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WO2014185601A1 - Composition pharmaceutique pour le traitement prophylactique ou thérapeutique des symptômes de la ménopause contenant un composé flavonoïde dérivé d'un extrait de toxicodendron vernicifluum au titre de principe actif - Google Patents

Composition pharmaceutique pour le traitement prophylactique ou thérapeutique des symptômes de la ménopause contenant un composé flavonoïde dérivé d'un extrait de toxicodendron vernicifluum au titre de principe actif Download PDF

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Publication number
WO2014185601A1
WO2014185601A1 PCT/KR2013/009056 KR2013009056W WO2014185601A1 WO 2014185601 A1 WO2014185601 A1 WO 2014185601A1 KR 2013009056 W KR2013009056 W KR 2013009056W WO 2014185601 A1 WO2014185601 A1 WO 2014185601A1
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extract
estrogen
preventing
active ingredient
flavonoid compound
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Korean (ko)
Inventor
나천수
홍철이
윤순영
김진범
노현정
노혜지
엄나나
동미숙
나대승
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LIFETREE BIOTECH Co Ltd
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LIFETREE BIOTECH Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the present invention relates to a pharmaceutical composition for preventing and treating menopausal syndrome, which contains a flavonoid compound derived from Rhus verniciflua extract or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Estrogens have a variety of biological actions, including cell number growth and differentiation.
  • the biological actions of estrogens are exerted through two estrogen receptor alpha (ER- ⁇ ) and estrogen receptor beta (ER- ⁇ ) belonging to the nuclear receptor superfamily (Nilsson et al., 2001, Physiol. Rev., 81 (4): 1535-1565.).
  • the mechanism of action of the estrogen receptor (ER) is a combination of estrogen and intracellular estrogen receptors to form dimers of the receptors, which are located in specific estrogen receptor elements located in the promoters of target genes. elements, EREs) to regulate the expression of related genes.
  • estrogen receptors Since the two estrogen receptors have different tissue distribution patterns, ligand binding forces and sites of metastatic activity, these differences allow different selective roles of agonists and antagonists of estrogen receptors in different tissues (Kuiper et et al. al., 1997, Endocrinology, 138 (3): 863-870.). Compounds acting on estrogen receptors have been used as targets for hormone replacement therapy in postmenopausal women and for the development of chemotherapeutic agents in genital cancer.
  • SERMs selective ER modulators
  • ER- ⁇ is known to induce the proliferation of breast cancer cells, while ER- ⁇ is known to be a tumor suppressor, it is histoselective and antagonizes ER- ⁇ while acting as an ER- ⁇ agonist.
  • Various attempts have been made to derive compounds and develop them as hormone replacement therapy.
  • Phytoestrogens are compounds that bind to estrogen receptors and mimic or regulate the roles of estrogens produced in the body (Setchell, 1998, Am. J. Clin. Nutr., 68: 1333-1346.). These compounds are structurally diverse and include flavonoids, stilbenes and lignans. Their structural features can exert estrogen or antiestrogenic activity through binding to estrogen receptors.
  • phytoestrogens activate genes of both types of estrogen receptors. If phytoestrogens that selectively activate ER- ⁇ or ER- ⁇ can be identified, they can be developed as hormone replacements to minimize the cancer-causing side effects of estrogens. Can be. Phytoestrogens that selectively act on two estrogen receptors, ER- ⁇ or ER- ⁇ , can be usefully used for the treatment and prevention of various menopausal syndromes.
  • the present inventors while studying substances having selective activity on the estrogen receptor alpha (ER- ⁇ ) and the estrogen receptor beta (ER- ⁇ ), purely known flavonoid compounds and novel flavonoid compounds from the sumac extract After separation and purification, the chemical structure was determined, and the present invention was completed by confirming that the compound exhibits selective activity on the estrogen receptor and thus can be usefully used for the prevention and treatment of menopausal syndrome.
  • ER- ⁇ estrogen receptor alpha
  • ER- ⁇ estrogen receptor beta
  • Another object of the present invention is to provide a health food composition for preventing and improving menopausal syndrome, which contains the lacquer extract-derived flavonoid compound as an active ingredient.
