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WO2023038480A1 - Composition pour la prévention, le traitement ou le soulagement d'une infection par le virus de la grippe, comprenant un mélange d'extrait d'agrimonia pilosa et d'extrait de galla rhois en tant que principes actifs - Google Patents

Composition pour la prévention, le traitement ou le soulagement d'une infection par le virus de la grippe, comprenant un mélange d'extrait d'agrimonia pilosa et d'extrait de galla rhois en tant que principes actifs Download PDF

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Publication number
WO2023038480A1
WO2023038480A1 PCT/KR2022/013577 KR2022013577W WO2023038480A1 WO 2023038480 A1 WO2023038480 A1 WO 2023038480A1 KR 2022013577 W KR2022013577 W KR 2022013577W WO 2023038480 A1 WO2023038480 A1 WO 2023038480A1
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Prior art keywords
influenza virus
extract
virus infection
preventing
aprg64
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Ceased
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English (en)
Korean (ko)
Inventor
강세찬
서영진
김형건
이영근
최순호
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aprg Inc
Sungkyunkwan University
Industry Academic Cooperation Foundation of Chung Ang University
Kyung Hee University
Original Assignee
Aprg Inc
Sungkyunkwan University
Industry Academic Cooperation Foundation of Chung Ang University
Kyung Hee University
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Priority claimed from KR1020220113158A external-priority patent/KR20230039782A/ko
Application filed by Aprg Inc, Sungkyunkwan University, Industry Academic Cooperation Foundation of Chung Ang University, Kyung Hee University filed Critical Aprg Inc
Publication of WO2023038480A1 publication Critical patent/WO2023038480A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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    • 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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • A—HUMAN NECESSITIES
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    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/21—Plant extracts
    • A23V2250/2116—Flavonoids, isoflavones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a composition for preventing, treating or improving influenza virus infection comprising a mixture of an extract of Agrimonia pilosa and an extract of Galla rhois .
  • Influenza commonly known as 'the flu', is an acute respiratory disease caused by the influenza virus. It is highly contagious and causes large and small group infections or pandemics around the world every year. It is a highly contagious disease that infects 10-20% of the general population within ⁇ 3 weeks.
  • influenza virus is one of the viruses that cause severe respiratory symptoms in the elderly, children, certain chronic diseases, and immunocompromised patients, leading to death in severe cases (Hien, TT et al. N. Eng. J. Med ., 350, 1179, 2004).
  • Influenza virus taxonomically belongs to Orthomyxovirus , and there are three types of A, B, and C types, and particularly, the epidemically spreading types are known as A and B types.
  • a and B types On the surface of these viruses, there are two types of surface antigens, glycoproteins, hamagglitinin (HA) and neuraminidase (NA), and eight segmented RNAs exist inside.
  • Hemagglutinin is one of the antigenic projections sprouting on the influenza virus surface. It is in the form of a trimer composed of a head and a stem, and the double head part is related to most antigenic mutations and attaches the virus by binding to the terminal sialic acid residue on the surface of the host cell and sequentially the virus enters the host cell.
  • Neuraminidase is an enzyme of a glycoprotein in the viral envelope membrane. It is a mushroom-shaped tetramer with a head and stem shape, and has an active site on the upper surface of the head. The virus replicated and multiplied in the infected cell cuts the alpha-ketosidic bond connecting the oligosaccharide portion on the cell surface and the terminal neuraminic acid residue to release the virus outside the host cell. It plays a major role in penetration into cells of the respiratory tract (a. Mark, VI Nature review 6, 987, 2007. b. Huberman, K et al. Virology 214, 294, 1995).
  • Virus surface antigens mutate within the same subtype, and new antigenic variants emerge every year.
  • the avian influenza virus which has been a problem until recently, among influenza viruses, has mutated to infect various types of birds such as chickens, turkeys, ducks and wild birds.
