WO2009151173A1 - Compositions pharmaceutiques destinées à la prévention et au traitement de maladies virales renfermant des extraits de rhodiola, des fractions, les composés flavonoïdes qui en sont isolés, leurs composés dérivés ou leurs sels pharmaceutiquement acceptables en tant que principe actif - Google Patents

Compositions pharmaceutiques destinées à la prévention et au traitement de maladies virales renfermant des extraits de rhodiola, des fractions, les composés flavonoïdes qui en sont isolés, leurs composés dérivés ou leurs sels pharmaceutiquement acceptables en tant que principe actif Download PDF

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Publication number
WO2009151173A1
WO2009151173A1 PCT/KR2008/003415 KR2008003415W WO2009151173A1 WO 2009151173 A1 WO2009151173 A1 WO 2009151173A1 KR 2008003415 W KR2008003415 W KR 2008003415W WO 2009151173 A1 WO2009151173 A1 WO 2009151173A1
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Prior art keywords
rhodiola
fraction
chemical formula
extract
compounds
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PCT/KR2008/003415
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English (en)
Inventor
Woo Song Lee
Byung Dae Yoon
Hyo Kon Chun
Hyung Jae Jeong
Hyung Jun Kwon
Jang Hoon Kim
Ki Hun Park
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Korea Research Institute Of Bioscience And Biotechnology
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Priority claimed from KR1020080055069A external-priority patent/KR100999872B1/ko
Priority claimed from KR1020080055068A external-priority patent/KR100981296B1/ko
Application filed by Korea Research Institute Of Bioscience And Biotechnology filed Critical Korea Research Institute Of Bioscience And Biotechnology
Publication of WO2009151173A1 publication Critical patent/WO2009151173A1/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)
    • A61K36/41—Crassulaceae (Stonecrop family)

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising as an active ingredient, a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the extract or the fraction, or a pharmaceutically acceptable salt of the flavonoid.
  • influenza virus is a highly infective agent causing acute pulmonary diseases. In more serious cases, influenza causes pneumonia, which can be particularly fatal in young children, the elderly, and patients with cardiopulmonary diseases. In addition, influenza spreads around the world in seasonal epidemics, killing in addition numerous people in pandemic years (Hien, T. T. et al. N. Eng. J. Med., 350, 1179, 2004) .
  • the influenza virus is an RNA virus of the family Orthomyxoviridae, which comprises Influenzavirus A, Influenzavi rus B, Influenzavirus C, and the other two genera. Of these, influenzavirus A and B are responsible for the epidemic spread of influenza. Influenzavi cus A, B and C are very similar in structure.
  • the influenza virus contains eight pieces of segmented RNA, with hemagglutinin (HA) and neuraminidase (NA) on the outside thereof, which serve as surface antigens.
  • Hemagglutinin the name of which comes from the protein' s ability to cause red blood cells to clump together in vitro, is a homotrimeric integral membrane glycoprotein, which consists of a head and a tail.
  • the head part responsible for most antigenic variations, contains binding sites for sialic acid residues on the surface of target cells, mediating the binding of the virus to target cells and the subsequent entry of the viral genome into the target cell (Chandrasekaran, A. et al. Nature biotechnology 26, 107, 2008) .
  • neuraminidase NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.
  • Influenza neuraminidase existing as a mushroom-shape projection on the surface of the influenza virus, is a tetrameric glycoprotein having a head with an active site topped thereon.
  • the neuraminidase cleaves the ⁇ -ketosidic bond linking a terminal neuraminic-acid residue to the adjacent oligosaccharide moiety, being essential for movement of the virus to and from sites of infection in the respiratory tract (a. Mark, V. T. Nature review 6 r 967, 2007. b. Huberman, K. et al . Virology 214, 294, 1995) .
  • antiviral agents have been developed, and there are four drugs Amantadine, Rimantadine, Zanamivir and Oseltamivir that have been approved by the FDA for use in the treatment of influenza.
