WO2010095858A2 - Composition pharmaceutique comprenant un extrait de rhei rhizoma, des fractions de celui-ci, ou des composés à base de stilbène pour prévenir ou traiter des maladies induites par une molécule 1 d'adhésion intercellulaire. - Google Patents

Composition pharmaceutique comprenant un extrait de rhei rhizoma, des fractions de celui-ci, ou des composés à base de stilbène pour prévenir ou traiter des maladies induites par une molécule 1 d'adhésion intercellulaire. Download PDF

Info

Publication number
WO2010095858A2
WO2010095858A2 PCT/KR2010/000991 KR2010000991W WO2010095858A2 WO 2010095858 A2 WO2010095858 A2 WO 2010095858A2 KR 2010000991 W KR2010000991 W KR 2010000991W WO 2010095858 A2 WO2010095858 A2 WO 2010095858A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
icam
composition
stilbene
extract
Prior art date
Application number
PCT/KR2010/000991
Other languages
English (en)
Korean (ko)
Other versions
WO2010095858A3 (fr
Inventor
노문철
이우송
이승웅
박수진
장종선
류영배
권형준
Original Assignee
한국생명공학연구원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020090052460A external-priority patent/KR20100094308A/ko
Application filed by 한국생명공학연구원 filed Critical 한국생명공학연구원
Publication of WO2010095858A2 publication Critical patent/WO2010095858A2/fr
Publication of WO2010095858A3 publication Critical patent/WO2010095858A3/fr