  • the present invention has estrogen activity, Sulfurintin (Sulfuretin), Gabanzol (Garbanzol), Resorcinol (Resorcinol), Fustin (Fisetin), Butene (Butein) And it provides a pharmaceutical composition for preventing or treating menopausal syndrome as an active ingredient of any one or more Flavonoid compound or a pharmaceutically acceptable salt thereof selected from Butin (Butin).
  • Sulfurin and Garbanzol do not affect estradiol by simultaneous treatment with estradiol, have excellent estrogen activity, and have selective activity on estrogen receptor beta (ER- ⁇ ).
  • ER- ⁇ estrogen receptor beta
  • the resorcinol does not affect estradiol by concurrent treatment with estradiol, has excellent estrogen activity at low concentrations, and has a selective activity on estrogen receptor beta (ER- ⁇ ). It is preferable as an active ingredient of a pharmaceutical composition for preventing or treating a syndrome.
  • Fustin and Fisetin have lower estrogen activity than Sulfurin, Garbanzol and Resorcinol, but dose-dependently increases estrogen activity.
  • Does not affect the estradiol action has selective activity on the estrogen receptor beta (ER- ⁇ ), and also contains more than 10 g, 1 g or more for each 100 g of Rhus verniciflua extract solids It is preferable as an active ingredient of the pharmaceutical composition for preventing or treating menopausal syndrome in that it can be obtained.
  • the present invention provides a having estrogenic activity, sumac (Rhus verniciflua) extract the menopausal syndrome preventive or therapeutic pharmaceutical composition of which, as an active ingredient.
  • nutraceutical composition for preventing or improving menopausal syndrome which comprises at least one flavonoid compound selected as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving menopausal syndrome having an estrogen activity, Rhus verniciflua extract as an active ingredient.
  • Flavonoid compounds and lacquer extracts of the present invention have selective activity on estrogen receptor beta (ER- ⁇ ), and thus are phytoestrogens with reduced side effects, compositions for the prevention and treatment of menopausal syndrome, or health functions for preventing or improving menopausal syndrome. It can be usefully used as a food composition.
  • ER- ⁇ estrogen receptor beta
  • Example 1 is a schematic view showing a process of separating the flavonoid compound of the present invention from the sumac extract in Example 2.
  • Figure 2 shows the structural formula of the compound isolated in Example 2.
  • Figure 3a is a graph showing the cytotoxicity according to the concentration of the lacquer extract (RV10) and the cytotoxicity according to the mixed administration of the lacquer extract and estradiol (E2) in MCF7 / ERE cells in Experimental Example 1,
  • Figure 3b It is a graph showing the cytotoxicity according to the concentration of seven species of flavonoid compounds isolated from the lacquer extract against MCF7 / ERE cells.
  • Figure 4a is a graph showing the in vitro estrogen activity according to the concentration of the lacquer extract (RV10)
  • Figure 4b is an estrogen when treated with ICI 182.770 (ICI), an estrogen receptor inhibitor with the lacquer extract (RV10) It is a graph showing the activity
  • Figure 4c is a graph showing the estrogen activity according to the concentration of the seven flavonoid compounds isolated from the lacquer extract.
  • estrogen-dependent genes namely estrogen receptor alpha (ER- ⁇ ), of seven species of the flavonoid compounds isolated in Example 2 and the lacquer extract powder of Example 1 in the estrogen dependent gene expression confirming experiment of Experimental Example 3; Northern blot images of estrogen receptor beta (ER- ⁇ ), progesterone receptor (PR) and pS2 genes are shown.
  • ER- ⁇ estrogen receptor alpha
  • PR progesterone receptor
  • 6A and 6B show the expression rate of DMSO using the result of Experiment 3 as a negative control group as 1, and estrogen receptor alpha (ER- ⁇ ), estrogen receptor beta (ER- ⁇ ) and pS2 according to the type and concentration of the sample, respectively. It is a graph showing the change in the expression rate of the gene.
