WO2013085338A2 - Composition pharmaceutique destinée à la prévention et au traitement de maladies métaboliques, comprenant un extrait de rhizome de nymphéa tétragonal, ses fractions, ou des composés à base de polyphénol isolés de l'extrait de rhizome de nymphéa tétragonal en tant que principes actifs - Google Patents

Composition pharmaceutique destinée à la prévention et au traitement de maladies métaboliques, comprenant un extrait de rhizome de nymphéa tétragonal, ses fractions, ou des composés à base de polyphénol isolés de l'extrait de rhizome de nymphéa tétragonal en tant que principes actifs Download PDF

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WO2013085338A2
WO2013085338A2 PCT/KR2012/010625 KR2012010625W WO2013085338A2 WO 2013085338 A2 WO2013085338 A2 WO 2013085338A2 KR 2012010625 W KR2012010625 W KR 2012010625W WO 2013085338 A2 WO2013085338 A2 WO 2013085338A2
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formula
root extract
metabolic diseases
pharmaceutical composition
preventing
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PCT/KR2012/010625
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English (en)
Korean (ko)
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WO2013085338A3 (fr
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이현선
김문옥
서지희
안종석
이철호
박정준
한아름
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한국생명공학연구원
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Priority claimed from KR1020120141752A external-priority patent/KR101462463B1/ko
Publication of WO2013085338A2 publication Critical patent/WO2013085338A2/fr
Publication of WO2013085338A3 publication Critical patent/WO2013085338A3/fr

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    • 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)
    • A61K36/62—Nymphaeaceae (Water-lily family)
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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

Definitions

  • compositions for the prevention and treatment of metabolic diseases containing water lily extract, fractions thereof or polyphenol-based compounds isolated therefrom as active ingredients
  • the present invention provides obesity, type 2 diabetes mellitus, dyslipidemia, insulin resistance, hepatic steatosis, and non-alcoholic activity containing water extract extract, fractions thereof, or polyphenol-based compounds isolated therefrom as active ingredients.
  • the present invention relates to a pharmaceutical composition for preventing and treating metabolic diseases such as fatty liver. .
  • the triglyceride biosynthesis is a multistage reaction, the first of which is catalyzed by glycerol-3-phosphate acyl transferase (GPAT) and the glycerol 3-phosphate of glycerol 3-phosphate.
  • the fatty acid (fatty acyl-CoA) a form of acyl-coenzyme A, is transferred to the STT 1 position to catalyze the ester reaction of producing lysophosphatidic acid OysophosphaticHc acid (LPA) and glycerol-3 It is known as the rate-1 imiting step that regulates the rate of the glycerol-3-phosphate pathway (Be 11 et al, Annu Rev Biochem 49: 459-487, 1980).
  • the final step is the biosynthesis of triglycerides by diacylglycerol acyl transferase (DGAT).
  • DGAT diacylglycerol acyl transferase
  • GPAT has four types of isoenzymes in mammalian tissues and is distinguished by their sensitivity to N-ethylmaleimide (NEM) and their location.
  • NEM N-ethylmaleimide
  • MtGPATl and mtGPAT2 present in the membrane (MOM) are resistant to NEM and have a characteristic of favoring saturated fatty acyl-CoO as a substrate (Gonzanlez-Baro et al. Biochim. Biophys. acta, 1771: 830-).
  • mtGPAT accounts for about 10% of total GPAT activity in most tissues of the human body, but up to 50% of total GPAT activity in liver tissues and high activity in adipose tissues. (Bell et al, Annu Rev Biochem 49: 459-487, 1980; Lewin et al. Arch. Biochem. Biophys. 396: 119-127, 2001), suggesting that mtGPAT is an important component of fatty liver formation, obesity and insulin resistance treatment. It can be a useful target.
  • mtGPAT is known to be affected by diet and exercise. Studies have shown that when high calorie diets can be used to consume excess calories, the mRNA expression of mtGPAT is increased and the activity of mtGPAT is increased as a result. In the mice group, mtGPAT activity was steadily increased compared with mice without exercise at all, resulting in a significant increase in triglyceride synthesis (KuMp et al. 2006).
  • mice CPT-1 and ⁇ —oxidation were activated, and mtGPAT-deficient (mtGPAT—) mice had 373 ⁇ 4 less triglyceride in the liver and 15% less blood than the control group.