Links

Images

Classifications

    • 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)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/708—Rheum (rhubarb)
    • 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
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention provides a pharmaceutical composition for the prevention and treatment of diseases caused by ICAM-1 and LFA-1 mediated cell adhesion using Rhei Rhizoma extract or fractions thereof, or stilbene compounds derived therefrom as an active ingredient. It is about. More specifically, the present invention provides a pharmaceutical for preventing or treating infectious diseases caused by rhinoviruses, coxsackieviruses, malaria or HIV-1, including Rhei Rhizoma extract or fractions thereof, or stilbene compounds derived therefrom. To a red composition. The present invention also relates to external skin preparations, foodstuffs and personal care products containing the composition.
  • Intercellular adhesion molecule-1 (ICAM-1; CD54) is an adhesion receptor belonging to the Ig-superfamily of vascular endothelial cells, some lymphocytes and monocytes. are expressed at low density in monocytes (Springer, Nature, 346: 425-434, 1990; Rothlein et al., J. Immunol., 137: 1270-1274, 1986) IL-1, TNF- ⁇ or IFN- ⁇ When treated with inflammatory cytokines or lipopolysaccharides (LPS), the expression of ICAM-1 is increased in multiple cell types (Hubbard and Rothlein, Free Radic. Biol. Med ., 28: 1379). -1386, 2000).
  • ICAM-1 Intercellular adhesion molecule-1
  • Leukocyte function associated antigen-1 (LFA-1; CD11a / CD18) is a ligand of ICAM-1 that is inactive in resting leukocytes but is mediated by T cell receptors or Activated by various stimulators such as phorbolester (Dustin and Springer, Nature, 341: 619-624, 1989; Rothlein and Springer, J. Exp. Med., 163: 1132-1149, 1986).
  • ICAM-1 is particularly expressed in vascular endothelial cells that have undergone inflammatory reactions, and promotes adhesion and penetration of blood cells such as monocytes, neutrophils, and lymphocytes to blood vessel walls. ICAM-1 also plays an important role in adhesion between platelets and vascular endothelial cells (Thomas and DeGraba, Neurology, 49: 15-19, 1997).
  • Cell adhesion is closely associated with atherosclerosis, arthritis, osteoporosis, bacterial infections, cancer metastasis, and intractable chronic diseases such as angiogenesis, psoriasis, asthma, allergies, lupus or Crohn's disease (Poston et al., Am. J. Pathol., 140: 665-673, 1992; Macchioni et al., J. Reumatol., 21 (10): 1860-1864, 1994; Mason et al., Arthritis Rheum., 36: 519-527 , 1993; Kling et al., Clin.Invest ., 71: 299-304, 1993).
  • ICAM-1 The significant involvement of ICAM-1 in inflammatory reactions has been demonstrated in animal experiments with monoclonal antibodies of ICAM-1 and several disease models. Inhibition of binding between ICAM-1 and LFA-1 using monoclonal antibodies that directly correspond to ICAM-1 or LFA-1 has been shown to be effective in autoimmune diseases such as atherosclerosis, asthma, glomerulonephritis or arthritis. In addition to antigen-specific signals through the T cell receptor, antigen-specific signals, such as ICAM-1 and LFA-1, are required for activation of T cells in the response (Cornejo et al., Adv. Pharmacol., 39: 99-141, 1997; Patel et al., Circulation, 97: 75-78, 1998; Nishikawa et al., J.
  • ICAM-1 plays an important role in viral infections as well as inflammatory diseases.
  • the cold viruses rhinovirus and Coxsackie virus have been shown to be infected using ICAM-1 as a receptor (Greve et al., Cell, 56: 839-847, 1989; Staunton et al. , Cell, 56: 849-853, 1989; Tomassini et al., Proc. Natl. Acad. Sci. (USA), 86: 4907-4911, 1989; Xiao, C. et al., Journal of Virology 75 (5 ): 2444-2451, 2001).
  • HIV-1 human immunodeficiency virus type-1
  • statin known as an inhibitor of binding of ICAM-1 and LFA-1.
  • Compounds have been reported to inhibit the proliferation of HIV-1 virus (Giguere and Tremblay, J. Virology 78: 12062-12065, 2004).
  • malaria PfEMP-1 protein and ICAM-1 plays an important role in cell adhesion, which has also demonstrated that malaria is mediated by ICAM-1 (Bertonati et al., Proteins 69 : 215). -222, 2007; Jenkins et al., J Infect Dis.
  • inhibitors of ICAM-1 and LFA-1 activity can be used not only for the treatment of inflammatory diseases, but also as antiviral agents of linovirus, coxsackievirus, HIV-1 and malaria.
  • rhinoviruses and coxsackieviruses which are infected by ICAM-1 and LFA-1 mediated cell adhesion, are common cold-induced viruses, influenza viruses that cause pneumonia and kill infected people. Unlike, it causes symptoms such as runny nose, chills, headache, and boredom, but it is not known to pose a threat to life. In other words, living together while living symbiosis is easy to multiply and is known to cause acute respiratory diseases such as asthma, chronic bronchitis.
  • Influenza viruses that cause pandemic influenza are classified into three types, A, B, and C, depending on the antigen type, of which A is the most common antigen mutation and accounts for 90% of the worldwide pandemic virus. .
  • the flu virus has a high mortality rate in children and the elderly with weak immunity, including chills, muscle pain, lethargy, respiratory pain, headache, and abdominal pain caused by high fever.
  • Complications include bronchial diseases such as pneumonia and cardiopulmonary disease. Entails.
  • a common cold is an acute upper respiratory tract infection caused by various viruses such as rhinovirus or coxsackie virus. Symptoms begin lightly and progress slowly, and there is no special treatment, and there are no nasal congestion, runny nose, sneezing, cough, tear, and sore throat. There is a symptom.
  • Influenza vaccines are vaccines against some antigens of influenza viruses, so they are ineffective against colds caused by other types of influenza. .
  • ICAM-1 and LFA-1 mediated cell adhesion inhibitors have been targeted by their neutralizing antibodies, and only a few kinds of inhibitors have been reported from natural products.
  • Abbott has reported ICAM-1 expression inhibitors as a synthetic product (Stewart et al., J. Med. Chem., 44: 988-1002, 2001) .
  • Antagonists of phosphorus LFA-1 were developed from Novartis and Roche (Welzenbach et al., J. Biol. Chem., 277: 10590-10598, 2002, Gadek et al., Science, 295). : 1086-1089, 2002), there are no reports of in vivo activity using disease animal models.
  • natural products include seco-limonids-based materials ( Trichilia rubra , IC 50 ; 10-25 nM), cucurbitacins, Conobea scoparioides , IC 50 ; 0.18-1.36 mM and adzans .
  • Mycins (adxanthromycins, Streptomyces sp. Na-148, IC 50 ; 1.5-6.5 mM) have been reported to inhibit ICAM-1 and LFA-1 mediated cell adhesion (Musza et al., Tetrahedron, 50: 11369-11378, 1994; Musza et al., J. Net.Prod ., 57: 1498-1502, 1994; Nakano et al., J. Antibiotics, 53: 12-18, 2000).
  • the present inventors searched for ICAM-1 / LFA-1 mediated cell adhesion inhibitors from natural resources, and as a result, rhubarb extract and its fractions and stilbene compounds separated therefrom were purified from ICAM-1 and LFA-1 mediated cell adhesion. The present invention was completed by confirming that it has inhibitory activity.
  • An object of the present invention is a pharmaceutical for the prevention and treatment of diseases caused by ICAM-1 and LFA-1 mediated cell adhesion using Rhei Rhizoma extract or fractions thereof, or stilbene compounds derived therefrom as an active ingredient. To provide a composition.
  • an object of the present invention is an infectious disease caused by ICAM-1 and LFA-1 mediated cell adhesion, comprising rhubarb extract or a fraction thereof as linovirus, coxsackievirus, malaria or HIV-. It is to provide a pharmaceutical composition for preventing or treating an infectious disease according to (1).
  • Another object of the present invention is an infectious disease caused by ICAM-1 and LFA-1 mediated cell adhesion, which comprises a stilbene compound represented by Formula 1 or Formula 2 as an active ingredient, rhinovirus, coxsackievirus, and malaria. Or to provide a pharmaceutical composition for the prevention or treatment of infectious diseases caused by HIV-1.
  • Another object of the present invention is to provide an external preparation for skin, foodstuffs and personal care products containing the composition.
  • Rhubarb extract, fractions or stilbene compounds thereof according to the present invention specifically inhibit the binding between intercellular adhesion factor-1 (ICAM-1) and leukocyte related antigen-1 (LFA-1; CD11a / CD18), It inhibits the adhesion and infiltration of blood cells such as monocytes, neutrophils and lymphocytes to vascular endothelial cells, thereby preventing or treating inflammatory diseases and viral infectious diseases mediated by intercellular adhesion factor-1.
  • the stilbene compound of the present invention shows an excellent effect on the improvement of cold symptoms or prevention and treatment of cold symptoms caused by linovirus or coxsackievirus, and thus can be widely applied to external skin preparations, foodstuffs, cosmetics and personal hygiene products. .
  • FIG. 1 is a diagram showing the adhesion inhibitory activity between CHO-ICAM-1 cells overexpressing ICAM-1 and THP-1 cells expressing LFA-1 in ethanol extract and chloroform fraction of rhubarb.
  • Figure 2 shows the adhesion inhibitory activity between soluble ICAM-1 (sICAM-1) and LFA-1 expressing THP-1 cells of chloroform extract of rhubarb.