  • 7A to 7F are results of confirming the selective expression of the estrogen receptor alpha or beta genes of Experimental Example 4, respectively, according to the concentrations of the lacquer extract (RV10), sulfuretin, gabansol, resorcinol, phycetin and fustin, respectively. It is a graph showing the estrogen activity of the estrogen receptor alpha (ER- ⁇ ) and beta (ER- ⁇ ).
  • the present invention relates to a pharmaceutical composition for preventing or treating menopausal syndrome, which comprises at least one selected flavonoid compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition for preventing or treating menopausal syndrome, which comprises at least one selected flavonoid compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • flavonoids selected from Sulfurintin (Sulfuretin), Garbanzol, Resorcinol, Resorcinol, Fustin, Fisetin, Butein and Butin Flavonoid) compounds can be isolated from Rhus verniciflua extract.
  • the wood portion of the lacquer is cut and dried in the shade for at least one week, preferably at least one month, more preferably at least three months, and then crushed or used as is.
  • the upper limit of the drying period does not need to be set separately, and one that is dried for one year or several years may be used. In addition, it can be used to produce wood chips or sawdust without drying the wood part of the lacquer.
  • the lacquer tree processed as described above may be prepared by using water, an organic solvent or a mixture thereof as an extraction solvent.
  • the lacquer extract may be extracted.
  • the kind of organic solvent used at this time and the mixing ratio of water and an organic solvent are not specifically limited.
  • the organic solvent may be one or more solvents selected from the group consisting of lower alcohols, hexane, acetone, ethyl acetate, chloroform, and diethyl ether.
  • the lower alcohol may be an alcohol having 1 to 6 carbon atoms.
  • methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol, normal-butanol, 1-pentanol, 2-butoxyethanol or ethylene glycol may be used as the lower alcohol.
  • Organic solvents include polar solvents such as acetic acid, dimethyl-formamide (DMFO) and dimethyl sulfoxide (DMSO), acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, 2,2,4-trimethylpentane, and decane.
  • polar solvents such as acetic acid, dimethyl-formamide (DMFO) and dimethyl sulfoxide (DMSO), acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, 2,2,4-trimethylpentane, and decane.
  • nonpolar solvents such as benzene, diethyl ether, diethyl sulfide, chloroform, dichloromethane, 1,2-dichloroethane, anneal, diethylamine, ether, carbon tetrachloride, and THF (Tetrahydrofuran).
  • the lacquer extract may be an extract of water, a lower alcohol or a mixture thereof, preferably, a lacquer hydrothermal extract or a lacquer ethanol aqueous solution, for example, lacquer alcohol extract.
  • the term 'extract' also includes fractions that additionally fractionate the extract. That is, the sumac extract includes not only those obtained by using the aforementioned extraction solvent, but also those obtained by additionally applying a purification process thereto.
  • the lacquer extract may be an ethyl acetate fraction obtained by fractionation with hexane to remove the nonpolar portion and the remaining aqueous layer fractionated with ethyl acetate.
  • the term 'extract' as used herein referring to the lacquer extract includes not only the crude extract obtained by treating the extracting solvent on the lacquer, but also the processed product of the lacquer extract.
  • the sumac extract may be prepared in powder form by additional processes such as distillation under reduced pressure and freeze drying or spray drying.
  • fractions obtained by passing the extract or fraction through an ultrafiltration membrane having a constant molecular weight cut-off value separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity), etc.
  • separation by various chromatography manufactured for separation according to size, charge, hydrophobicity or affinity
  • Any one or more flavonoid compounds may be isolated.
  • this separation process first extract the lacquer extract with hexane to separate the non-polar part, and the remaining aqueous layer is fractionated with ethyl acetate and concentrated under reduced pressure, the hexane layer, ethyl acetate layer, water divided by polarity Three fractions of the layer can be separated by silica gel and then separated using a variety of chromatographic methods such as sephadex LH-20, ODS-A, diol, preparative MPLC, or preparative HPLC.