  • VLDL very low density lipoprotein
  • mtGPAT ⁇ /- was observed in mice to increase insulin sensitivity after weight and fat loss (Hammond et al, Mol Cell Biol 22). : 8024-8214, 2002; Hammond et al, J Biol Chem 280: 25629x25636, 2005).
  • GPAT inhibition may be a function of inhibiting intracellular accumulation of triglycerides, and the development of low molecular weight inhibitors that regulate the fat accumulation and energy metabolic role of GPAT has been associated with obesity, type 2 diabetes, dyslipidemia, insulin resistance, It may be a strategy to develop therapeutic agents for metabolic diseases such as hepatic steatosis and non-alcoholic fatty liver.
  • mtGPAT inhibitor compounds include cyclopentenyl acetic acid ⁇ 010 6] ⁇ 1 ⁇ 1 acetic acid derivatives (Eydysh et al. Bioorg. Med. Chem. 2010, 18: 6470-6479), 2- (nonylsulfonamido) and benzoic acid (benzoic acid) derivatives (Eydysh et al. J. Med. Chem. 2009, 52: 3317-3327) are known, but exhibited weak inhibitory activity as enzyme inhibitors with IC 50 values between 25 ⁇ and 350 ⁇ . The enzyme source used was interpreted as a mitochondrial fraction of 3 ⁇ 4, which is still in its infancy.
  • Patent No. 1 in which the genetic inhibition of mtGPAT and lipid metabolism-related enzymes in collaboration with FASgen and Princeton University of the United States, is effective in the inhibition and treatment of various viral infections is known (TO 2011/019498).
  • An object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of metabolic diseases containing water lily root 0V73 ⁇ 4oA3es tetragona) extract as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing and treating metabolic diseases, comprising a fraction obtained by fractionating the water lily root extract using an organic solvent.
  • another object of the present invention is a pharmaceutical composition for preventing and treating metabolic diseases comprising a polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for preventing and treating metabolic diseases comprising a polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention to provide a health food composition for preventing and improving metabolic diseases containing water lily root extract, fractions thereof or polyphenol-based compounds isolated therefrom as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of metabolic diseases containing water lily root (vVj / ⁇ ea tetragona) extract as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing and treating metabolic diseases, including a fraction obtained by fractionating the water lily root extract using an organic solvent.
  • the present invention is a polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof as an active ingredient
  • a pharmaceutical composition for preventing and treating metabolic diseases including a fraction obtained by fractionating the water lily root extract using an organic solvent.
  • the present invention also provides a method for treating metabolic disease comprising administering a pharmaceutically effective amount of a water lily root extract to an individual suffering from metabolic disease.
  • the present invention provides a method of preventing metabolic diseases comprising administering to a subject a pharmaceutically effective amount of a water lily root extract.
  • the present invention also provides a method of treating metabolic disease comprising administering a pharmaceutically effective amount of an organic solvent fraction of water lily root extract to an individual suffering from metabolic disease.
  • the present invention provides a method for preventing metabolic diseases comprising the step of throwing a pharmaceutically effective amount of an organic solvent fraction of water lily root extract to an individual.
  • the present invention comprises administering a pharmaceutically effective amount of the polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof to an individual suffering from metabolic disease. It provides a method of treating metabolic diseases.
  • the present invention provides a method for treating a metabolic disease comprising administering to a subject a pharmaceutically effective amount of the polyphenolic compound of Formula 1, Formula 2 or Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically effective amount of the polyphenolic compound of Formula 1, Formula 2 or Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof comprising administering to a subject a pharmaceutically effective amount of the polyphenolic compound of Formula 1, Formula 2 or Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a composition for preventing and improving metabolic diseases containing water lily extract as an active ingredient. ⁇
  • the present invention provides a composition for preventing and improving metabolic diseases, including a fraction obtained by fractionating the water lily root extract using an organic solvent.
  • the present invention provides a composition for preventing and improving metabolic diseases, including the polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the present invention also provides a composition containing a water lily root extract for use in the prevention and treatment of metabolic diseases.
  • the present invention also provides a composition containing an organic solvent fraction of water lily root extract for use in the prevention and treatment of metabolic diseases.
  • the present invention also provides a polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof, for use in the prevention and treatment of metabolic diseases.
  • the present invention also provides the use of water lily root extract for use in the preparation of pharmaceutical compositions for the prevention and treatment of metabolic diseases.
  • the present invention also provides the use of an organic solvent fraction of a water lily root extract for use in the preparation of a pharmaceutical composition for the prevention and treatment of metabolic diseases.
  • the present invention provides a use of the polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for preventing and treating metabolic diseases. do.