  • Amantadine and Rimantadine show antiviral activity by blocking the M2 ion channel which is essential for viral proliferation, thereby interfering with viral uncoating inside cells.
  • Both the M2 inhibitors are, however, effective only against influenza virus A and are associated with several toxic effects in the digestive system and the autonomic nervous system, and with the rapid emergence of drug-resistant variants during the 40 years of its use (Bantia, S. et al. Antiviral Research 69, 39, 2006) .
  • Zanamivir and Oseltamivir have been used for the treatment and prophylaxis of influenza virus A and influenza virus B because they act as inhibitors of neuraminidase which plays an important role in viral proliferation and is stably present in both influenza viruses A and B (Zhang, J. et al. Bioorg. Med. Chem. Lett. 16, 3009, 2006) .
  • Zanamivir shows high antiviral activity, but suffers from the disadvantage of low bioavailability and fast renal excretion (Ryan, D. M. et al . Antimicrob . Agents Chemother. , 39, 2583, 1995) while nausea and vomiting were reported more frequently among adults receiving Oseltamivir .
  • the antiviral drugs administered to this time must be applied with extreme caution because they are reported to produce significant adverse side effects. Additionally, vaccination may be useless in preventing the infection and proliferation of influenza viruses if a virus type of a vaccine is different from that of the epidemic influenza virus. For these reasons, there is an imperative need for an antiviral agent that has high inhibitory activity against influenza viruses and can be generally utilized without adverse side- effects .
  • Rhodiola is a perennial herbaceous plant in the Crassulaceae family that grows in cold regions. Thus far, 96 kinds of the plant have been reported with 50% thereof found in China. This plant inhibits highlands at an altitude from 1,700 to 2,300 meters, which highlands are dry and of low-temperature in years with large diurnal ranges, and the plant is exposed to intense UV light.
  • Rhodiola has also been called highland ginseng because it is found to have the function of invigoration and detoxification like ginseng and acanthopanax (Kim, Joo-Cheol, Ahn, Sang-Deuk, Lee, Myoung-Rye, Colorful Illustrated Guide to Resource Plants of Mt. Baek Doo, Academybook, Seoul, p.324) .
  • Rhodiola can be used for food and medicine.
  • Rhodiola has been used as a sedative, an antipyretic and an astringent.
  • Rhodiola is used as a tonic particularly for senile cardiac failure and impotence.
  • Korean Patent No. 10-0179087 entitled “Composition for Lowering Blood Alcohol Concentration Comprising Rhodiola schalinesis Extract”
  • Koren Patent No. 10-01790808 entitled “Composition Containing Rhodiola sachalinesis Extract for Prophylaxis and Treatment of Diabetes Mellitus”
  • Korean Patent No. 10-0265385 entitled “Extract of Rhodiola sp . for Preventing and Treating Circulatory Diseases”
  • Korean Patent No.10- 0316790 entitled “Composition for Preventing Liver Fibrosis Comprising Extract from Rhodiola sachalinensis A. Bor”
  • Rhodiola extracts are used in the treatment and prophylaxis of viral diseases, especially influenza, in Lhe prior art.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of viral diseases, comprising as an active ingredient a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the Rhodiola extract or fraction, or a pharmaceutically acceptable salt of the flavonoid compound.
  • a pharmaceutical composition for the prevention and treatment of viral diseases comprising as an active ingredient a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the Rhodiola extract or fraction, or a pharmaceutically acceptable salt of the flavonoid compound.
  • the present invention provides a health food composition for the prevention of viral diseases, comprising as an active ingredient a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the Rhodiola extract or fraction, or a pharmaceutically acceptable salt of the flavonoid compound.