  • chickens are infected due to rapid propagation, more than 80% of them die, so it is a viral disease that causes the greatest damage and threat to the poultry industry worldwide, and its ripple effect is not limited to the poultry industry. It has been reported to cause disease to (Gubareva, L. V. et al. Lancet, 355, 2000).
  • Influenza is contracted by inhaling aerosols containing the virus, which are usually airborne through coughing or sneezing. In addition to this, it can be transmitted by excrement, saliva, nasal mucus, feces and blood of other objects, but most transmission is droplet infection caused by inhalation of aerosols.
  • the most obvious symptom is a sudden high fever of 38-40 ° C within 24 hours of infection, systemic symptoms such as headache, muscle pain and fatigue, and respiratory symptoms such as sore throat, cough, expectoration and rhinitis also appear. In addition, abdominal pain, vomiting and convulsions may occur rarely. Healthy people recover after showing symptoms for several days, but patients with chronic lung disease, heart disease, and immunocompromised patients may die from complications such as pneumonia, as well as encephalopathy, myelitis, Reye syndrome, myositis, Complications such as myocarditis and pericarditis may be accompanied. Children have similar symptoms as adults, but they have higher fevers, febrile seizures may occur, and otitis media, pseudomembranous laryngitis, and myalgia are more common.
  • Oseltamivir (trade name: Tamiflu), zanamivir (trade name: Relenza), peramivir (en: Peramivir), amantadine (en: Amantadine), and the like.
  • Oseltamivir also called Tamiflu, is currently used primarily for the treatment of H1N1 influenza type A. Tamiflu is the only avian influenza (AI) treatment exclusively produced in the world. It is an antiviral drug that has a therapeutic effect by blocking the enzyme function that proliferates the virus, and it is most effective when taken within 48 hours of the onset of symptoms.
  • the main treatment effects are reduction of flu symptoms exacerbation, reduction of secondary complications such as bronchitis or pneumonia, and reduction of incubation period of flu. It is also used as a treatment for influenza A and B.
  • Zanamivir is also known as Zanamivir and the trade name is Relenza. It acts as a neuraminidase inhibitor and is used for the treatment of influenza types A and B.
  • oseltamir has a side effect of severe vomiting
  • zanamivir has a high antiviral effect, but has low bioavailability and rapid excretion from the kidneys.
  • the present inventors completed the present invention by confirming that influenza virus infection can be effectively prevented or treated using the Seonhakcho extract and gall nut extract.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating influenza virus infection, a food composition for preventing or improving influenza virus infection, and influenza virus infection containing a mixture of an extract of Agrimonia pilosa and a galla rhois extract as an active ingredient. It is to provide a quasi-drug composition for preventing or suppressing a viral infection.
  • Another object of the present invention is a flavonoid compound represented by the following formula (1) or a triterpenoid compound represented by the following formula (2), isomers thereof, and pharmaceutically acceptable salts thereof selected from the group consisting of It is to provide a pharmaceutical composition for preventing or treating influenza virus infection and a quasi-drug composition for preventing or suppressing influenza virus infection, comprising any one or more as active ingredients:
  • R 1 is H or OH
  • R 2 is any one selected from the group consisting of ⁇ -L-rhamnopyranosyl, H, ⁇ -D-glucopyranosyl, rutinosyl, and OH;
  • R 3 is H or ⁇ -D-glucuronosyl
  • Another object of the present invention is selected from the group consisting of a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and food-acceptable salts thereof. It is to provide a food composition for preventing or improving influenza virus infection comprising at least one of the active ingredients.
  • the present invention is a pharmaceutical composition for preventing or treating influenza virus infection and influenza virus infection comprising a mixture of an extract of Agrimonia pilosa and an extract of galla rhois as an active ingredient It provides a quasi-drug composition for prevention or suppression.
  • the present invention provides a food composition for preventing or improving influenza virus infection comprising a mixture of an extract of Agrimonia pilosa and an extract of galla rhois as an active ingredient.