  • the present invention provides the use of water lily root extract for use in the manufacture of a composition for the prevention and improvement of health foods for metabolic diseases.
  • the present invention provides the use of the organic solvent fraction of the water lily root extract for use in the preparation of the composition for the health food for preventing and improving metabolic diseases.
  • the present invention provides a use of the polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof for use in the preparation of a health food composition for the prevention and improvement of metabolic diseases to provide.
  • Water lily root extract, extracts thereof or polyphenolic compounds isolated from the fractions according to the present invention effectively inhibit the activity of mtGPATl causing metabolic disease, inhibit the biosynthesis of intracellular triglycerides and insulin-dependent in skeletal muscle cells As it was confirmed that it showed the activity to increase glucose intake, Including the polyphenolic compounds of the present invention, water extracts or their fractions containing them are useful for the prevention and treatment of metabolic diseases such as obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis and nonalcoholic fatty liver. Can be used.
  • 1 and 2 is a diagram showing the inhibitory activity of hGPATl of the water extract methanol extract, butanol fraction and the compound isolated from the fraction.
  • 1 is a diagram showing the inhibitory activity of hGPATl of the water extract methanol extract and solvent fractions.
  • Figure 2 is a diagram showing the hGPATl inhibitory activity of the formula (1), (2), (3) or (4).
  • FIG. 3 is a diagram showing the effect of inhibiting triglyceride biosynthesis in HepG2 cells (human-derived hepatocytes) of the methanol extract and the solvent fraction of the water lily root.
  • 4 and 5 are views showing the glucose intake activity of the water lily root extract and fractions and the separated compounds.
  • L6 cells which are the murine skeletal muscle cells of the extract and fraction of the water lily root.
  • L6 cells which are skeletal muscle cells of the mouse of Formula 1, Formula 2, Formula 3 or Formula 4.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of metabolic diseases containing water lily root GVJ 3es tetragona) extract as an active ingredient.
  • the present invention provides a composition comprising a water lily root extract for use in the prevention and treatment of metabolic diseases.
  • ⁇ Nymphaea tetragonaY means all organs of natural, hybrid, or cultivar, including all roots, branches, branches, leaves, and flowers. .
  • the extract may be extracted with water, a solvent of C 4 alcohol or a mixture thereof, and specifically, the alcohol may be ethanol or methanol, but is not limited thereto.
  • the water lily root extract may be prepared by a manufacturing method comprising the following steps, but is not limited thereto:
  • step 3 drying the filtered extract of step 2) under reduced pressure.
  • the water lily root of step 1) can be used without limitation, such as being grown or commercially available.
  • the water lily root may be to use the water lily underground, but is not limited thereto.
  • Extraction method of the water lily root extract may be used in the art, such as filtration, hot water extraction, immersion extraction, reflux kinkak extraction and ultrasonic extraction, may be one to five times by the hot water extraction method, More specifically, the extraction may be repeated three times, but is not limited thereto.
  • the extraction solvent may be added 0.1 to 10 times to the dried water lily root, it is preferable to add 0.3 to 5 times.
  • the extraction temperature may be 20 to 40, but is not limited thereto.
  • the extraction time may be 12 to 48 hours, but is not limited thereto.
  • the decompression concentration in step 3) may be to use a vacuum decompression concentrator or a vacuum rotary evaporator, but is not limited thereto.
  • the drying may be, but not limited to, drying under reduced pressure, vacuum drying, boiling drying, spray drying or freeze drying.
  • the metabolic disease consists of obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis and non-alcoholic fatty liver. It may be selected from the group, but is not limited thereto.
  • the present invention provides a pharmaceutical composition for preventing and treating metabolic diseases, including a fraction obtained by fractionating the water lily root extract using an organic solvent.
  • the present invention also provides a composition comprising an organic solvent fraction of water lily root extract for use in the prevention and treatment of metabolic diseases.
  • the organic solvent may be selected from the group consisting of nucleic acid, chloroform and butanol, but is not limited thereto.
  • the fraction may be a nucleic acid fraction, chloroform fraction, butanol fraction or water fraction obtained by systematic fractionation of water lily root extract in the order of hexane, chloroform, butanol and water, but is not limited thereto.
  • the nucleic acid is n-nucleic acid.