  • the Rhodio La extract, the Rhodiola fraction, the flavonoid compounds isolated from the Rhodiola extract or fraction, or the pharmaceutically acceptable salts of the flavonoid compounds is useful in the prevention and treatment of viral diseases and the suppression of virus proliferation. Therefore, the compositions comprising as an active ingredient the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds isolated from the Rhodiola extract or fraction, or the pharmaceutically acceptable salts of the flavonoid compound in accordance with the present invention can be applied for use in the prevention and treatment of viral diseases and as prophylaxis against influenza virus.
  • the present invention pertains to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising an extract from Rhodiola as an active ingredient.
  • Rhodiola from which an extract useful in the present invention can be obtained may be a cultured or a commercially available variety. As long as it may be used to produce a useful extract therefrom, any Rhodiola is applicable for purposes of the present invention.
  • a Rhodiola extract may be prepared by a typical extraction method known in the art, such as ultrasonication, filtration or reflux extraction.
  • an extract may be obtained from dried Rhodiola and water, a Ci-C 3 alcohol or a mixture thereof, more preferably with a Ci-C 3 alcohol, and most preferably with methanol or ethanol .
  • Rhodiola roots are finely sectioned and immersed in a lower alcohol of Ci ⁇ C 3 or a mixture thereof at room temperature for a predetermined period of time, followed by filtration to afford an alcohol extract. Preferably, extraction is performed for one week in the alcohol. Concentration or lyophilization may be further conducted.
  • the present invention pertains to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising a Rhodiola fraction as an active ingredient .
  • the Rhodiola fraction may be preferably obtained during sequential fractionation with hexane, chloroform and ethylacetate in that order from a suspension of the Rhodiola extract in water.
  • the present invention pertains to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising as an active ingredient at least one selected from a group consisting of kaempferol, represented by the following chemical formula 1, kaempferol-3-O-glucoside, represented by the following chemical formula 2, kaempferol-3-O-rutinoside, represented by the folJ owing chemical formula 3, herbacetin, represented by the foJ lowing chemical formula 4, rhodiolinm, represented by the following chemical formula 5, rhodionin, represented by the following chemical formula 6, rhodiosin, represented by the following chemical formula 7, herbacetin-3, 8-0- diglucoside, represented by the following chemical formula 8, and pharmaceutically acceptable salts thereof.
  • kaempferol represented by the following chemical formula 1
  • kaempferol-3-O-glucoside represented by the following chemical formula 2
  • kaempferol-3-O-rutinoside represented by the folJ owing chemical formula 3
  • the compounds of chemical formula 1 to 8 may be separated from the Rhodiola extract or the Rhodiola fraction, may be purchased from commercial manufacturers thereof, or may be chemically synthesized. Among them, the compounds ot chemical formulas 1, 5, 6 and 7 are known as representative active ingredients of Rhodiola, and can be isolated as described below.
  • the present invention is concerned with a method for preparing compounds of chemical formulas 1, 5, 6 and 7, comprising :
  • Step 2 Separating an active fraction from the extract of Step 1 sequentially with hexane, chloroform and ethyl acetate in that order (Step 2); and
  • Rhodiola is extracted with water, a C X ⁇ C 3 alcohol or a mixture thereof to give a Rhodiola extract.
  • Rhodiola roots are finely sectioned to a predetermined size and extracted with a suitable volume of water, an alcohol, or a mixture thereof in an extraction vessel lor three weeks, followed by filtration and then concentration in a vacuum to afford a Rhodiola extract.
  • Step 2 is to fraction the Rhodiola extract in the sequential order of hexane, chloroform and ethyl acetate to give an active fraction.
  • Step 3 the active fraction is subjected to column chromatography to yield the flavonoid compounds of chemical formula 1, 5, 6 and 7.
  • the ethyl acetate fraction thus obtained in Step 2 is submitted to two rounds of fractionation using silica gel column chromatography eluting with mixtures of chloroform and methanol, followed by open column chromatography.