  • the Seonhakcho extract or the gall nut extract may be extracted with one or more solvents selected from the group consisting of water, C 1 to C 4 alcohol, and mixed solvents thereof, but is limited thereto It is not.
  • the Seonhakcho extract or the nut gall extract may be extracted using 30 to 95% ethanol, but is not limited thereto.
  • the mixture may be mixed so that the weight ratio of Seonhakcho extract: Nut gall extract is 10: 1 to 1: 10, but is not limited thereto.
  • influenza virus may be an influenza A type H1N1 virus, but is not limited thereto.
  • the mixture can inhibit the expression of M1 or NP gene of influenza virus, but is not limited thereto.
  • the present invention is any one selected from the group consisting of flavonoid compounds represented by the following formula (1) or triterpenoid compounds represented by the following formula (2), isomers thereof, and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition for preventing or treating influenza virus infection and a quasi-drug composition for preventing or suppressing influenza virus infection, comprising at least one as an active ingredient are provided:
  • R 1 is H or OH
  • R 2 is any one selected from the group consisting of ⁇ -L-rhamnopyranosyl, H, ⁇ -D-glucopyranosyl, rutinosyl, and OH;
  • R 3 is H or ⁇ -D-glucuronosyl
  • the quasi-drug may be at least one selected from the group consisting of disinfectant cleaner, shower foam, gargreen, wet tissue, detergent soap, hand wash, and ointment, but is not limited thereto.
  • the present invention is any one selected from the group consisting of a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and food-acceptable salts thereof. It provides a food composition for preventing or improving influenza virus infection containing one or more as active ingredients.
  • the food composition may be a health functional food composition, but is not limited thereto.
  • the flavonoid compound is Afzelin, Apigenin, Apigenin 7-O- ⁇ -D-glucuronide (Apigenin 7-O- ⁇ - It may be any one or more selected from the group consisting of D-glucuronide), Astragalin, Nicotiflorin, Quercetin, Quercitrin, and Rutin, but is not limited thereto. no.
  • the triterpenoid compound may be ursolic acid, but is not limited thereto.
  • the present invention provides a method for preventing or treating influenza virus infection comprising the step of administering to a subject in need of a composition containing a mixture of the extract of Agrimonia pilosa and the extract of Galla rhois as an active ingredient do.
  • the present invention provides a method for preventing or inhibiting influenza virus infection comprising the step of using a composition comprising a mixture of an extract of Agrimonia pilosa and an extract of Galla rhois as an active ingredient by an individual in need thereof do.
  • the present invention is any one selected from the group consisting of a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and pharmaceutically acceptable salts thereof.
  • a method for preventing or treating influenza virus infection comprising administering a composition containing one or more active ingredients to a subject in need thereof.
  • the present invention is any one selected from the group consisting of a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and pharmaceutically acceptable salts thereof.
  • a method for preventing or inhibiting influenza virus infection comprising the step of using a composition containing one or more active ingredients by an individual in need thereof.
  • the present invention provides a composition comprising a mixture of an extract of Agrimonia pilosa and an extract of galla rhois as an active ingredient for preventing, treating, improving, or inhibiting influenza virus infection.
  • the present invention provides the use of a mixture of an extract of Agrimonia pilosa and a galla rhois extract for the preparation of a preparation for preventing, treating, improving or inhibiting influenza virus infection.
  • the present invention is a group consisting of a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and pharmaceutically or food-acceptable salts thereof.
  • a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and pharmaceutically or food-acceptable salts thereof.
  • the present invention relates to a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and It provides the use of a composition containing at least one selected from the group consisting of pharmaceutically or food-acceptable salts thereof as an active ingredient.
  • a composition for preventing, treating, or improving influenza virus infection containing a mixture of an extract of Agrimonia pilosa and an extract of Galla rhois as an active ingredient has no side effects on the human body and is safe, while cell lesions through a virus-dependent pathway It has excellent antiviral activity according to effect, influenza virus-related gene reduction effect, etc.
