, room temperature drying, freeze drying, etc. as needed. In particular, when the method of freeze-drying is applied, there is an advantage that the loss of volatile organic substances in the extract can be reduced.

In one aspect of the present invention, the compound represented by Formula 1, the compound represented by Formula 2, and the compound represented by Formula 3 are each independently isolated from the Guulcho extract, improvement, prevention of premenstrual syndrome Or it provides a composition for treatment.

In one aspect of the present invention, the composition provides a composition, characterized in that it inhibits prolactin secretion in premenstrual luteal women.

In one aspect of the present invention, the symptoms of the premenstrual syndrome are minor psychological discomfort, bloating (bloating), weight gain, breast tenderness, muscle pain (muscular tension or aches) ), decrease in concentration (poor concentration) and change in appetite (change in appetite) is any one or more, the premenstrual syndrome symptoms are characterized in that appear only in the luteal phase of the menstrual cycle, it provides a composition.

In one aspect of the present invention, the composition for preventing or treating premenstrual syndrome is a pharmaceutical composition, it provides a composition.

In one aspect of the present invention, the composition for improving premenstrual syndrome provides a health functional food composition, the composition.

In one aspect of the present invention, the content of chlorogenic acid, esculetin and linarin in the composition may each independently be provided in an amount of 0.001 to 50% by weight based on the total weight of the composition.

The compositions effectively inhibit the secretion of prolactin from the pituitary cells. In addition, the compositions are compounds isolated from natural products that have been routinely ingested and taken, and can be safely used for preventing, improving, or treating PMS.

Accordingly, in one aspect of the present invention, the composition provides a composition, characterized in that it safely inhibits prolactin secretion in premenstrual women in the luteal phase.

When the pharmaceutical composition is used clinically, it is formulated with a carrier conventional in the pharmaceutical field to prepare conventional formulations in the pharmaceutical field, for example, tablets, capsules, powders, granules, pills, liquids and suspensions. formulations for oral administration; Injection preparations in the form of solutions or suspensions for injection, or ready-to-use dry powder for injection that can be prepared with distilled water for injection at the time of injection; Or it can be formulated into various preparations such as ointments. Pharmaceutical preparations prepared using conventional carriers can be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or topically. Accordingly, the pharmaceutical composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceuticals.

Carriers, excipients and diluents that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, hydroxymethyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, povidone, crospovidone, croscarmellose sodium, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, noi At least one selected from sirin, colloidal silicon dioxide, lactose, talc, magnesium stearate, colloidal magnesium stearyl, and mineral oil may be included.

In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, troches, rosins, capsules, and the like, and these solid preparations include at least one excipient in the composition of the present invention, for example, lactose, saccharose, sorbitol. , mannitol, starch, amylopectin, cellulose, calcium carbonate, gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, elixirs, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol gelatin and the like can be used. For parenteral administration, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection may be common.

The preferred dosage of the pharmaceutical composition of the present invention varies depending on the patient's age, weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art. However, for desirable effects, the pharmaceutical composition of the present invention may be administered at 0.001 mg/kg to 10 g/kg per day, preferably 0.1 mg/kg to 1 g/kg. Administration may be administered several times a day at regular time intervals according to the judgment of a doctor or pharmacist, preferably 1 to 6 divided doses.

In one aspect of the present invention, the composition for improving premenstrual syndrome provides a health functional food composition, the composition.

The health functional food composition according to the present invention contains chlorogenic acid, esculetin, and linarin compounds contained in Gujeolcho as active ingredients, and can be ingested for the purpose of improving the premenstrual state. The active ingredient may be ingested as food prepared in tablets, capsules, powders, granules, pills, liquids, suspensions, or the like, or added to general food. Since the health functional food uses food as a raw material unlike general drugs, there is an advantage in that there are no side effects that may occur when taking the drug for a long time. The content of the active ingredient may be appropriately determined depending on the purpose of its use (for prevention or improvement). In general, the active ingredient in the health functional food composition may be included in 0.1 to 90% by weight. However, in the case of long-term ingestion for health and hygiene purposes or for health control, the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

There is no particular limitation on the type of the food. Examples of foods to which the active ingredient can be added include drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, and various soups. , beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, and includes all health functional foods in the ordinary sense. The properties of the food are also not particularly limited, and may be any of a solid form, a semi-solid form, a gel form, a liquid form, a powder form, and the like.

It can be prepared as a beverage by using the health functional food composition of the present invention. As a component included in the beverage, there is no particular limitation in the selection of other components other than the active component, and it may contain various flavoring agents or natural carbohydrates as additional components as in a conventional beverage. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.