  • the two rounds of silica gel column chromatography eluting with a mixture of various ratios of chloroform and methanol (e.g., 9:1) afford fractions showing high inhibitory activity against neuraminidase from which the f] avonoids can be then isolated by open column chromatography on sephadex LH-20 eluting with a mixture of 1:1 chloroform : methanol (v/v) .
  • the ethanol extract of Rhodiola showed 0.58 ⁇ g/mL of IC50 value, and the ethyl acetate fraction showed 1.17 ⁇ g/mL.
  • the Hot water extract also showed 1.01 ⁇ g/mL (see Table 3) .
  • Rhodiola, and derivatives of the flavonoids in accordance with the present invention may be used as active ingredients of a pharmaceutical composition for the prevention and treatment of viral diseases or in an antiviral composition.
  • the flavonoid compounds of the present invention may be used in the form of pharmaceutically acceptable salts.
  • the derivative represented by chemical formula 1 in accordance with the present invention may be in the form of pharmaceutically acceptable salts.
  • acid addition salts formed with pharmaceutically acceptable free acids are included.
  • the free acids are inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate and alkanedioate, aromatic acids, aliphatic and aromatic sulfonic acids.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid
  • non-toxic organic acids such as aliphatic mono- and dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate and alkanedioate, aromatic acids, aliphatic and aromatic sulfonic acids.
  • non-toxic bases examples include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprilate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1 , 4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate,
  • the acid addition salts of the compounds according to the present invention may be prepared using a conventional method, for example, by dissolving the compound of chemical formula 1 in excess acid in water and precipitating the resulting salt in a water-miscible organic solvent, e.g., methanol., ethanol , acetone or acetonitrile .
  • a water-miscible organic solvent e.g., methanol., ethanol , acetone or acetonitrile.
  • the compounds of chemical formulas 1 to 8 may be heated along with the same amount of acid or alcohol in water, followed by evaporating the mixture and drying or suction filtering the precipitate to prepare acid addition salts thereof.
  • metal salts formed with bases may fall within the range of pharmaceutically acceptable salts of the compounds of the present invention.
  • the metal salts useful in the present invention include al kali metal salts and alkaline earth metal salts.
  • the compound of the present invention may be dissolved in excess alkali metal hydroxide or alkaline earth metal hydroxide in water, and after the removal of non- dissolved compound salts through filtration, the filtrate thus obtained may be dried to afford the pharmaceutically acceptable salts of the compound of the present invention.
  • Suitable for use in pharmaceutics are sodium, potassium or calcium salts.
  • Corresponding silver salts may be obtained by reacting the alkali metal or alkaJine earth metal salts with suitable silver salt (e.g., silver nitrate ) .
  • the composition in accordance with the present invention may be used in oral or non- oral forms. It is usually formulated in combination with a diluent or an excipient, such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant , a surfactant, etc.
  • a diluent or an excipient such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant , a surfactant, etc.
  • Solid preparations intended for oral administration of the compound of the present invention may take the form of tablets, pills, powders, granules, capsules, and the like.
  • the Rhodiola extract, the Rhodlola fraction, the flavonoids compounds or the pharmaceutically acceptable salts are formulated in combination with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin.
  • a lubricant such as magnesium stearate, talc, or the like may also be added.
  • Liquid preparations intended for oral administration include suspensions, internal use solutions, emulsion, syrups, and the like.
  • various excipients such as wetting agents, sweetening agents, aromatics, preservatives, and the like may be contained in the liquid preparations.
  • the compound of the present invention may be administered via a non-oral route. For this, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophil izates, suppositories, and the like may be used.
  • Injectable propylene glycol, polyethylene glycol, vegetable oiJ s such as olive oil, and esters such as ethyl oleate may be suitable for non- aqueous solvents and suspensions.
  • the basic materials of suppositories include Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, and glycerogelatin .
  • the pharmaceutical composition of the present invention may be administered non-orally (i.e., intravenously, subcutaneously, intraperitoneally, or topically) or orally.