  • the antiviral effect was confirmed in vivo, and the active ingredients of the mixed extract also have remarkably excellent antiviral activity, it can be usefully used as a composition for preventing, treating, or improving influenza virus infectious diseases.
  • 1 is a graph showing the results of testing the cytotoxicity of APRG64 in MDCK cell lines.
  • FIGS. 2a and 2b are photographs and graphs showing the cytopathic effect inhibitory activity of APRG64 in IAV-infected MDCK cell lines.
  • Figure 2c is a graph showing that the cytopathic effect inhibitory activity of APRG64 is by a virus-dependent pathway.
  • Figure 3a is a graph showing the inhibitory effect of influenza virus M1 and NP gene expression according to APRG64 treatment, and a photograph showing the result of Western blot experiment on the expression inhibitory effect of influenza virus M1 and NS1 protein.
  • Figure 3b is a graph showing the plaque analysis results for the influenza virus particle reduction effect according to the treatment of APRG64.
  • Figure 3c is a photograph and a graph showing the results of immunocytochemical analysis on the effect of reducing cells expressing influenza virus NP according to APRG64 treatment.
  • 4 is a diagram showing structural formulas and functional groups of 9 compounds isolated from APRG64.
  • 5a and 5b are graphs showing the effect of reducing the gene expression of M1 and NP of influenza virus when treated with 9 compounds isolated from APRG64 cancer cell lines.
  • Figures 6a and 6b are photographs and graphs showing the cytopathic effect inhibitory activity in IAV-infected MDCK cell lines by apigenin.
  • 6C is a graph showing that the activity of apigenin to inhibit the effect of apigenin on cell damage is a virus-dependent pathway.
  • Figure 7a is a graph showing the effect of suppressing the expression of influenza virus M1 and NP genes according to apigenin treatment, and a photograph showing the results of Western blot experiments on the effect of suppressing the expression of influenza virus M1 and NS1 proteins.
  • Figure 7b is a graph showing the results of plaque analysis on the effect of reducing influenza virus particles according to apigenin treatment.
  • 7c is a photograph and a graph showing the results of immunocytochemical analysis on the effect of reducing cells expressing influenza virus NP according to apigenin treatment.
  • Figure 8a is a photograph showing the results of Western blot experiments showing the activity of inhibiting influenza virus replication according to apigenin treatment.
  • 8b and 8c are graphs showing the reduction of M1 and NP gene expression of influenza virus in an experiment confirming the inhibitory activity of APRG64 and apigenin on influenza virus replication through the initial mechanism of viral replication.
  • Figure 8d is a graph showing the experimental results confirming the influenza virus replication inhibitory activity of APRG64 and apigenin through RNA polymerase activity inhibition.
  • 8e is a photograph showing the results of a Western blot experiment confirming the inhibitory activity of APRG64 and apigenin on influenza virus replication through inhibition of MAPK activity.
  • 9a is a diagram showing a schematic view of a mouse model for intranasal administration of APRG64 and apigenin.
  • 9B is a graph showing the effect of reducing IAV titers in the lungs of influenza virus-infected mice when APRG64 and apigenin were administered intranasally.
  • 10a is a diagram showing a schematic view of a mouse model for oral administration of APRG64.
  • Figure 10b is a graph showing the effect of inhibiting weight loss in mice infected with influenza virus when APRG64 was orally administered.
  • 10c is a graph showing the effect of suppressing the death of influenza virus-infected mice when APRG64 was orally administered.
  • 10d is a graph showing the effect of reducing viral RNA and infectious virus particles in the lungs of influenza virus-infected mice when APRG64 was orally administered.
  • 10e is a graph showing the reduction of IFN- ⁇ , TNF- ⁇ , and IL-6 expressions induced in influenza virus-infected mice upon oral administration of APRG64.