  • FIG. 3 is a diagram showing the adhesion inhibitory activity between soluble ICAM-1 (sICAM-1) and LFA-1 expressed THP-1 cells of the stilbene-based component isolated from rhubarb chloroform extract.
  • FIG. 4 is a diagram showing the adhesion inhibitory activity between soluble ICAM-1 (sICAM-1) and LFA-1 expressed THP-1 cells of the stilbene-based component isolated from rhubarb chloroform extract.
  • FIG. 5 is a diagram showing adhesion inhibitory activity between CHO-ICAM-1 cells overexpressing ICAM-1, a stilbene-based component isolated from chloroform extract of rhubarb, and THP-1 cells expressing LFA-1.
  • FIG. 6 is a diagram showing the inhibitory activity of linovirus (HRV-2, 3, 14) of the compound of Formula 1, which is a stilbene-based component isolated from chloroform extract of rhubarb.
  • 7 is a compound of formula 1 with a virus inoculated into cells after the reaction for 1 hour (before 1h) and the virus was first inoculated into the cell and after 1 hour the compound of formula 1 (after 1h) to the rhinovirus (HRV2 ) Inhibitory activity.
  • the present invention provides a method for the prevention of diseases caused by ICAM-1 and LFA-1 mediated cell adhesion comprising Rhei Rhizoma extract or fractions thereof, or stilbene compounds derived therefrom as an active ingredient, and It relates to a therapeutic pharmaceutical composition.
  • the rhubarb extract is extracted with a solvent selected from the group consisting of water, lower alcohols having 1 to 4 carbon atoms and mixed solvents thereof, preferably methanol, ethanol or butanol.
  • the said extract shall contain the extract obtained by an extraction process, the dilution or concentrate of an extract, the dried material obtained by drying an extract, or any of these modifiers or refined products.
  • Rhubarb pulverized powder is made up of a lower alcohol having 1 (C 1 ) to 4 (C 4 ) carbon, such as water, methanol, ethanol and butanol in volumes of about 2 to 20 times, preferably about 3 to 5 times the dry weight.
  • a polar solvent or a mixed solvent having a mixing ratio of about 1: 0.1 to 1:10 thereof is used as the elution solvent, and the extraction temperature is 20 to 100 ° C, preferably at room temperature, and the extraction period is about 12 hours to 4 days,
  • extraction is performed using an extraction method such as hot water extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction for three days.
  • the extract is filtered 1 to 5 times by cold extraction and subjected to filtration under reduced pressure, and the filtrate is concentrated under reduced pressure at 20 to 100 ° C., preferably at room temperature using a vacuum rotary condenser, and soluble in water, lower alcohols, or a mixed solvent thereof.
  • One rhubarb crude extract can be obtained.
  • Ethanol extract of rhubarb of the present invention concentration-dependently inhibited cell adhesion induced by LFA-1 / 2 antibody (FIG. 1). Therefore, it is suitable for the prevention and treatment of inflammatory diseases or infectious diseases caused by ICAM-1 and LFA-1 mediated cell adhesion.
  • the solvent fraction of the rhubarb extract may be obtained by suspending the rhubarb extract with water and then fractionating it using a nonpolar solvent such as n -hexane or chloroform to obtain a polar solvent fraction and a nonpolar solvent fraction, respectively.
  • a nonpolar solvent such as n -hexane or chloroform
  • the solvent fraction is provided with water fraction, n -hexane fraction or chloroform fraction.
  • Method for obtaining a fraction of the rhubarb extract in the present invention is as follows. After the crude rhubarb extract obtained above is suspended in distilled water, it is preferably 1 to 10 times by adding a nonpolar solvent such as hexane, ethyl acetate or chloroform in a volume of about 1 to 100 times, preferably about 1 to 5 times the suspension. Preferably it can be obtained by extracting and separating the nonpolar solvent soluble layer in two to five times. It is also possible to further carry out conventional fractionation processes (Harborne JB Phytochemical methods: A guide to modern techniques of plant analysis, 3rd Ed. P6-7, 1998).
  • a nonpolar solvent such as hexane, ethyl acetate or chloroform
  • n-hexane and chloroform can be obtained by continuous extraction of each of the rhubarb solvents by continuous extraction, and more specifically, the rhubarb crude extract in water.
  • the same amount of n-hexane can be mixed and fractioned to obtain n-hexane soluble fraction and water soluble fraction, and chloroform can be added to the water soluble fraction to obtain chloroform soluble fraction and water soluble fraction.
  • the chloroform fraction of rhubarb of the present invention inhibited more than 70% adhesion between sICAM-1 and THP-1 cells (expressed by LFA-1), a human monocyte cell line, at a concentration of 50 ⁇ g / ml (FIG. 2). Therefore, it is suitable for the prevention and treatment of inflammatory diseases or infectious diseases caused by ICAM-1 and LFA-1 mediated cell adhesion.
  • rhubarb extract or a fraction thereof specifically inhibits the binding between intercellular adhesion factor-1 (ICAM-1) and leukocyte related antigen-1 (LFA-1; CD11a / CD18), thereby reducing monocytes, neutrophils and lymphocytes.
  • IMM-1 intercellular adhesion factor-1
  • LFA-1 leukocyte related antigen-1
  • rhubarb extract or a fraction thereof specifically inhibits the binding between intercellular adhesion factor-1 (ICAM-1) and leukocyte related antigen-1 (LFA-1; CD11a / CD18), thereby reducing monocytes, neutrophils and lymphocytes.
  • a disease caused by ICAM-1 and LFA-1 mediated cell adhesion is a disease caused by ICAM-1 and LFA-1 mediated cell adhesion, and includes an inflammatory disease and an infectious disease.
  • Inflammatory diseases in the present invention include autoimmune diseases related to multiple organs such as systemic lupus erythematosus and scleroderma; Inflammatory bowel disease, including ulcerative colitis and Crohn's disease; Central nervous system inflammatory diseases such as Alzheimer's disease, multiple sclerosis, motor neuron disease, Parkinson's disease, chronic fatigue syndrome; Inflammation including IgE mediated (type I) hypersensitivity such as atopic dermatitis, psoriasis, anaphylaxis and dermatitis; Eye diseases such as diabetic retinopathy, retinitis, macular disease, uveitis, conjunctivitis; Stroke, Coronary Artery Disease, Myocardial Infarction, Unstable Angina, Vasculitis, Atherosclerosis, Vascular Stenosis, Wegener's Granulomatosis, Chug-Strauss Syndrome Vasculitis, Henoch-Schonlein Vascular diseases such as purpura, Kawasaki disease, giant cell art
  • an infectious disease in the present invention includes an infectious disease caused by rhinovirus, coxsackievirus, malaria or HIV-1.
  • the present invention is an infectious disease caused by ICAM-1 and LFA-1 mediated cell adhesion, comprising a stilbene-based compound represented by the following formula (1) or (2) as an active ingredient, rhinovirus, cock It relates to a pharmaceutical composition for the prevention or treatment of infectious diseases caused by Saki virus, malaria or HIV-1.
  • the stilbene compound of the present invention may be obtained by extraction, separation and purification from rhubarb, but is not limited thereto and may be obtained by extraction, separation and purification from other raw materials.
  • raw materials for extracting, separating and purifying the stilbene compound of the present invention include rhubarb, knotweed, rye root, grape, wine, strawberry, raspberry, cranberry, mulberry, plum, cocoa, pine or peanut.
  • the stilbene-based compound of the present invention may be prepared by a known synthesis method, or may use a commercially available reagent.
  • the compounds of formula 1 or formula 2 of the present invention may be used in the form of pharmaceutically acceptable salts and include all salts, hydrates and solvates prepared by conventional methods.
  • salts are acid addition salts formed with pharmaceutically acceptable free acids.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • organic acids and inorganic acids may be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid
  • methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid may be used as the organic acid.
  • maleic acid succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanic acid, hydroiodic acid, and the like can be used. It is not limited.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salt, but is not limited thereto.
  • Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of Formula 1 or Formula 2 include salts of acidic or basic groups which may be present in compounds of Formula 1 or Formula 2 unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and the like. It can be prepared through.
  • Extraction, separation and purification methods of stilbene compounds from rhubarb according to the present invention are as follows.
  • the chloroform soluble fraction of rhubarb is separated by silica gel column chromatography using a mixed solvent of chloroform and methanol. At this time, it is preferable to use a solvent of chloroform and methanol of 100: 1 to 0: 100 (v / v).
  • ICAM-1 and LFA-1 mediated cell adhesion inhibitory activity of the isolated active fractions were measured and the fractions with the highest inhibitory activity were collected and 50%, 60%, 70%, 80%, 90%, 100% methanol Was separated by reverse phase column chromatography using elution solvent, and the fractions having the highest inhibitory activity were collected and silica gel column chromatography was performed using a mixed solvent of methylene chloride and methanol (50: 1 to 1: 1, v / v). Separate by graphy. Among the final fractions obtained, fractions having high ICAM-1 and LFA-1 mediated cell adhesion inhibitory activity were collected, and the final compound was separated by HPLC while flowing at 5 ml / min using 55% methanol.