  • the metabolic disease may be selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis, and nonalcoholic fatty liver, but not limited thereto.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of metabolic diseases containing a polyphenol-based compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of metabolic diseases containing a polyphenol-based compound of Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for the prevention and treatment of metabolic diseases-containing a cliphenol-based compound of Formula 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of metabolic diseases containing a polyphenol-based compound of Formula 4 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention is for use in the prevention and treatment of metabolic diseases It provides a polyphenolic compound of Formula 1, Formula 2, Formula 3 or Formula 4, or 0 pharmaceutically acceptable salts.
  • Compounds of Formula 1, Formula 2, Formula 3 and Formula 4 may be isolated from the water lily root extract, respectively, but are not limited thereto, and those derived from other substances or synthesized may be used.
  • the metabolic disease may be selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis, and nonalcoholic fatty liver, but is not limited thereto.
  • the present inventors pulverized the water lily root to prepare a water lily root extract and fractions were extracted by dipping in methanol. The extract was filtered, concentrated under reduced pressure to obtain methane. The extract was extracted with methane, chloroform, butanol, and water, and the fractions were extracted to obtain active fractions. — Inhibition of 3-phosphate acyltransferase (huraan glycerol-3-phosphate acyl transferase (hGPATl)) showed that butane was better inhibited in fractions.
  • 3-phosphate acyltransferase huraan glycerol-3-phosphate acyl transferase (hGPATl)
  • the present inventors separated the butanes into eight fractions using reverse phase column chromatography while increasing the polarity sequentially with a methanol / water mixed solvent.
  • Fractions 1 to 8 the fractions with the strongest inhibitory activity were collected and the active fractions were separated by eluting with methane using Sephatex LH-20 (Sephadex LH20).
  • fractions with strong inhibitory activity were collected, and high-performance liquid chromatography (YMC J'sphere ODS H-80 column, 250 20 ⁇ ) was carried out by pouring methanol / water mixed solvent at 5 ml / min as elution solvent.
  • Four compounds (Formula 1, Formula 2, Formula 3, and Formula 4) were obtained.
  • the present inventors have determined the properties, molecular weights, molecular formulas, mass spectrometry, ' 3 ⁇ 4-NMR spectra, and 13 C-NMR spectra of the compounds as disclosed in Hideyuki Kurihara et a. ⁇ . Biosci. Biotech. Biochem. , 57 (9): 1570-1571, 1993; Wen-Hua Zhao et al. J. Chroma togr. B., 850, 523-527, 2007; RW Owen et al. Food and Chemical Toxicology. , 41, 1727-1738, 2003], geranin,
  • the present inventors cloned human hGPATl cDNA (NCBI accesstion No. NM ⁇ 020020) into pFastBacl vector and transfected recombinant bacmid DNA into Sf9 cells in order to isolate the mass expression of hGPATl (human GPAT1) and hGPATl enzyme source.
  • hGPATl human GPAT1
  • hGPATl enzyme source human GPATl
  • a baculovirus containing human hGPATl 0 ⁇ ' was assembled and amplified. Cells were recovered and homogenized using an ultrasonic cell crusher. Only supernatant was taken and centrifuged. The obtained precipitate was suspended in a complete sucrose solution and used as an enzyme source of mitochondrial hGPATKmitochondrial hGPATl).
  • the precipitate obtained by centrifugation of the supernatant from which the precipitate was removed was suspended in sucrose buffer and used as a microsomal h
  • the radiation dose of [ 14 C] lysophosphatidic acid ([ 14 C] Lysophosphat lic acid) was measured.
  • the activity of mitochondrial hGPATl was measured in an ice bath with 2 mM N 2ethylmaleimide for 15 minutes in the mitochondrial hGPATl enzyme source before the experiment.
  • microsomal hGPATl activity was measured by pretreatment of N-ethylmaleimide (2 mM) with microsomal hGPATl enzyme source to determine the ratio of total hGPATl activity and enzymatic activity of microsomal hGPATl.
  • the enzyme activity was measured by correcting the activity result of the microsomal hGPATl enzyme source.
  • Substrates used for enzyme reaction were [ 14 C] glycerides -3 ⁇ phosphate (1.8 ⁇ ) and palmitoleyl-CoA (100 ⁇ ). The reaction was stopped by water and water. The reaction product was separated into a water layer and a butanol layer by centrifugation.
  • a supernatant (layered butane) containing [ 14 C] lysophosphatidic acid was taken.
  • the supernatant was shaken with the same amount of water and separated again into a water layer and a butanol layer by centrifugation.
  • the supernatant was taken up to 600 ⁇ to obtain the amount of radioactivity (Disintegrations per minute (DPM)) using a liquid scintillation counter (LSC).