  • the active ingredient according to the present invention may be administered in a single dose or in multiple doses per day at a daily dose ranging from 0.1 to 500 mg/kg of body weight, preferably from 1 to 100 mg/kg of body weight, and most preferably from 0.5 to 10 mg/kg of body weight.
  • the effective dosage of the active ingredient in accordance with the present invention depends on various factors, including the patient's weight, age, gender, state of health, diet, the L Lme ol administration, route of administration, excretion rate, severity of diseases, etc.
  • the compounds of the present invention were proven safe with an oral lethal dose (LD J50 ) of at least 1,000 mg/kg as measured by an acute oral toxicity assay in rats .
  • LD J50 oral lethal dose
  • the present invention is concerned with a health food composition for the prevention and treatment of viral diseases, comprising as an active ingredient the Rhodiola extract, the Rhodiola fraction, the flavonoid compound isolated from the extract or fraction, or a pharmaceutically acceptable salt of the flavonoid.
  • the viral diseases may be caused by influenza viruses .
  • the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds of Rhodiola, or the pharmaceutically acceptable salts of the flavonoids according to the present invention may be added to health food.
  • a food additive at least one of the active ingredients according to the present invention may be properly used alone or in combination with other food ingredients according to a conventional method.
  • the amount of the active ingredient according to the present invention may vary depending on the purpose thereof (prevention, health improvement or therapeutic treatment) .
  • the active ingredient according to the present invention may be added in an amount of 0.01 to 20 weight % based on the total weight of the health food and preferably in an amount of 0.1 to 5 weight % .
  • the active ingredient In the case where the active ingredient is applied to health foods which are designed to be taken habitually, its content may be below the above-mentioned range.
  • the extract has no problems of being harmful to the body and thus can be used in an amount exceeding the ranges specified.
  • the active ingredient e.g., the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds of Rhodiola, or the pharmaceutically acceptable salts of the compounds
  • the foods include meat, sausages, bread, chocolate, candies, snacks, confectionaries , pizza, ramen and other noodles, dairy products including ice creams, soups, beverages, teas, drinks, alcoholic beverages, vitamin tablets, etc. and are not limited thereto. All usually accepted health foods may contain the active ingredient according to the present invention.
  • the health food composition of the present invention may further contain various fragrant or natural carbohydrates.
  • Such naturaJ carbohydrates include monosaccharides, such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • sweeteners e.g., natural sweeteners such as thaumatin and a stevia extract, or synthetic sweeteners such as saccharin and aspartame, may be added to the health food to which the active ingredient of the present invention is applied.
  • the natural carbohydrate may be used in an amount of about 0.01 ⁇ 0.04 weight parts based on 100 weight parts of the composition of the present invention, and preferably in an amount of about 0.02 ⁇ 0.03 weight parts.
  • the health food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH modifiers, stabilizers, antiseptics, glycerin, alcohols, and carbonating agents used in carbonated beverages.
  • the composition of the present invention can contain fruit flesh for preparing natural fruit juices, fruit beverages and vegetable beverages. These ingredients may be used individually or in combination. The ratio of these additives is not important, but is generally selected Ln a range of 0.01 to 0.1 weight parts per 100 weight parts of the composition of the present invention.
  • the present invention pertains to an antiviral composition, particularly against influenza viruses.
  • the present invention pertains to a method for preventing and treating a viral disease, comprising administering at least one selected from among the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds of Rhodiola and the pharmaceutically acceptable salts thereof according to the present invention at a therapeutically effective dose to a subject in need thereof .
  • the viral disease may be caused by influenza virus, particularly by Influenza virus A, B or C.
  • the subject in need of administration wi th the active ingredient of the present invention may suffer from chills, fever, sore throat, bronchitis, or pneumonia, and may be birds afflicted with avian influenza.