  • the compound of formula 1 of the present invention thus inhibited the adhesion of sICAM-1 and THP-1 cells by about 80% at 10 ⁇ g / ml, and the compound of formula 2 inhibited at least 80% at 12.5 ⁇ g / ml At 25 ⁇ g / ml, the adhesion between CHO-ICAM-1 cells overexpressing ICAM-1 and THP-1 cells expressing LFA-1 was inhibited by about 80%.
  • the compound of the present invention effectively inhibited the adhesion between ICAM-1 and THP-1 cells, which are human monocyte cell lines, as concentration increased (FIGS. 3 to 5). Accordingly, the compounds of formula 1 or 2 of the present invention are suitable for the prevention and treatment of inflammatory diseases or infectious diseases caused by ICAM-1 and LFA-1 mediated cell adhesion.
  • the stilbene-based compound of Formula 1 or Formula 2 specifically inhibits binding between intercellular adhesion factor-1 (ICAM-1) and leukocyte related antigen-1 (LFA-1; CD11a / CD18), thereby providing monocytes, It is possible to prevent or treat inflammatory diseases and infectious diseases mediated by intercellular adhesion factor-1 by inhibiting adhesion and penetration of blood cells such as neutrophils and lymphocytes to vascular endothelial cells.
  • ICM-1 intercellular adhesion factor-1
  • LFA-1 leukocyte related antigen-1
  • a disease caused by ICAM-1 and LFA-1 mediated cell adhesion is a disease caused by ICAM-1 and LFA-1 mediated cell adhesion, and includes an inflammatory disease and an infectious disease.
  • Inflammatory diseases in the present invention include autoimmune diseases related to multiple organs such as systemic lupus erythematosus and scleroderma; Inflammatory bowel disease, including ulcerative colitis and Crohn's disease; Central nervous system inflammatory diseases such as Alzheimer's disease, multiple sclerosis, motor neuron disease, Parkinson's disease, chronic fatigue syndrome; Inflammation including IgE mediated (type I) hypersensitivity such as atopic dermatitis, psoriasis, anaphylaxis and dermatitis; Eye diseases such as diabetic retinopathy, retinitis, macular disease, uveitis, conjunctivitis; Stroke, Coronary Artery Disease, Myocardial Infarction, Unstable Angina, Vasculitis, Atherosclerosis, Vascular Stenosis, Wegener's Granulomatosis, Chug-Strauss Syndrome Vasculitis, Henoch-Schonlein Vascular diseases such as purpura, Kawasaki disease, giant cell art
  • an infectious disease in the present invention includes an infectious disease caused by rhinovirus, coxsackievirus, malaria or HIV-1.
  • a composition comprising rhubarb extract of the present invention, a fraction thereof, and a stilbene-based compound represented by Formula 1 or Formula 2 as an active ingredient is particularly suitable for improving cold symptoms or preventing or treating cold symptoms caused by linovirus or coxsackievirus. .
  • the term "amelioration of cold symptoms or prevention or treatment of a cold” includes the prevention and complete or partial treatment of a cold by rhinoviruses or coxsackieviruses. It also includes reducing cold symptoms, ameliorating cold symptoms, alleviating the pain of a cold or its symptoms, reducing the incidence of colds, or any other change in a patient that increases treatment outcome.
  • Symptoms of a cold caused by rhinovirus or coxsackie virus in which the composition of the invention is effective are sneezing, runny nose, nasal obstruction, nasal congestion, laryngitis or sore throat, cough, sore throat, asthma and headache And one or more of the common symptoms, such as fever, chills, and poor physical condition.
  • the present invention is a cough, sneezing, runny nose, myalgia, sore throat, nasal obstruction, laryngitis, sore throat, hoarseness, asthma, headache, sinus pain, rhinitis, mucosal boil, pharyngitis, bronchitis chills, chills and nausea It is effective in improving, treating or preventing one or more, especially sore throats.
  • the compound of formula 1 of the present invention effectively inhibits adhesion between ICAM-1 and THP-1 cells as described above, it is caused by rhinoviruses and coxsackie viruses, which are known to be infected using ICAM-1 as a receptor. Suitable for the prevention and treatment of colds.
  • the inhibitory effect of the compound of formula (1) against the rhinovirus was measured.
  • the compound of formula (1) was inoculated into cells after 1 hour of reaction with the virus, the virus was first inoculated into the cells and When the compound of Formula 1 was added after 1 hour (hr 1), all of them showed excellent inhibitory activity against rhinovirus (HRV2).
  • HRV2 inhibitory activity against rhinovirus
  • the compound of Formula 1 directly acts on the rhinovirus, which also shows antiviral and antiviral effects. It can be confirmed that (Figs. 6 to 8).
  • the cytopathic effect of the compound of formula 1 on the coxsackie virus was measured.
  • the compound of formula 1 of the present invention exhibited an inhibitory activity of 57.6% at 60 ⁇ M. Therefore, it can be seen that the compound of formula 1 directly acts on the coxsackievirus and exhibits antiviral efficacy (Table 1).
  • compositions of the present invention can be used in a variety of products, including foodstuffs for humans and animals, pharmaceutical products, veterinary products, cosmetics, personal care products and household products.
  • composition of the present invention can be used as an external preparation for skin, and preferably used as an external preparation for skin in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel or gel.
  • composition of the present invention can be used as foodstuff, preferably margarine, fat continuous or water continuous or bicontinuous spreads, fat reduced spreads, chocolate, bread, sweets It can be used as a gum, ice cream, ice cream coating, ice cream ingredient, dressing, mayonnaise, cheese, cream substitute, dry soup, drink, cereal bar, sauce, snack bar, dairy product, clinical nutrition or pediatric preparation.
  • composition of the present invention can be used as personal hygiene products, preferably soap, cosmetics, wipes, tissue paper, shampoo, skin cream, face cream, toothpaste, mouthwash, lipstick, perfume, make-up, foundation, It can be used as a ball touch, mascara, eye shadow, sunscreen lotion, hair care product, air freshener gel or cleansing gel.
  • Rhubarb extract of the present invention or fractions thereof, or the compound of formula (1) or (2) is derived from rhubarb, a drug that has been used for a long time as a herbal, so there are no problems such as toxicity and side effects.
  • the pharmaceutical composition for preventing and treating inflammatory diseases or infectious diseases of the present invention comprises 0.0001 to 10% by weight, preferably 0.001 to 1% by weight of the extract and its fraction or compound 1 based on the total weight of the composition.
  • compositions comprising rhubarb extracts, fractions or stilbene compounds of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • Rhubarb extracts, fractions or stilbene-based compounds of the present invention can be used alone or in combination with other pharmaceutically active extracts, fractions or compounds as well as in suitable collections.
  • Composition comprising rhubarb extract, fractions or stilbene compounds according to the present invention, powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. And in the form of sterile injectable solutions.
  • carriers, excipients and diluents which may be included in the composition comprising rhubarb extract, fractions thereof or stilbene-based compound 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 Can be mentioned.
  • 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 rhubarb extract, a fraction thereof, or a stilbene-based compound of Formula 1 separated therefrom.
  • excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants.
  • 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 rhubarb extract, a fraction thereof, or a stilbene-based compound of Formula 1 separated therefrom.
  • starch, calcium carbonate, sucrose or lactose, gelatin and the like are mixed and prepared.
  • lubricants such as magnesium styrate and talc are also used.
  • Liquid preparations for oral use may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • 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, glycerogelatin and the like can be used.
  • the preferred dosage of rhubarb extract, fractions or stilbene compounds of the present invention depends 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 rhubarb extract of the present invention or a fraction thereof is preferably administered at 0.0001 to 100 mg / kg, preferably at 0.001 to 100 mg / kg, and stilbene compounds at 0.0001 to 10 mg / day. In kg, it is preferable to administer at 0.001 to 10 mg / kg. Administration may be administered once a day or may be divided several times.
  • the pharmaceutical composition of the present invention can be administered to various mammals such as rats, mice, livestock, humans, and the like. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • Rhubarb was washed with water, dried in the shade, and then powdered by Waring brand. 5.5 kg of powdered rhubarb was added to 20 l of ethanol, followed by cold extraction at room temperature for 3 days, followed by filtration under reduced pressure with a filter paper (Watman, USA), and then the filter extract was extracted with ethanol solvent at room temperature using a vacuum rotary condenser. 500 g of rhubarb crude extract was obtained.