  • Figure 1 shows a schematic process of obtaining each compound through this process.
  • the present invention includes not only the flavonoid compounds but also all pharmaceutically acceptable salts thereof, and possible solvates, hydrates, racemates, or stereoisomers which may be prepared therefrom.
  • the flavonoid compound of the present invention can be used in the form of a pharmaceutically acceptable salt, and the salt is an acid addition salt formed by a pharmaceutically acceptable free acid.
  • 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, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts according to the invention can be prepared by conventional methods, for example, by dissolving the flavonoid compound in an excess of aqueous acid solution, and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
  • An equivalent amount of the flavonoid compound and an aqueous acid solution or alcohol may be heated, and then the mixture is evaporated to dryness, or the precipitated salt may be produced by suction filtration.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-dissolving compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
  • Flavonoid compounds or lacquer extract showed MCF7 / ERE cell viability of at least 80% up to 100 ⁇ g / ml, showing no cytotoxicity.
  • the flavonoid compound or lacquer extract of the present invention was treated with an estrogen receptor inhibitor ICI 182.770, the activity was lowered, the flavonoid compound or lacquer extract showed a concentration dependence and was dependent on the estrogen receptor.
  • the uterine weight was significantly increased at a dose of 20 mg / kg or more in vivo ( in In vivo ) estrogen activity was confirmed.
  • the term 'comprising as an active ingredient' in the present specification is a sulfurintin (Sulfuretin), Gabanzol (Garbanzol), Resorcinol (Resorcinol), Fustin (Fisetin), Butane It is meant to include an amount sufficient to achieve the efficacy or activity of any one of the flavonoid compounds selected from (Butein) and Butin (Butin) or a pharmaceutically acceptable salt thereof, or lacquer extract.
  • the pharmaceutical composition for preventing or treating menopausal syndrome of the present invention preferably comprises 0.1 to 50% by weight of the flavonoid compound or lacquer extract based on the total weight of the composition, but is not limited thereto.
  • composition of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of a medicament.
  • composition according to the present invention can be used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods. have.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the composition of the present invention, for example, starch, calcium carbonate, sucrose (sucrose), lactose (lactose), gelatin, etc. are mixed and prepared.
  • lubricants such as magnesium stearate and talc are also used.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • the non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol gelatin and the like can be used.
  • composition of the present invention can be administered orally or parenterally, any parenteral administration method can be used, systemic or topical administration is possible, but systemic administration is more preferred, and intravenous administration is most preferred.
  • compositions of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art.
  • the composition of the present invention is preferably administered at 0.0001 to 0.03 g / kg, preferably at 0.001 to 8 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
  • the present invention is any one selected from Sulfurintin (Sulfuretin), Garbanzol, Resorcinol (Resorcinol), Fustine (Fustin), Pisetin (Fisetin), Butein (Butein) and Butin (Butin) It provides a health functional food composition for preventing and improving menopausal syndrome containing one flavonoid compound or lacquer extract as an active ingredient.
  • the health functional food composition there is no particular limitation on the type of food.
  • foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and the like includes all the health functional foods in the conventional sense.
  • the flavonoid compound or lacquer extract of the present invention may be added to food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the flavonoid compound or lacquer extract When preparing a beverage, there are no special limitations to the other ingredients except for containing the flavonoid compound or lacquer extract as essential ingredients in the ratios indicated, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of natural carbohydrates is generally from about 1 to 20 g, preferably from about 5 to 12 g per 100 compositions of the present invention.
  • flavonoid compounds or lacquer extract of the present invention various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, coloring and neutralizing agents (such as cheese, chocolate), 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 drinks and the like.
  • the flavonoid compound or lacquer extract of the present invention may contain a pulp for the production of natural fruit juice and fruit juice beverage and vegetable beverage.
  • the proportion of such additives is not so critical but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the flavonoid compounds or lacquer extract of the present invention.