  • 11a to 11c show the results of influenza virus suppression experiments through molecular docking simulation using APRG64-derived Chemical Formulas 1 to 3.
  • the present invention provides a pharmaceutical composition for preventing or treating influenza virus infection comprising a mixture of an extract of Agrimonia pilosa and an extract of Galla rhois as an active ingredient.
  • Seonhakcho extract may be a whole plant extract including Seonhakcho leaves, stems, roots, or both, and according to an embodiment of the present invention, it may be an Agrimonia pilosa leaf extract, but is not limited thereto don't
  • the seonhakcho can be used without limitation, such as directly harvested, cultivated, or commercially available.
  • gall extract may be a nut gall leaf, stem, branch, root, or whole plant extract including both thereof, and according to an embodiment of the present invention, galla rhois may be a leaf extract, but thereby Not limited.
  • the gall nut can be used without limitation, such as directly collected, cultivated, or commercially available.
  • Seonhakcho Agrimonia pilosa Extract and nut gall ( Galla rhois )
  • the mixture of the extract was abbreviated as APRG64.
  • extract refers to an extract obtained by the extraction treatment of the sagebrush or gall gall, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, a purified product or a purified product of the extract, or a mixture thereof. Etc., the extract itself and extracts of all formulations that can be formed using the extract.
  • extract may include a crude extract, a polar solvent-soluble extract or a non-polar solvent-soluble extract, a fermented extract, and the like.
  • any lactic acid bacteria may be applied to enhance the influenza virus inhibitory effect of the Seonhakcho or Nut gall extract according to the present invention, but is not limited thereto.
  • the Seonhakcho extract or the gall nut extract may be in the form of a dried product, but is not limited thereto.
  • the method for extracting the Sunhakcho or gall nut is not particularly limited, and can be extracted according to a method commonly used in the art.
  • a method using an extraction device such as supercritical extraction, subcritical extraction, high-temperature extraction, high-pressure extraction, or ultrasonic extraction, or a method using an adsorption resin including XAD and HP-20 may be used.
  • Non-limiting examples of the extraction method include a heating extraction method, a cold extraction method, a reflux cooling extraction method, a steam distillation method, an ultrasonic extraction method, an elution method, a compression method, and the like, which are performed alone or in combination of two or more methods. It can be.
  • the extract may be additionally subjected to a conventional fractionation process and may be purified according to a conventional purification method.
  • the extract included in the composition of the present invention may be prepared by pulverizing the primary extract extracted by the hot water extraction or solvent extraction method through an additional process such as distillation under reduced pressure and freeze drying or spray drying.
  • the primary extract can be further purified by various chromatography methods such as silica gel column chromatography, high performance liquid chromatography, and thin layer chromatography to obtain additional purified fractions.
  • the extract may include all extracts, separated compounds, fractions and purified products obtained in each step of extraction, fractionation or purification, dilution, concentration, or drying thereof.
  • the type of extraction solvent used to extract the Sunhakcho or the gallbladder is not particularly limited, and according to a conventional method known in the art for extracting an extract from natural products, that is, conventional temperature and pressure It can be extracted using conventional solvents under the conditions.
  • a solvent alcohol having 1 to 4 carbon atoms including purified water, ethanol, methanol, isopropanol, butanol, etc., and acetone, ether, benzene ), chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, and the like may be used alone or in combination.
  • the Seonhakcho extract or the nut gall extract may be extracted with one or more solvents selected from the group consisting of water, C 1 to C 4 alcohol, and mixed solvents thereof, and according to an embodiment of the present invention, ethanol It can be extracted using a solvent, but is not limited thereto.
  • methanol or ethanol aqueous solution may be used, and the methanol or ethanol aqueous solution is 30 to 95% (v / v), more specifically 40 to 60% (v / v), most specifically 50% (v / v ) may be methanol or ethanol, but is not limited thereto.