  • rhubarb crude extract was suspended in 1 L of water and then mixed with the same amount of n-hexane, and the mixture was fractionated by repeating this process four times to obtain 4 L of n-hexane fraction. Obtained.
  • an equivalent amount of chloroform was added to 1 L of the water-soluble fraction, followed by mixing. The procedure was repeated four times to obtain 1 L of the water-soluble fraction and 4 L of the chloroform-soluble fraction, and then the chloroform-soluble fraction was concentrated under reduced pressure. 100 g of a chloroform soluble extract was obtained.
  • Fraction 22 (1.23 g) having the highest intercellular adhesion inhibitory activity in the active fraction was reversed by column chromatography using 50%, 60%, 70%, 80%, 90%, 100% methanol as the elution solvent.
  • the active fractions were separated by -phase column chromatography (ODS gel).
  • CHO-ICAM-1 and CHO-K1 cells were cultured in 96-well plates for 3 days after seeding 1 ⁇ 10 4 cells / 200 mL and 1 ⁇ 10 5 cells / 200 mL, respectively.
  • THP-1 cells (1 ⁇ 10 6 cells / ml) were reacted at 37 ° C. for 30 to 60 minutes after BCECF-AM (5 mM) was added and fluorescently labeled, and washed once with RPMI 1640 medium.
  • THP-1 cells adjusted to 1 ⁇ 10 6 cells / ml were treated with 100 ⁇ l in 96-well plates with fully grown CHO-ICAM-1 or CHO-K1 cells.
  • the 96-well plate was treated with 5 ml of LFA-1 / 2 antibody (500 ng / ml) and a sample which increase the activity of LFA-1, and reacted at 37 ° C. for 30 minutes.
  • LFA-1 / 2 antibody 500 ng / ml
  • 150 ⁇ l of the medium was added and sealed, and the plate was inverted and left at room temperature for 30 minutes.
  • the medium was removed, washed three times with PBS, solubilized the cells with PBS (1% Triton X-100), and fluorescence (ex. 485, em. 592) was measured.
  • ethanol extract and chloroform fraction of rhubarb were added to the cell culture medium to measure cell adhesion inhibition.
  • the ethanol extract and chloroform fraction of rhubarb were concentration dependent on the cell adhesion induced by LFA-1 / 2 antibody. It was confirmed that inhibition (Fig. 1).
  • the IC 50 value of the stilbene compound represented by Chemical Formula 1 separated from the rhubarb chloroform fraction was found to be 16.4 ⁇ g / ml (FIG. 3 ). Rovastatin was used as a positive control.
  • Recombinant sICAM-1 (R & D Systems, Abingdon, UK) was diluted to 10 ⁇ g / ml (in PBS), 100 ⁇ l each into a 96-well plate and reacted at 4 °C for 12 hours. After washing once with PBS, 10 mg / ml BSA was added 100 ⁇ l each and blocked for 1 to 2 hours at room temperature. THP-1 cells (1 ⁇ 10 7 cells / ml) were reacted at 37 ° C. for 30 to 60 minutes after BCECF-AM (5 ⁇ M) addition. THP-1 cells were washed with PBS, treated with LFA-1 / 2 antibody (500 ng / mL), and reacted at 37 ° C. for 10-20 minutes.
  • THP-1 cells and the samples were coated with recombinant sICAM-1. 100 ⁇ l of each well was added and reacted at 37 ° C. for 30 to 60 minutes. After the reaction, unbound THP-1 cells were removed and washed three times with PBS. Cells were solubilized with PBS (1% Triton X-100) and fluorescence (ex. 485, em. 592) was measured.
  • the chloroform fraction of rhubarb inhibited adhesion of sICAM-1 and THP-1 cells by about 70% at a concentration of 50 ⁇ g / ml (FIG. 2).
  • lovastatin As a positive control, lovastatin was used, and the IC 50 value of the stilbene compound represented by Chemical Formula 2 of the present invention was found to be 7.3 ⁇ g / ml (FIG. 4).
  • the stilbene compound represented by Formula 2 inhibited the adhesion of CHO-ICAM-1 and THP-1 cells overexpressed with ICAM-1 at a concentration of 25 ⁇ g / ml by about 80% (FIG. 5 ).
  • WI-38 cells were put in a 96 well microplate to 1 X 10 5 / well per well and cultured in medium EMEM (penicillin 100 units, streptomycin 100 ⁇ g, 10% FBS). When WI-38 cells became a monolayer, they were washed twice with EMEM medium containing only antibiotics.
  • HRV-2, HRV-3 and HRV-14 strains were diluted to 100 TCID 50 and placed in EP tubes.
  • the compound of Formula 1 diluted with DMSO (dimethylsulfoxide) was added to each tube at a final concentration of 100 ⁇ M, 60 ⁇ M, 30 ⁇ M, 10 ⁇ M, 1 ⁇ M and reacted at 4 ° C. for 1 hour. After 1 hour, pre-washed WI-38 cells were inoculated in 3 wells per concentration, respectively.
  • interferon alpha which is known for its antiviral effect
  • non-infected, non-administered control, and infected and non-administered control were inoculated into WI-38 cells after 1 hour of reaction under the same conditions.
  • Infected and non-administered controls were incubated for 3-4 days until complete cytopathic effect (CPE).
  • CPE cytopathic effect
  • the cells were photographed by observing the magnification of 50X daily with an inverted microscope.
  • 10 ⁇ l of Cell Counting kit-8 Dojin, Japan, tetrazolium salt WST-8) was added to each well, followed by reaction at 33 ° C.
  • the rhinovirus inhibitory effect exhibited by the compound of the present invention was determined by using DMSO-only cells and DMSO, HRV-2, HRV-3, HRV-14 as a control.
  • the interferon alpha (INF- ⁇ ) used as a positive control showed a low inhibitory capacity of 22% in HRV-2, and 55.6% and 80.8% in HRV-3 and HRV-14, respectively.
  • Compounds of Formula 1 of the present invention showed high inhibitory activity of 100% and 78% at 60 ⁇ M, respectively, in HRV-2 and HRV-3, and 100% inhibitory activity at 90 ⁇ M in HRV-14 strains (FIG. 6 ).
  • virus inoculation alone HRV-2, 3, 14
  • the group treated with 100 ⁇ M confirmed that the WI-38 cells were similar to the control without any treatment (FIG. 8).
  • the virus inhibitory activity of the compound of Formula 1 after infection was examined.
  • WI-38 cell linovirus (HRV-2) washed twice with EMEM medium containing only antibiotics was inoculated and incubated at 33 ° C. for 1 hour. After 1 hour, all the inoculated virus solution was removed, and the compound of Formula 1 was added to the medium so that the final concentrations were 100 ⁇ M, 60 ⁇ M, 30 ⁇ M, and 10 ⁇ M 1 ⁇ M, and placed in the virus-inoculated WI-38 cells. . Then, the linovirus inhibitory effect represented by the compound of the present invention was determined in the same manner as above.
  • the compound of formula 1 was able to confirm good antiviral efficacy in all the various strains of rhinovirus (HRV-2, HRV-3, HRV-14), a cold virus, and also acts directly on the virus to prevent viral infection It also seems to show an effect together.
  • H1-HeLa ATCC: CRL-1958
  • a human cervical cancer cell line H1-HeLa
  • H1-HeLa cells were put in a 96 well microplate to 1 x 10 5 / well per each well and cultured in medium EMEM (penicillin 100 units, streptomycin 100 ⁇ g, 10% FBS). Once the H1-HeLa cells were monolayers, they were washed twice with EMEM medium containing only antibiotics. Coxsackievirus A21 strains were diluted to 200 TCID 50 / 0.1 ml and placed in EP tubes. The compound of Formula 1 diluted with DMSO (dimethylsulfoxide) was added to each tube at a final concentration of 60 ⁇ M, 30 ⁇ M, 10 ⁇ M, and reacted at 4 ° C. for 1 hour. After 1 hour, pre-washed H1-HeLa cells were inoculated in 3 wells per concentration, respectively.
  • EMEM penicillin 100 units, streptomycin 100 ⁇ g, 10% FBS.
  • the infected and non-administered control (Virus control) is inoculated in H1-HeLa cells after 1 hour reaction under the same conditions and incubated at 33 ° C.
  • Infected and non-administered controls were cultured for 3-4 days until complete cytopathic effect (CPE).
  • CPE cytopathic effect
  • 10 ⁇ l of Cell Counting kit-8 Dojin, Japan, tetrazolium salt WST-8) was added to each well, followed by reaction at 33 ° C. for 2 hours, and then absorbance at 450 nm. It was.
  • the inhibitory effect of coxsackievirus A21 represented by the compound of the present invention was determined using DMSO-only cells and cells treated with DMSO and coxsackievirus A21 as controls.
  • the compound of formula 1 of the present invention showed an inhibitory activity of 57.6% at 60 ⁇ M (Table 1).
  • the compound of the formula (1) was able to confirm the antiviral efficacy in coxsackievirus A21, a cold virus that is infected by using ICAM-1 as a cell receptor, like the rhinovirus.
  • the SPF rats of 6 weeks of age were divided into 5 rats per group, and the rhubarb extract of the present invention, each fraction thereof, and the stilbene compound of formula 1 or formula 2 were suspended in 0.5% methylcellulose solution.
  • Single oral administration at a dose of 10 mg / kg. After administration, the mortality, clinical symptoms, and weight changes of the animals were observed. Hematological and hematological examinations were performed. Necropsy was performed to observe abdominal and thoracic organ abnormalities.
  • Rhubarb extract its fractions, or 0.1 g of the compound of formula 1 or 2
  • the above ingredients are mixed and filled in an airtight cloth to prepare a powder.
  • Rhubarb extract its fractions, or 0.1 g of the compound of formula 1 or 2
  • a tablet is prepared by a direct tableting method.
  • the total amount of each tablet is 500 mg, of which the active ingredient content is 50 mg.
  • Rhubarb extract its fractions, or 0.1 g of the compound of formula 1 or 2
  • Rhubarb extract its fractions, or 0.1 g of the compound of formula 1 or 2
  • the amount of the above ingredient is prepared per ampoule (2 ml).
  • Rhubarb extract its fractions, or 0.1 g of the compound of formula 1 or 2