  • DPM Disintegrations per minute
  • LSC liquid scintillation counter
  • the water lily root extract, fractions thereof, or acyclic polyphenol-based compounds isolated therefrom showed excellent hGPATl inhibitory activity and showed hGPATl inhibitory activity in a concentration-dependent manner (see Table 1, Table 2, Figs. 1 and 2). ).
  • HepG2 cells which are human-derived hepatocytes, were used to measure the triglyceride biosynthesis inhibitory activity in cells against two substrates.
  • Table 3 the water lily extract and the fractions were treated at a concentration of 50 /, respectively.
  • the water extracts of Butyl root extract or butane were treated with fractions of the water extracts and butane including insulin, and then Krebs-Ringer buffer (Krebs-Ringer Buffer, KRB).
  • KRB Krebs-Ringer Buffer
  • Cells cultured in KRB were labeled with 2-deoxy-D-glucose and labeled 2-deoxy-2-glucose, 2-deoxy-D- [ 14 C] glucose, 0.2 uCi. / ml) and reacted for 10 minutes.
  • the glucose intake was determined by measuring with a scintillation counter.
  • the treatment of water extract or butane significantly increased glucose uptake compared to the control group (DMS0) and was dependent on insulin.
  • the following experiment was performed using a mouse.
  • the experimental animals were specific pathogen free (SPF) animals, and 7-week-old male ICR mice were divided into a control group and a test group, and the control group received only 0.5% carboxymethyl cellulose (CMC) solution.
  • the test group was orally administered to the water lily root extract of the present invention prepared in Example 1 at a dose of 1,000 mg / kg, 500 mg / kg for 2 weeks to observe the toxicity. As a result, no animals died in all groups, and no animals with unusual behavior or toxic symptoms were found.
  • body weight gain was observed in all groups, and abnormal lesions and abnormal findings in all organs in the thoracic cavity and abdominal cavity observed at autopsy Not found.
  • the water lily root extract, fractions thereof, and polyphenolic compounds isolated from the fractions effectively inhibit the activity of mtGPATl causing metabolic disease, inhibit the biosynthesis of intracellular triglycerides and insulin in skeletal muscle cells. Since it was confirmed that the dependent glucose uptake activity, the polyphenol-based compounds of the present invention, water extract root or fractions thereof are obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis and non-alcoholic fatty liver, etc. It can be used as an active ingredient of a pharmaceutical composition for the prevention and treatment of metabolic diseases.
  • It contains 0.1 to 99.9% by weight of the water lily root extract of the present invention or a fraction thereof based on the total weight of the composition of the present invention as an active ingredient, and may include a pharmaceutically acceptable carrier, excipient or diluent.
  • compositions of the present invention may be in various oral or parenteral formulations.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used.
  • Solid form preparations for oral administration include tablets, powders, granules, capsulants, and the like, which may contain at least one excipient such as starch, carbohydrate, sucrose or lactose ( lactose) and gelatin.
  • the "lubricant such as magnesium stearate, in addition to simple excipients, thoracic, and talc are also used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.
  • ком ⁇ онентs such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous and suspending solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
  • composition of the present invention can be administered orally or parenterally, and it is preferable to select the external or intraperitoneal, rectal, intravenous, intramuscular, subcutaneous intrauterine dural or cerebrovascular injection method for parenteral administration. Use for external skin.
  • the dosage of the composition of the present invention varies depending on the weight, age, sex, health status, diet, time of administration, administration method, excretion rate and severity of the disease of the patient, the daily dosage of the extract 0.01 to 1000 mg / kg based on the amount, preferably 30 to 500 mg / kg, more preferably 50 to 300 rag / kg, may be administered 1 to 6 times a day.
  • composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological reaction modifiers.
  • the present invention also provides a method for preventing metabolic disease comprising administering to a subject a pharmaceutically effective amount of the composition according to the present invention.
  • the present invention also provides a method of treating a metabolic disease comprising administering a pharmaceutically effective amount of the composition according to the present invention to a subject having metabolic disease.
  • the metabolic disease may be any one selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis, and nonalcoholic fatty liver, but is not limited thereto.
  • the pharmaceutically effective amount is 0.0001 to 100 mg / kg, 0.001 to
  • Dosage may vary depending on the weight, age, sex, health status, diet, duration of administration, rate of elimination, and severity of the particular patient.