  • 'menopausal syndrome' refers to a symptom caused by a decrease in hormone production in postmenopausal women
  • the menopausal or menopausal symptoms generally include hot flashes, sweating, sweating during sleep, dry skin, vaginal dryness, vaginal atrophy, Lower urethral atrophy, intercourse pain, vaginitis, cystitis, urination pain, urination, concentration disorders, short-term memory disorders, anxiety, nervousness, decreased memory, decreased libido, myalgia or joint pain.
  • the wood parts of the sumac collected from Wonju-si, Gangwon-do were naturally dried for more than 3 months, and then crushed to about 11 ⁇ 1 ⁇ 0.2cm in the wood chip maker.
  • the lacquer extract powder (490 g) of Example 1 was separated with hexane to separate the non-polar part, and the remaining aqueous layer was partitioned with ethyl acetate, and concentrated under reduced pressure. The hexane layer, the ethyl acetate layer, and the water layer divided by polarity were separated. In the ethyl acetate layer of the fractions, a single compound was isolated and purified by applying various chromatographic techniques.
  • Butin (8) and butein (5) were purified through a reverse phase chromatography (ODS-A, 12nm S-75 ⁇ m, TMC GEL) column process.
  • ODS-A reverse phase chromatography
  • Fraction 6 (SB3-6-6, 8g) was subjected to a silica open column using chloroform and methanol to obtain Sulfuretin (9) and urs-12-en-18 ⁇ H-3 ⁇ -O- ⁇ -D-glucopyranoside (18). was isolated, and the remaining fractions were purified by 4-hydroxybenzoic acid (11) and guibourtacacidin (19) through prep-HPLC, respectively.
  • Example 2 Seven kinds of flavonoid compounds isolated from Example 2 for MCF7 / ERE cells in which MCF7 cells, which are breast cancer cell lines, contain 3x estrogen response element (ERE) in a promoter region and were permanently transfected with plasmid using luciferase as a reporter gene.
  • EEE estrogen response element
  • MCF7 / ERE cells were plated at a concentration of 1.2 X 10 4 in 96 well plates and the samples were treated at various concentrations after 24 hours. After 24 hours of incubation at 37 ° C. in a 5% CO 2 incubator, cytotoxicity was performed using a CellTiter 96 AQ ueous Non-Radioactive Cell Proliferation Assay kit (Promega, USA). After removing the cell culture medium, the medium was changed to a medium containing MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfopheny) -2H-tetrazolium) solution. After standing at 1 ° C.
  • MTS 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfopheny) -2H-tetrazolium
  • the absorbance values were compared with the control group by reading the absorbance at 490 nm using a microplate reader.
  • the negative control group was treated with 0.1% DMSO instead of the sample, and the positive control group was treated with 100 pM of ethynyl estradiol (E2).
  • luciferase reporter gene analysis was performed by the following method.
  • MCF7 / ERE cells incubated with 5% charcoal stripped FBS phenol-red free DMEM medium for 24 hours were plated with 1.2 X 10 4 cells per well in 96 well plates and treated with various concentrations of lacquer extract or isolates after 24 hours. .
  • luciferase activity in lysates obtained by lysis of cells was measured using a mono luciferase assay kit (Promega, USA). The total protein mass in lysate was quantified using a Bio-Rad protein assay kit (Bio-Rad, USA) to correct luciferase values.
  • RT-PCR Reverse transcription-polymerase chain reaction
  • estrogen receptor alpha is reduced by estrogen, but the expression of progesterone receptor (PR) and pS2 genes is increased, and the expression of these genes was observed to observe the estrogen action of the isolates.
  • estrogen receptor beta was observed to determine whether the expression of the ER- ⁇ -mediated reporter gene assay is increased by the expression of flavonoid compounds isolated.
  • the estrogen-dependent genes of the lacquer extract powders of the seven species and Example 1 namely the estrogen receptor alpha (ER- ⁇ ), the estrogen receptor beta (ER- ⁇ ), the progesterone receptor (PR) and pS2 Northern blot images of genes are shown in FIGS. 5A and 5B.