  • Rhodiola was extracted with 3 L of water by stirring it for 6 hours at 70 ° C , to give an hot water extract (90 g)
  • Example 2 After being suspended in 1000 mL of water, the ethanol extract obtained in Example 1 was fractioned sequentially with n-hexane, chloroform and ethyl acetate in that order to afford 11 g of an n-hexane-soJ uble fraction, 14 g of a chloroform (CHCl 3 ) -soluble fraction and 59 g of an ethyl acetate (ELO ⁇ c) -soluble fraction, respectively.
  • EXAMPLE 3 Isolation and Structural Identification of Flavonoid Compounds
  • ethyl acetate-soluble fraction obtained in Example 2 was subjected to two rounds of silica gel column chromatography eluting with a mixture of chloroform and methanol, followed by purification through column chromatography on sephadex.
  • the ethyl acetate-soJ uble fraction was developed in silica gel column chromatography (silica gel: Merck, Art 9385, column size : ⁇ 7 x 40 cm) eluting with 1.5 L of a mixture of 9:3, 7:1, 5:1, 3:1 or 1:1 chloroform : methanol (v/v) or 1.5 L of 100% methanol to give three fractions, named Fraction 1, 2 and 3.
  • RP-18 (40-63 ⁇ m, Merck) into rhodionin of chemical formula 6 and rhodiosin of chemical formula 7.
  • the structural analysis of the four compounds was achieved by a VG high resolution GC/MS spectrometer (Election Ionization MS, Autospec-Ul tima, Micromass, UK) for determining molecular weights and molecular formulas, a polarimeter (DIP-181 digital polarimeter, Jasco, Japan) for measuring optical rotation, and an NMR spectrophotometer (AMX 500, Bruker, Germany) for 1 H NMR, 13 C NMR, HOMO-COSY, HMQC ( ⁇ -Detected heteronuclear Multiple-Quantum Coherence) , HMBC (Heteronuclear Multiple-Bond Coherence) , DEPT (Distortionless Enhancement by Polarization) spectra. From these spectrophotometric data, molecular structures of the compounds were determined
  • Example 3 Derivatives of the compounds isolated in Example 3 were purchased from Sigma Aldrich. These are represented kaempferol-3-O-glucoside of chemical formula 2, kaempferol-3-0-rutinoside of chemicaL formula 3, herbacetin of chemical formula 4, and herbacetin-3, 8-0- diglucoside of chemical formula 8.
  • the inhibitory activities against influenza virus neuraminidase of the Rhodiola extract of Example 1 and the Rhodiola fractions of Example 2 were determined using a modification of the Markus et al . method (Anal. Biochem. 250, 176, 1997) . ⁇ s a substrate for neuraminidase (concentration, 0.1 ⁇ 0.11 ⁇ , from Vibrio cholera, Sigma), synthetic 2 ' - (4-methylumbelliferyl ) - ⁇ -D- W-acetylneuraminic acid sodium salt (Sigma) was used. The extract of Example 1 and the fractions of Example 2 were individually diluted in methanol.
  • Example 3 The four compounds isolated and identified in Example 3 were assayed for inhibitory activity against neuraminidase in a similar manner to that of Experimental Example 1.
  • the compounds of the present invention can act as excellent neuraminidase inhibitors with low TC 50 values.
  • the active ingredients according to the present invention that is, the Rhodiola extract, the Rhodlola fractions, the flavonoid compounds of Rhodiola, and the pharmaceutically acceptable salts of the flavonoids can be useful in the prevention and treatment of viral diseases and in virus suppression, particularly, influenza virus activity.
  • Administration was performed once.
  • the mice were observed for abnormal changes in body, clinical symptoms and death. That is, they were monitored for changes in body and death at 1, 4, 8 and 12 hours after the administration and once or more times on the forenoon and the afternoon each from Day 1 to Day 7 after the administration. Neither particular clinical symptoms nor death of animals were observed.