  • composition can be administered orally or parenterally during clinical administration and intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, It can be administered by intrauterine epidural injection, cerebrovascular injection, or intrathoracic injection, and can be used in the form of general pharmaceutical preparations.
  • the subject is a vertebrate, specifically a mammal, more specifically an experimental animal such as a rat, rabbit, guinea pig, hamster, dog, or cat, and more specifically, may be an ape-like animal such as a chimpanzee or a gorilla. have.
  • administration means introducing a certain substance into a patient in any suitable way and the route of administration of the substance can be administered via any general route as long as it can reach the target tissue.
  • the pharmaceutical composition may be administered by any device that allows the active substance to migrate to the target cell.
  • administration means that the composition of the present invention is introduced by “systemic delivery” or “topical delivery” to pancreatic cancer cells.
  • “Whole body delivery” refers to delivery that causes widespread biodistribution of a compound in an organism. Some administration techniques result in systemic delivery of certain compounds, and others may not.
  • Systemic delivery means that a useful, preferably therapeutically effective amount of a compound is exposed to most of the body. Generally, in order to obtain a broad biodistribution, fast non-specific cell binding or by a fast passage of organs (liver, lung, etc.) to ensure that the compound is not rapidly degraded or eliminated before reaching the disease site far from the site of administration. Life expectancy in the blood is required.
  • topical delivery refers to the delivery of a compound directly to a target site in an organism.
  • the compound can be delivered locally by injection directly into a disease site, such as a tumor or other target site, such as a target organ, such as the pancreas.
  • the present invention provides a composition for preventing and improving metabolic diseases containing water lily extract as an active ingredient.
  • the present invention provides a composition for preventing and improving metabolic diseases, including a fraction obtained by fractionating a water lily root extract using an organic solvent.
  • the present invention also provides a composition for preventing and improving metabolic diseases, which contains a polyphenolic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides the use of water lily root extract for use in the manufacture of a composition for the prevention and improvement of health foods for metabolic diseases.
  • the present invention provides the use of the organic solvent fraction of the water lily root extract for use in the preparation of the composition for the health food for preventing and improving metabolic diseases.
  • the present invention provides a use of the polyphenol-based compound of Formula 1, Formula 2, Formula 3 or Formula 4, or a pharmaceutically acceptable salt thereof for use in the preparation of a health food composition for preventing and improving metabolic diseases to provide.
  • the polyphenol-based compound is represented by Chemical Formula 1, Chemical Formula 2, Chemical Formula 3 and Chemical Formula
  • It may be selected from the group consisting of four, but is not limited thereto.
  • the metabolic disease may be selected from the group consisting of obesity, type 2 diabetes mellitus, dyslipidemia, insulin resistance, hepatic steatosis and nonalcoholic fatty liver, but is not limited thereto.
  • the water lily root extract, its fractions and polyphenol compounds isolated from the fractions have been found to effectively inhibit the activity of mtGPATl causing metabolic diseases, including the polyphenolic compounds of the present invention, water lily root extract or Fractions thereof may be used as an active ingredient in the composition for the prevention and improvement of metabolic diseases such as obesity, type 2 diabetes, dyslipidemia, insulin resistance, hepatic steatosis and non-alcoholic fatty liver.
  • the functional food of the present invention may contain various ' flavours, natural carbohydrates, and the like as additional ingredients.
  • Natural carbohydrates mentioned above include glucose, fructose and Disaccharides such as monosaccharides, maltose, sucrose, and polysaccharides such as dextrin, cyclodextrin, xyli, sorby, erythr, and the like.
  • sweetening agent natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame can be used.
  • the ratio of natural carbohydrate and water may be selected from 0.01 to 0.04 parts by weight, specifically about 0.02 to 0.03 parts by weight, per 100 parts by weight of the health food of the present invention.
  • the functional food of the present invention includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols.
  • the carbonizing agent used in the carbonated beverage may contain a flesh for preparing natural fruit juice, fruit juice beverage and vegetable beverage. These components can be used independently or in combination. The proportion of such additives is not critical but is usually selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health food of the present invention.
  • Example 2 Separation of Compound from Water Lily Root Extract The butanes fraction (about 25 g) . A total of 8 fractions were separated by reverse phase column chromatography with increasing polarity sequentially with a 20%, 30%, 40%, 50% methanol / water mixture (fractions 1 to 8). .
  • LH20 was used to elute the methane to separate the active fractions. Among them, fractions with strong inhibitory activity were collected, and high-performance liquid chromatography (YMC J 1 sphere ODS H-80 column, 250X20 mm) was performed by flowing 90% methanol / water mixed solvent at 5 mi / min as the elution solvent. Four pure compounds (Formula 1, Formula 2, Formula 3, and Formula 4) were obtained.