In addition, the health functional food composition of the present invention, in addition to the active ingredient, various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and Salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like may be contained as additives. In addition, it may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages. These components may be used independently or in combination. Although the proportion of these additives is not so important, it is generally selected in the range of 0.1 to 20% by weight in the health functional food composition of the present invention.

Hereinafter, the present invention will be described in more detail through specific examples. The following examples are merely examples to help the understanding of the present invention, and the scope of the present invention is not limited thereto.

[Example]

Preparation Example: Preparation of Gujeolcho Extract

Gujeolcho was purchased from the Gyeongdong Market, dried in the shade and ground, then 1 kg of ground gujeolcho was extracted with 70% alcohol at 80°C for 5 hours, and then concentrated and freeze-dried to obtain 117.4 g of gujeolcho extract (yield 11.7%).

[Experimental example]

Experimental Example 1: Analysis of components contained in Gujeolcho extract

The Guulcho extract obtained in Preparation Example was analyzed using high performance liquid chromatography (HPLC).

HPLC (LC-20AD, Shimadzu Corp., Japan) was used for the analysis of the gujeolcho extract, and after diluting the gujeolcho extract in the preparation example to a concentration of 10 mg/mL, it was filtered with a 0.45 μm syringe filter, and the 10 μL was injected and analyzed. As the analytical column, Skypak C18 (250X4.6 mm) was used, the mobile phase A used for analysis was an acetonitrile solution, and the mobile phase B used a 0.05% trifluoacetic acid aqueous solution. The conditions of the mobile solvent were initially 15% for mobile phase A and 85% for mobile phase B, and at 47 minutes, 23% for mobile phase A and 77% for mobile phase B. The mobile phase flow rate was 0.5 mL/min, and analysis was performed at a UV wavelength of 254 nm.

The chromatography results of each component are shown in FIG. 1 .

As shown in FIG. 1, chlorogenic acid, esculetin, and linarin compounds were detected in the 70% alcohol extract of Gujeolcho, and the contents were 34.8±0.36, 43.7±5.66, and 25.4±0.92 mg/g, respectively.

1) Chlorogenic acid

2) Esculetin

3) Linarin

Experimental Example 2: Measurement of Prolactin Secretion Inhibition Efficacy

The inhibitory efficacy of prolactin secretion with respect to the chlorogenic acid, esculetin, and linarin compounds isolated from the Guulcho extract was measured using pituitary cells.

Rat pituitary cell GH3 was purchased from ATCC (American Type Culture Collection), DMEM culture medium, trypsin, and FBS (Fetal bovine sereu) were ^{purchased from Gibco (Gibco TM} , Invitrogen corporation), and the prolactin ELISA kit for measurement was Mol- Purchased from innovation and used.

First, GH3 pituitary cells at a concentration of 4 × 10 ⁴ cells/well were dispensed in a 24-well plate, and cultured for 24 hours. Then, for the induction of high prolactin, estradiol (E ₂ ) was treated with 1 nM to each cell. For the evaluation of prolactin secretion inhibitory efficacy, each of chlorogenic acid, esculetin, and linaline compounds were treated at 1, 5, and 25 μg/mL, and for comparison with the positive control group, prefemin tablet, a commercialized premenstrual syndrome treatment, was used. Treated with 100 μg/mL. After culturing the sample-treated cells for 48 hours, the amount of prolactin secretion was quantified by substituting the standard curve for the rat prolactin ELISA kit.

The secretion amount of prolactin from chlorogenic acid is schematically illustrated in FIG. 2 , esculetin is illustrated in FIG. 3 , and linarin is illustrated in FIG. 4 .

As shown in FIG. 3 , chlorogenic acid exhibited very good prolactin secretion inhibitory efficacy when treated at a concentration of 5 μg/mL, and as shown in FIGS. 4 and 5, esculetin and linarin were very It showed a high inhibitory effect on prolactin secretion. In addition, each active ingredient showed a significant inhibitory effect when compared to prefemin tablets sold as a treatment for premenstrual syndrome.

[Formulation example]

On the other hand, the pharmaceutical composition comprising the active ingredient according to the present invention can be prepared in various forms depending on the purpose. The following formulations 1 to 4 exemplify the pharmaceutical preparation method containing the active ingredient according to the present invention, but the present invention is not limited thereto.

Formulation 1: Tablet (Direct Pressurization)

After 5.0 mg of the active ingredient was sieved, lactose 14.1 mg, crospovidone USNF 0.8 mg, and magnesium stearate 0.1 mg were mixed and pressurized to make tablets.

Formulation 2: Tablet (wet granulation)

After sieving 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving 0.3 mg of polysorbate 80 in pure water, an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation 3: Powders and Capsules

After sieving 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. Mix the mixture into a solid No. Filled in 5 gelatin capsules.