  • no acute toxicity was observed in body weight change, haematological tests, serobiochemi ca L tests, or autopsy examination .
  • Lactose 2 g The above ingredients were mixed and loaded into an airtight sac to produce a powder agent.
  • Rhodiola Extract, Fraction, Fl avonoid Cpd. Or Salt 100 mg
  • Rhodiola Extract Fraction, FJ avonoid Cpd. Or Salt:
  • Rhodiola Extract Fraction, Fl avonoid Cpd. Or Salt: lO ⁇ g/ml DiI.
  • HCl BP added to form pH 3.5
  • Rhodiola extract, fraction, flavonoid compound or salt according to the present invention was dissolved in a suitable volume of an NaCl BP injection, and the solution was adjusted to a pH of 3.5 with diluted HCl BP and to a desired volume with an NaCl BP injection, followed by sufficient mixing.
  • the solution was loaded into transparent 5 m.L type I ampules, which were hermetically sealed by melting, followed by autoclaving at 120 0 C for 15 min to prepare LnjectJons.
  • a health-improving seasoning was prepared to contain the Rhodiola extract, fraction, flavonoid compound or salt according to the present invention in an amount of 0.2 ⁇ 10 wt%.
  • Rhodiola extract, fraction, flavonoid compound or salt according to the present invention was added in an amount of 0.1 ⁇ 1.0 wt% to typical soups or gravies to prepare health-improving soups or gravies for consumption with meat processed products or noodles.
  • Rhodiola extract, fraction, f3 avonoid compound or salt according to the present invention was added in an amount of 10 wt% to typicai ground beel to prepare health-improving ground beef.
  • Unmilled rice, barley, glutinous rice, and unshelled adlay were pregelatinized using a typical method, dried and roasted before grinding into powder with a particle size of 60 meshes.
  • Black soybean, black sesame and wild sesame were steamed according to a typical method, dried and roasted before grinding into powder with a particle size of 60 meshes .
  • Rhodiola extract, fraction, frlavonoid compound or salt according to the present invention was concentrated in a vacuum using a vacuum concentrator and dried in a convection oven, followed by grinding into powder with a particle size of: 60 meshes.
  • the powders made of the grains, the seeds, and the Rhodiola extract, fraction, fJ avonoid compound or salt according to the present invention were formulated at the following ratios to yield a zen food.
  • Grains unmilled rice 30 wt%, unshelled adlay 15 wt%, barley 20 wt%) ,
  • a mixture containing 5 ⁇ 10% of sugar, 0.05 ⁇ 0.3% of citric acid, 0.005 ⁇ 0.02% of caramel and 0.1 ⁇ 1% of vitamin C was admixed with 79 ⁇ 94% of pure water to give syrup which was then sterilized at 85 ⁇ 98°C for 20 ⁇ 180 sec.
  • the sterilized syrup was mixed at a ratio of 1:4 with cold water, followed by injecting 0.5 ⁇ 0.82% of carbon dioxide to afford a carbonated beverage containing the Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention.
  • Liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%) and water (75%) were homogeneously formulated, along with the Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention and the formulation was subjected to pasteurization and loaded into a bottle, such as a glass bottle, a PET bottle, etc.
  • Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention was added to 1,000 mL of typical tomato or carrot juice to give a health-improving vegetable juice.
  • Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention 1 g was added to 1,000 mL of typical apple or grape juice to give a health-improving frui t jui ce

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique destinée à la prévention et au traitement de maladies virales renfermant, en tant que principe actif, un extrait de Rhodiola, une fraction de Rhodiola, un composé flavonoïde isolé de l’extrait ou de la fraction de Rhodiola ou un sel pharmaceutiquement acceptable du composé flavonoïde. En présentant une excellente activité inhibitrice contre la neuraminidase, le principe actif est utile dans la prévention et le traitement de maladies virales et la répression d’une prolifération virale. Ainsi, les compositions peuvent être appliquées en vue d’une utilisation dans la prévention et le traitement de maladies virales et en tant que prophylaxie contre le virus de la grippe.