  • the compound was determined by measuring the properties, molecular weight, molecular formula, mass spectrometry, -NMR spectrum and 13 ONMR spectrum of the material, published by Hideyuki Rurihara et al. Biosci. Biotech. Biochew. , 57 (9): 1570-1571, 1993; Wen-Hua Zhao et al. J. Chromatogr. B., 850, 523-527, 2007; RW Owen et al. Food and Chemical Toxicology.
  • Mitochondrial protein isolated from sf9 cells overexpressing Human GPATK hGPATl was used as the enzyme source.
  • hGPATl cDNA NCBI accesstion No. ⁇ _020918
  • pFastBacl vector Invitrogen
  • the resulting recombinant bacmid DNA was transformed into Sf9 cells to assemble and amplify baculovirus containing human hGPATl cDNA.
  • Sf9 cells (1 ⁇ 10 6 cells / ral) were infected with 10 M () I virus and cells were harvested by centrifugation after 48 hours, homogenize buffer (250 mM sucrose, 10 niM Tris (H).
  • hGPATl enzyme The activity of hGPATl enzyme was measured by the amount of radiation of [14C] lysophosphatidic acid ([l] Lysophosphaticlic acid), a reaction product produced by the mitochondrial hGPATl enzyme source. Mitochondrial hGPATl activity was compared to other isoenzymes, and 2 mM N—ethylmaleimide was added to the hGPATl enzyme source before the experiment, according to previous studies, in which hGPATl was maintained by treatment with ethylmaleimide (NEM). Pre-treatment in an ice bath for minutes. Deactivated isozyme activity other than hGPATl.
  • NAM ethylmaleimide
  • Substrates used for enzyme reaction were [ 14 C] glycerol -3-phosphate (1.8 ⁇ ) and palmitoyl-CoAKlOO ⁇ and these substrates were the reaction solution (75 mM Tris (pH 7.5), 4 After reaction for 20 minutes at 26 ° C. with mM MgCl 2 , 8 mM NaF, 2 mg / i BSA), reaction was stopped by saturated butanol and water. The reaction was centrifuged to separate the water layer and the butane, and the supernatant containing the reaction product [ 14 C] lysophosphatidic acid (layer of butane) was taken up to 800 ⁇ .
  • the supernatant was shaken with the same amount of water, and the water layer and butane were separated into layers by centrifugation, and the supernatant was taken up to 600 ⁇ to obtain a liquid scintillation counter (LSC). ) was measured.
  • the final concentration of the water lily root extract and fractions prepared in Examples 1 and 2 was treated at a concentration of 30,100 g /, the final concentration of the compounds of Formula 1, Formula 2 and Formula 3 prepared in Example 2 100, 30 , 10 , 3 , 1, hGPATl enzyme by treatment at concentration of 0.3 / g / m £ Activity was measured.
  • the inhibition rate of hGPATl enzyme activity by the sample was calculated by the following equation.
  • Inhibitory activity (%) 1-[(T-B (C-B)] X 100
  • HepG2 cells which are human-derived hepatocytes, were used for two substrates. Triglyceride biosynthesis inhibitory activity in cells was measured. HepG2 cells were cultured at ATCC, with minimum essential medium (MEM; 2 mM L ⁇ glutamine; 1.5 g / L sodium bicarbonate, 0.1 mM essential amino acid nonessential amino acids). And 10% fetal bovine serum (FBS) and antibiotics (100 U / ml. Penicillin and 100 g / ml streptomycin) in earle ⁇ BSS medium formulated to contain 1 mM sodium pyruvate.
  • MEM minimum essential medium
  • FBS fetal bovine serum
  • antibiotics 100 U / ml. Penicillin and 100 g / ml streptomycin
  • [ 14 C] acetate [ 14 C] acetate) (Amersham) was added and reacted for 6 hours. Also used in other substrate [14 C] In the case of the glyceryl ([14 C] glycerol), the reaction was carried out for 18 hours. The sample was dissolved in dimethyl sulfoxide (DMS0), and the control group in the neutron room production reaction was reacted only with dimethyl sulfoxide without adding the sample, and the production rate of triglycerides was 100. .