  • Beta-actin ( ⁇ -actin) was used as a control to confirm gene expression.
  • the expression rate of DMSO used as a negative control group was reported as 1, and changes in the expression rates of the estrogen receptor alpha (ER- ⁇ ), the estrogen receptor beta (ER- ⁇ ), and the pS2 gene according to the type and concentration of the sample were shown in FIGS. Shown in
  • Rhus oleracea (RV10) and Resosinol showed estrogen action at low concentrations, and the expression of pS2 gene was decreased at low concentrations, especially the expression of estrogen receptor beta (ER- ⁇ ).
  • ER- ⁇ estrogen receptor beta
  • Gene expression was also significantly increased, which may contribute to the estrogen action of R. chinensis extract (RV10).
  • HEK293T cells were seeded in a 48-well plate at a concentration of 4.0 x 10 4 cells / well. After 24 hours, the medium was removed and ER- ⁇ -plasmid, ER- ⁇ -plasmid, pERE reporter gene plasmid, and pRL-TK lipofectamine. 2000 (invitrogen, USA) was mixed with medium mixed with 5% charcoal stripped FBS phenol-red free DMEM and temporarily transfected. After 24 hours the samples were treated at various concentrations. After 24 hours of incubation at 37 ° C. in a 5% CO 2 incubator, luciferase activity in lysates obtained by lysis of cells was measured using a dual luciferase assay kit (Promega, USA). The results were determined by the ratio of firefly luciferase activity and RL-TK derived renilla luciferase activity.
  • the lacquer extract (RV10) was able to confirm that estrogen receptor beta (ER- ⁇ ) mediated estrogen action was much greater, and estrogen receptor beta (ER- ⁇ ) mediated in sulfuretin and gaborazole of FIGS. 7B and 7C. It was confirmed that the estrogen action is remarkably large, the estrogen receptor beta (ER- ⁇ ) mediated estrogen action in the case of the resorcinol, phycetin and fustin of Figure 7d to 7f compared to the estrogen receptor alpha (ER- ⁇ ) It was somewhat larger, but not large compared to sulfuretin and gabansol.
  • Seventy seven-week-old female Sprague-Dawley rats were purchased and adapted for one week, and 60 uterus were extracted under ether anesthesia. After 2 weeks recovery, 1) sham control, 2) control, 3) ethynylestradiol (EE) alone, 4) sumac extract (RV10) low concentration (20mg / kg) , 5) medium concentration group of lacquer extract (100mg / kg), 6) high concentration of lacquer extract and 7) simultaneous administration of ethynyl estradiol (EE) and lacquer extract (500mg / kg).
  • the sumac extract was suspended orally by 1% CMC, and ethynyl estradiol (EE) was administered intraperitoneally for 3 consecutive days at a dose of 0.2 ⁇ g / kg / day.
  • EE ethynyl estradiol
  • Figure 8a shows the weight
  • Figure 8c shows the weight of the uterus
  • Figure 8d shows the weight of the dried uterus.
  • Uterine weight of the ethynyl estradiol (EE) treated group was similar to that of the Sham group.
  • Sumac extract (RV10) treated group significantly increased uterine weight but showed no concentration dependence.
  • wet uterine weight was not significantly higher than that of ethynyl estradiol (EE) treatment group, but increased.
  • Body weight did not change significantly by administration of the sumac extract.
  • the above ingredients are mixed and filled in an airtight cloth to prepare a powder.
  • tablets are prepared by tableting according to a conventional method for preparing tablets.
  • the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
  • the amount of the above ingredient is prepared per ampoule (2 ml).
  • each component is added to the purified water to dissolve, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled into a brown bottle.
  • the liquid is prepared by sterilization.
  • Vitamin B 2 0.15 mg
  • Vitamin B 6 0.5 mg
  • composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method.
  • the granules may be prepared and used for preparing a health food composition according to a conventional method.
  • the resulting solution is filtered and obtained in a sterilized 2l container, sealed sterilization and refrigerated and then stored in a healthy beverage Used to prepare the composition.