PCT/KR2008/003415 2008-06-12 2008-06-17 Compositions pharmaceutiques destinées à la prévention et au traitement de maladies virales renfermant des extraits de rhodiola, des fractions, les composés flavonoïdes qui en sont isolés, leurs composés dérivés ou leurs sels pharmaceutiquement acceptables en tant que principe actif WO2009151173A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR1020080055069A KR100999872B1 (ko) 2008-06-12 2008-06-12 홍경천 추출물, 홍경천 분획물, 이로부터 분리한플라보노이드계 화합물, 이의 유도체 화합물 또는 이의약학적으로 허용 가능한 염을 유효성분으로 함유하는바이러스 질환의 예방 및 치료용 약학적 조성물
KR10-2008-0055068 2008-06-12
KR1020080055068A KR100981296B1 (ko) 2008-06-12 2008-06-12 홍경천 추출물, 홍경천 분획물, 이로부터 분리한플라보노이드계 화합물, 이의 유도체 화합물 또는 이의약학적으로 허용 가능한 염을 유효성분으로 함유하는바이러스 질환의 예방 및 치료용 약학적 조성물
KR10-2008-0055069 2008-06-12

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WO2012118287A2 (fr) * 2011-03-03 2012-09-07 Konkuk University Industrial Cooperation Corp. Nouveau composé isolé à partir d'ail chinois, et utilisation de celui-ci en tant qu'agent antiviral
CN103923138A (zh) * 2014-05-08 2014-07-16 江西天施康中药股份有限公司 一种烟花苷的制备方法及其应用
WO2017050717A1 (fr) * 2015-09-21 2017-03-30 Eberhard Karls Universitaet Tuebingen Medizinische Fakultaet Substance pour la prophylaxie et le traitement d'infections provoquées par des virus influenza
CN107074798A (zh) * 2016-02-19 2017-08-18 泰州永恒生物科技有限公司 红景天中提取草质素的方法
CN111529564A (zh) * 2020-05-19 2020-08-14 广东海洋大学 一种红景天中低极性活性成分及其制备方法

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012118287A2 (fr) * 2011-03-03 2012-09-07 Konkuk University Industrial Cooperation Corp. Nouveau composé isolé à partir d'ail chinois, et utilisation de celui-ci en tant qu'agent antiviral
WO2012118287A3 (fr) * 2011-03-03 2013-06-13 Konkuk University Industrial Cooperation Corp. Nouveau composé isolé à partir d'ail chinois, et utilisation de celui-ci en tant qu'agent antiviral
CN103923138A (zh) * 2014-05-08 2014-07-16 江西天施康中药股份有限公司 一种烟花苷的制备方法及其应用
CN103923138B (zh) * 2014-05-08 2016-03-23 江西天施康中药股份有限公司 一种烟花苷的制备方法及其应用
WO2017050717A1 (fr) * 2015-09-21 2017-03-30 Eberhard Karls Universitaet Tuebingen Medizinische Fakultaet Substance pour la prophylaxie et le traitement d'infections provoquées par des virus influenza
CN107074798A (zh) * 2016-02-19 2017-08-18 泰州永恒生物科技有限公司 红景天中提取草质素的方法
WO2017139962A1 (fr) * 2016-02-19 2017-08-24 泰州永恒生物科技有限公司 Procédé d'extraction d'herbacétine à partir de rhodiola rosea
CN107074798B (zh) * 2016-02-19 2020-01-03 泰州丹鼎生物科技有限公司 红景天中提取草质素的方法
CN111529564A (zh) * 2020-05-19 2020-08-14 广东海洋大学 一种红景天中低极性活性成分及其制备方法
CN111529564B (zh) * 2020-05-19 2022-05-03 广东海洋大学 一种红景天中低极性活性成分及其制备方法

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