  • DMS0 dimethyl sulfoxide
  • [ 14 C] acetate a substrate that is not absorbed by the cells and remains in the medium to determine the amount of triglycerides produced in the finished cells
  • L6 myoblasts were cultured in DMEM (4 mM L-glutamine, 1.5 g / L sodium bicarbonate, 4.5 g / L glucose) medium containing 10% FBS.
  • DMEM 4 mM L-glutamine, 1.5 g / L sodium bicarbonate, 4.5 g / L glucose
  • FBS 0.2% FBS DMEM
  • the following experiment was performed using a mouse.
  • the experimental animals were SPF-specific animals and were introduced to 7-week-old male ICR mice (Korea Biolink, Chungbuk Negative), followed by a 1-week acclimatization period. At the age of five, five animals were assigned to each group and used in the experiment.
  • the control group was administered only 0.5% carboxymethyl cellulose (CMC) solution, the test group was prepared in Example 1. After the oral administration of the water lily root extract of the present invention at a dose of 1,000 mg / kg, 500 rag / kg, respectively, the toxicity was observed for 2 weeks.
  • CMC carboxymethyl cellulose
  • the powder through According to the manufacturing method was filled in hard capsule to prepare a capsule.
  • 0.1 g of the compound of Formula 2 of ⁇ Example 2> sterile distilled water dose pH adjuster dose for injection according to the conventional method for preparing an injection was prepared in the above component content (2 iii ⁇ ) per ampule.
  • Vitamin A Acetate 70 Mg
  • Vitamin B6 0.5 rag
  • Vitamin C 10 mg
  • composition ratio of the vitamin and mineral mixtures is a relatively suitable composition for a healthy food in a preferred embodiment, but may be modified arbitrarily, and the mixture of the above ingredients in accordance with the usual health food manufacturing method
  • the granules may be prepared and used for preparing a health food composition according to a conventional method.
  • Plum concentrate Taurine 1 g purified water was added to mix the above ingredients according to the general method of preparing a healthy beverage in 900 ml ' , then stirred and heated at 85 for about 1 hour, the resulting solution was filtered and obtained in a sterile 21 container and sealed. After sterilization and refrigerated it was used to prepare a healthy beverage composition.
  • composition ratio is a relatively suitable composition for a preferred beverage and beverage in a preferred embodiment
  • the compounding ratio may be arbitrarily modified according to the demand hierarchy, demand country, usage, regional and ethnic preferences.

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Abstract

La présente invention concerne une composition pharmaceutique destinée à la prévention et au traitement de maladies métaboliques, comprenant un extrait de rhizome de nymphéa tétragonal, des fractions dudit rhizome, ou des composés à base de polyphénol isolés de l'extrait de rhizome de nymphéa tétragonal. Ledit extrait de rhizome de nymphéa tétragonal et ses fractions inhibent efficacement l'activité du glycérol-3-phosphate (GPAT), susceptible de provoquer des maladies métaboliques ; en outre, ils présentent une activité inhibitrice contre la biosynthèse de graisses neutres dans des cellules, ainsi qu'une activité accrue en termes d'assimilation insulinodépendante du glucose dans les cellules de muscles squelettiques. Ainsi, l'extrait de rhizome de nymphéa tétragonal, ses fractions, ou des composés à base de polyphénol isolés de l'extrait de rhizome de nymphéa tétragonal peuvent être utilisés efficacement dans la prévention et le traitement de maladies métaboliques, telles que l'obésité, le diabète de type 2, la dyslipidémie, l'insulinorésistance, la stéatose hépatique et la stéatose hépatique non alcoolique.
PCT/KR2012/010625 2011-12-07 2012-12-07 Composition pharmaceutique destinée à la prévention et au traitement de maladies métaboliques, comprenant un extrait de rhizome de nymphéa tétragonal, ses fractions, ou des composés à base de polyphénol isolés de l'extrait de rhizome de nymphéa tétragonal en tant que principes actifs WO2013085338A2 (fr)

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JP2016522255A (ja) * 2013-06-19 2016-07-28 アクセス ビジネス グループ インターナショナル エルエルシーＡｃｃｅｓｓ Ｂｕｓｉｎｅｓｓ Ｇｒｏｕｐ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｌｌｃ 体重管理を支援するための植物をベースとしたケトヘキソキナーゼ阻害剤
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CN112057374A (zh) * 2019-06-10 2020-12-11 大江生医股份有限公司 芒果幼果萃取物及由其所得化合物用于护肤及保健的用途
CN112057374B (zh) * 2019-06-10 2023-11-21 大江生医股份有限公司 芒果果实萃取物用于护肤及保健的用途

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