  • composition ratio is mixed with a component suitable for a favorite beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
  • Chewing gum was prepared using conventional methods using the above composition and content.
  • Example 1 0.5 to 5 parts by weight of the RV10 of Example 1 or the flavonoid compound of Example 2 was added to 100 parts by weight of wheat flour, and the mixture was used to prepare bread, cake, cookies, crackers, and noodles to prepare health promoting food.
  • Flavonoid compounds and lacquer extract of the present invention can be usefully used as a composition for the prevention and treatment of menopausal syndrome, or a health functional food composition for the prevention or improvement of menopausal syndrome.

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Abstract

La présente invention concerne une composition pharmaceutique destinée au traitement prophylactique ou thérapeutique des symptômes de la ménopause, la composition contenant un extrait de Toxicodendron vernicifluum, ou un composé flavonoïde qui en est dérivé ou l'un de ses sels de qualité pharmaceutique, au titre de principe actif. L'extrait de Toxicodendron vernicifluum ou le composé flavonoïde qui en est dérivé selon la présente invention présente une activité qui est plus sélective vis-à-vis du récepteur bêta des œstrogènes (ER-β) que du récepteur alpha des œstrogènes (ER-α) et ainsi, étant un phyto-œstrogène avec moins d'effets secondaires, peut être employé avantageusement dans le traitement prophylactique et thérapeutique des symptômes de ménopause.
PCT/KR2013/009056 2013-05-16 2013-10-10 Composition pharmaceutique pour le traitement prophylactique ou thérapeutique des symptômes de la ménopause contenant un composé flavonoïde dérivé d'un extrait de toxicodendron vernicifluum au titre de principe actif Ceased WO2014185601A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200027344A (ko) * 2018-09-04 2020-03-12 경희대학교 산학협력단 칠피 추출물 중 피세틴 성분을 포함하는 자궁근종의 예방 또는 치료용 약학 조성물

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KR20080071655A (ko) * 2007-01-31 2008-08-05 (주)생명의나무 옻나무 추출물을 포함하는 성기능 개선용 제약 조성물
KR20080107049A (ko) * 2007-06-05 2008-12-10 한국과학기술연구원 옻나무 추출물, 이의 분획물 또는 상기 분획물에서 분리한화합물을 포함하는 당뇨병 합병증 예방 및 치료용 조성물
WO2009158007A2 (fr) * 2008-06-27 2009-12-30 Limerick Biopharma, Inc. Procédés et compositions pour traitement thérapeutique
KR20130040663A (ko) * 2011-10-14 2013-04-24 (주)생명의나무 옻나무 추출물을 함유하는 고지혈증 및 지방간 개선 및 예방용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030008437A (ko) * 2001-07-18 2003-01-29 (주)생명의나무 옻나무 추출물을 포함하는 성호르몬 분비촉진용 조성물
KR20080071655A (ko) * 2007-01-31 2008-08-05 (주)생명의나무 옻나무 추출물을 포함하는 성기능 개선용 제약 조성물
KR20080107049A (ko) * 2007-06-05 2008-12-10 한국과학기술연구원 옻나무 추출물, 이의 분획물 또는 상기 분획물에서 분리한화합물을 포함하는 당뇨병 합병증 예방 및 치료용 조성물
WO2009158007A2 (fr) * 2008-06-27 2009-12-30 Limerick Biopharma, Inc. Procédés et compositions pour traitement thérapeutique
KR20130040663A (ko) * 2011-10-14 2013-04-24 (주)생명의나무 옻나무 추출물을 함유하는 고지혈증 및 지방간 개선 및 예방용 조성물

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200027344A (ko) * 2018-09-04 2020-03-12 경희대학교 산학협력단 칠피 추출물 중 피세틴 성분을 포함하는 자궁근종의 예방 또는 치료용 약학 조성물
KR102134376B1 (ko) 2018-09-04 2020-07-15 경희대학교 산학협력단 칠피 추출물 중 피세틴 성분을 포함하는 자궁근종의 예방 또는 치료용 약학 조성물

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