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour prévenir ou traiter des maladies induites par une adhésion cellulaire à médiation ICAM-1 et LFA-1, dans laquelle une composition contient comme ingrédients actifs, un extrait de Rhei Rhizoma, des fractions de celui-ci, ou des composés à base de dérivés de celui-ci. L'invention concerne plus particulièrement une composition pharmaceutique pour prévenir ou traiter des maladies infectieuses causées par un rhinovirus, le virus Coxsackie, la malaria, ou HIV-1, la composition pharmaceutique comprenant un extrait de Rhei Rhizoma, des fractions de celui-ci, ou de composés à base de stilbène dérivés de ceux-ci. L'invention concerne également des préparations pour application externe sur la peau, des produits alimentaires, et des articles d'hygiène personnelle contenant la composition.
PCT/KR2010/000991 2009-02-17 2010-02-17 Composition pharmaceutique comprenant un extrait de rhei rhizoma, des fractions de celui-ci, ou des composés à base de stilbène pour prévenir ou traiter des maladies induites par une molécule 1 d'adhésion intercellulaire. WO2010095858A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20090012982 2009-02-17
KR10-2009-0012982 2009-02-17
KR1020090052460A KR20100094308A (ko) 2009-02-17 2009-06-12 대황 추출물, 이의 분획물 또는 스틸벤계 화합물을 포함하는 세포간접착인자-1로 매개되는 질환의 예방 또는 치료용 약학적 조성물
KR10-2009-0052460 2009-06-12