Formulation 4: Injection

An injection was prepared by containing 100 mg as an active ingredient, and also containing 180 mg of mannitol, _{26 mg of Na 2} HPO ₄ 12H ₂ O, and 2974 mg of distilled water.

In addition, the health food composition comprising the active ingredient according to the present invention can be prepared in various forms depending on the purpose. The following formulations 5 to 9 exemplify the manufacturing method of a health food containing the active ingredient according to the present invention, but the present invention is not limited thereto.

Formulation 5. Granular Health Food

Active ingredient 1000 mg, vitamin A acetate 70 µg, vitamin E 1.0 mg, vitamin 0.13 mg, vitamin B ₂ 0.15 mg, vitamin B ₆ 0.5 mg, vitamin B ₁₂ 0.2 µg, vitamin C 10 mg, biotin 10 µg, nicotinic acid amide 1.7 mg, folic acid 50 μg, calcium pantothenate 0.5 mg, ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, potassium monophosphate 15 mg, dibasic calcium phosphate 55 mg, potassium citrate 90 mg, calcium carbonate 100 ㎎, magnesium chloride 24.8 mg was mixed, and then granular health food was prepared according to a conventional method.

Formulation 6. Health drink

Active ingredient 1000 mg, citric acid 1000 mg, oligosaccharide 100 g, plum concentrate 2 g, and taurine 1 g were mixed, and purified water was added thereto to adjust the total volume to 900 ml. After stirring and heating at 85° C. for about 1 hour, the resulting solution was filtered and obtained in a sterilized 2L container, sealed and sterilized to prepare a health drink.

Although the composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demanding class, demanding country, and use.

Formulation 7. Flour Foods

0.5 to 5 g of the active ingredient was added to 100 g of wheat flour, and the mixture was used to prepare breads, cakes, cookies, crackers, and noodles to prepare health-promoting foods.

Formulation 8. Dairy Products

5 to 10 g of the active ingredient was added to 100 g of milk, and various dairy products such as butter and ice cream were prepared using the milk.

Formulation 9. Seonshik

30 g of brown rice, 20 g of barley, 10 g of glutinous rice, and 15 g of barley radish were pregelatinized by a known method, dried, and then roasted and prepared as a powder having a particle size of 60 mesh with a grinder. 7 g of black soybeans, 7 g of black sesame, and 7 g of perilla were steamed and dried by a known method, and then dried to prepare a powder having a particle size of 60 mesh with a grinder. A wire meal was prepared by mixing 3 g of the active ingredient of the present invention with the grains and seeds prepared above.

Above, the embodiments of the present invention have been described with reference to the accompanying drawings, but those of ordinary skill in the art to which the present invention pertains can practice the present invention in other specific forms without changing its technical spirit or essential features. You will understand that there is Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (9)

a chlorogenic acid compound represented by the following Chemical Formula 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
Esculetin compound represented by the following Chemical Formula 2, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and
Linarin compound represented by the following formula (3), its optical isomer, its pharmaceutically acceptable salt, its hydrate or its solvate;
A composition for improving, preventing or treating premenstrual syndrome, comprising any one or more of them as an active ingredient.
[Formula 1]

[Formula 2]

[Formula 3]

The method of claim 1,
The active ingredient is a chlorogenic acid compound represented by Formula 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, and a composition for improving, preventing or treating premenstrual syndrome.
3. The method of claim 2,
The active ingredient may include a chlorogenic acid compound represented by Formula 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
Esculetin compound represented by Formula 2, its optical isomer, its pharmaceutically acceptable salt, its hydrate or its solvate; and
Linarin compound represented by Formula 3, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; A composition for improving, preventing or treating premenstrual syndrome, which includes all of them.
According to claim 1,
The compound represented by Formula 1, the compound represented by Formula 2, and the compound represented by Formula 3 are each independently isolated from or synthesized from Guulcho extract, a composition for improving, preventing or treating premenstrual syndrome .
According to claim 1,
The compound represented by Formula 1, the compound represented by Formula 2, and the compound represented by Formula 3 are each independently isolated from Guulcho extract, a composition for improving, preventing or treating premenstrual syndrome.
According to claim 1,
The composition is characterized in that it inhibits the secretion of prolactin in women in the premenstrual luteal phase, the composition.
According to claim 1,
Symptoms of the premenstrual syndrome include minor psychological discomfort, bloating, weight gain, breast tenderness, muscle tension or aches, poor concentration And any one or more of appetite change (change in appetite),
The premenstrual syndrome symptoms are characterized in that only appear in the luteal phase of the menstrual cycle, the composition.
8. The method according to any one of claims 1 to 7,
The composition for preventing or treating premenstrual syndrome is a pharmaceutical composition.
8. The method according to any one of claims 1 to 7,
The composition for improving premenstrual syndrome is a health functional food composition, composition.

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