Publications (2)

Publication Number Publication Date
WO2010095858A2 true WO2010095858A2 (fr) 2010-08-26
WO2010095858A3 WO2010095858A3 (fr) 2010-12-09

Family

ID=42634325

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2010/000991 WO2010095858A2 (fr) 2009-02-17 2010-02-17 Composition pharmaceutique comprenant un extrait de rhei rhizoma, des fractions de celui-ci, ou des composés à base de stilbène pour prévenir ou traiter des maladies induites par une molécule 1 d'adhésion intercellulaire.

Country Status (1)

Country Link
WO (1) WO2010095858A2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102552440A (zh) * 2012-02-17 2012-07-11 唐本芬 一种平喘消炎药物及其制备方法和用途
CN102697886A (zh) * 2012-06-21 2012-10-03 陈慧婷 治疗风湿性关节炎的海风藤中药制剂及制备方法
CN102743486A (zh) * 2012-06-07 2012-10-24 无为县陡沟镇中心卫生院 一种治疗肝肾两亏型风湿性关节炎的膏药
CN103301249A (zh) * 2012-03-15 2013-09-18 涂子雄 一种关节炎外用中草药
CN103565950A (zh) * 2013-10-15 2014-02-12 姜席赋 一种用于治疗寒湿痹痛的中药配方
CN105250406A (zh) * 2015-11-11 2016-01-20 郑州后羿制药有限公司 一种防治淡水鱼病毒性疾病的中草药发酵提取液及其制备方法
CN111346075A (zh) * 2020-03-24 2020-06-30 深圳市金汇球高科技有限公司 大黄蒽醌类提取物在广谱抗病毒中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040146594A1 (en) * 2002-11-14 2004-07-29 Romano Mongiorgi Odontostomatological use of plant compounds based on rhubarb roots (species belonging to the Rheum genus) and spinach leaves (Spinacia oleracea L.)
KR20050097614A (ko) * 2004-04-02 2005-10-10 김형환 대황추출물을 포함하는 혈관질환의 예방 또는 치료제
JP2008248133A (ja) * 2007-03-30 2008-10-16 Nippon Meat Packers Inc アラメ由来のβ−グルカン素材
KR20100002963A (ko) * 2008-06-30 2010-01-07 원광대학교산학협력단 복합 생약 추출물을 유효성분 함유하는 혈관질환 예방 및치료용 조성물
KR20100010205A (ko) * 2008-07-22 2010-02-01 한국생명공학연구원 오수유로부터 분리된 세포접착저해 물질을 유효성분으로하는 약학 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040146594A1 (en) * 2002-11-14 2004-07-29 Romano Mongiorgi Odontostomatological use of plant compounds based on rhubarb roots (species belonging to the Rheum genus) and spinach leaves (Spinacia oleracea L.)
KR20050097614A (ko) * 2004-04-02 2005-10-10 김형환 대황추출물을 포함하는 혈관질환의 예방 또는 치료제
JP2008248133A (ja) * 2007-03-30 2008-10-16 Nippon Meat Packers Inc アラメ由来のβ−グルカン素材
KR20100002963A (ko) * 2008-06-30 2010-01-07 원광대학교산학협력단 복합 생약 추출물을 유효성분 함유하는 혈관질환 예방 및치료용 조성물
KR20100010205A (ko) * 2008-07-22 2010-02-01 한국생명공학연구원 오수유로부터 분리된 세포접착저해 물질을 유효성분으로하는 약학 조성물

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102552440A (zh) * 2012-02-17 2012-07-11 唐本芬 一种平喘消炎药物及其制备方法和用途
CN103301249A (zh) * 2012-03-15 2013-09-18 涂子雄 一种关节炎外用中草药
CN102743486A (zh) * 2012-06-07 2012-10-24 无为县陡沟镇中心卫生院 一种治疗肝肾两亏型风湿性关节炎的膏药
CN102697886A (zh) * 2012-06-21 2012-10-03 陈慧婷 治疗风湿性关节炎的海风藤中药制剂及制备方法
CN103565950A (zh) * 2013-10-15 2014-02-12 姜席赋 一种用于治疗寒湿痹痛的中药配方
CN105250406A (zh) * 2015-11-11 2016-01-20 郑州后羿制药有限公司 一种防治淡水鱼病毒性疾病的中草药发酵提取液及其制备方法
CN111346075A (zh) * 2020-03-24 2020-06-30 深圳市金汇球高科技有限公司 大黄蒽醌类提取物在广谱抗病毒中的应用

Also Published As

Publication number Publication date
WO2010095858A3 (fr) 2010-12-09

Similar Documents

Publication Publication Date Title
KR101181216B1 (ko) 오수유 추출물, 이의 분획물 또는 퀴놀론 알칼로이드계 화합물을 포함하는 약학 조성물
WO2010095858A2 (fr) Composition pharmaceutique comprenant un extrait de rhei rhizoma, des fractions de celui-ci, ou des composés à base de stilbène pour prévenir ou traiter des maladies induites par une molécule 1 d'adhésion intercellulaire.
KR100954866B1 (ko) 호초로부터 분리된 세포접착저해 물질을 유효성분으로 하는염증성 질환 의 예방 및 치료용 조성물
WO2011043631A2 (fr) Composition pharmaceutique pour la prévention et le traitement du rhume, contenant un extrait de reynoutria elliptica, une fraction de celui-ci ou un composé à base de stilbène
WO2015002393A1 (fr) Composition de traitement ou de prévention d'une maladie cutanée inflammatoire comprenant, comme ingrédient actif, un extrait d'agrumes immatures ou de la synéphrine, ou leur sel
WO2017014502A1 (fr) Composition pharmaceutique pour la prévention ou le traitement de maladies médiées par il-6 comprenant un extrait de fleur de rosa rugosa en tant que substance active
KR100954865B1 (ko) 필발로부터 분리된 세포접착저해 물질을 유효성분으로 하는염증성 질환 의 예방 및 치료용 조성물
KR100579752B1 (ko) 리그난계 화합물을 함유하는 염증성 질환의 치료 또는예방용 약학적 조성물
WO2023249393A1 (fr) Composition pour la prévention, l'atténuation ou le traitement d'une infection à coronavirus, contenant un extrait d'herbe médicinale utilisé en tant que principe actif
KR100895613B1 (ko) 신규한 비환식 트리테르페노이드계 화합물, 및 초두구추출물 또는 이로부터 분리된 비환식 트리테르페노이드계화합물을 포함하는 약학 조성물
KR101009992B1 (ko) 대황 추출물, 이의 분획물 또는 스틸벤계 화합물을 포함하는 세포간접착인자-1로 매개되는 질환의 예방 또는 치료용 약학적 조성물
KR101021244B1 (ko) 오수유로부터 분리된 세포접착저해 물질을 유효성분으로하는 약학 조성물
KR101666524B1 (ko) 초과(Amomi Tsao-ko)로부터 분리된 화합물 및 이의 항염 용도
WO2013012117A1 (fr) Utilisation de compositions pharmaceutiques comprenant un phytostérol pour prévenir ou traiter les maladies inflammatoires
WO2022139524A1 (fr) Nouveau dérivé de fk506 et composition le comportant pour favoriser la pousse des cheveux
WO2021150077A1 (fr) Composition pharmaceutique ou aliment fonctionnel pour la santé pour la prévention ou le traitement de la stéatose hépatique non alcoolique
KR101098952B1 (ko) 갈잎떨기나무 추출물을 포함하는 염증성 질환 또는 감염성 질환의 예방 또는 치료용 조성물
WO2024063550A1 (fr) Composition pour la prévention, l'amélioration ou le traitement de maladies provoquées par une matière particulaire contenant un extrait de pépins de citri tangerinae et son utilisation
WO2023214706A1 (fr) Nouveau composé dérivé de diaryl-propanedione, son procédé de préparation et composition pharmaceutique le comprenant pour la prévention ou le traitement de maladies inflammatoires ou allergiques
CN115403545B (zh) 愈创木烷类倍半萜前药及其用途
WO2022039345A1 (fr) Composition pour la prévention, le soulagement, ou le traitement d'une maladie inflammatoire contenant de l'isookanine ou un sel de celle-ci en tant que principe actif
KR102524083B1 (ko) 한약재 추출물을 유효성분으로 포함하는 코로나바이러스 감염증의 예방, 개선 또는 치료용 조성물
WO2011118953A2 (fr) Composition destinée à prévenir ou à traiter l'obésité ou les maladies métaboliques d'origine lipidique
WO2022255746A1 (fr) Vésicule dérivée de lactobacillus acidophilus et utilisation associée
WO2016013793A1 (fr) Utilisation d'extraits de robinia pseudoacacia, d'acacétine et d'apigénine pour améliorer et traiter l'infection par l'herpès virus gamma

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10743933

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10743933

Country of ref document: EP

Kind code of ref document: A2