  • the ethanol when used as a solvent to extract the sunflower or the nut gall, for example, 10% to 100% ethanol, 10% to 90% ethanol, 10% to 80% ethanol, 10% to 70% ethanol, 10% to 60% Ethanol, 10% to 50% Ethanol, 20% to 90% Ethanol, 20% to 80% Ethanol, 20% to 70% Ethanol, 20% to 60% Ethanol, 20% to 50% Ethanol, 30 % to 90% Ethanol, 30% to 80% Ethanol, 30% to 70% Ethanol, 30% to 60% Ethanol, 30% to 50% Ethanol, 40% to 90% Ethanol, 40% to 80% Ethanol, 40% to 70% ethanol, 40% to 60% ethanol, 40% to 50% ethanol, 45% to 55% ethanol, or 50% ethanol, but is not limited thereto.
  • the prepared extract may then be filtered or concentrated or dried to remove the solvent, and both filtration, concentration and drying may be performed.
  • filtration may use filter paper or a vacuum filter
  • concentration may use a vacuum vacuum concentrator or vacuum rotary evaporator
  • drying may be performed by vacuum drying, vacuum drying, boiling drying, spray drying, freeze drying, and the like.
  • vacuum drying vacuum drying, boiling drying, spray drying, freeze drying, and the like.
  • the number of extractions may be carried out one or more times, but as the extraction continues, the yield of the active ingredient significantly decreases, so it may not be economical to perform the extraction repeatedly five times or more. Accordingly, the number of extractions is preferably 1 to 5 times, and more preferably 2 to 5 repeated extractions, but is not limited thereto.
  • the extraction temperature is preferably 20°C to 100°C, more preferably 20°C to 80°C, and most preferably room temperature, but is not limited thereto.
  • the extraction time is preferably one to 10 hours, but is not limited thereto.
  • the mixture may be mixed so that the weight ratio of Seonhakcho extract: gall nut extract is 10:1 to 1:10, and also, the weight ratio is 1:0.1 to 9, 1:0.1 to 8, 1:0.1 to 7, 1:0.1 to 6, 1:0.1 to 5, 1:0.1 to 4, 1:0.1 to 3, 1:0.1 to 2, 1:0.1 to 1, 1:0.1 to 0.9, 1:0.1 to 0.8, 1:0.1 to 0.7, or 1:0.1 to 0.6.
  • it may be mixed in a weight ratio of 6:4, but is not limited thereto.
  • the mixture may inhibit the expression of the M1 or NP gene of influenza virus, but is not limited thereto.
  • the present invention relates to at least one selected from the group consisting of a flavonoid compound represented by Formula 1 or a triterpenoid compound represented by Formula 2, isomers thereof, and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition for preventing or treating influenza virus infection comprising as an active ingredient:
  • R 1 is H or OH
  • R 2 is any one selected from the group consisting of ⁇ -L-rhamnopyranosyl, H, ⁇ -D-glucopyranosyl, rutinosyl, and OH;
  • R 3 is H or ⁇ -D-glucuronosyl
  • the flavonoid compounds include Afzelin, Apigenin, Apigenin 7-O- ⁇ -D-glucuronide, It may be at least one selected from the group consisting of Astragalin, Nicotiflorin, Quercetin, Quercitrin, and Rutin, but is not limited thereto.
  • the triterpenoid compound may be ursolic acid, but is not limited thereto.
  • the compound represented by Compound 10 may have a molecular formula of C 41 H 32 O 28 and a molecular weight of 940.67, [(2R,3R,4S,5R,6S)-3,4,5,6-tetrakis[ (3,4,5-trihydroxybenzoyl)oxy]oxan-2-yl]methyl 3,4,5-trihydroxybenzoate may have the IUPAC name.
  • the compound represented by Compound 2 may have a molecular formula of C 30 H 48 O 3 and a molecular weight of 456.7, (1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10 -hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H It can have the IUPAC name of -picene-4a-carboxylic acid.
  • the compound represented by compound 3 may have a molecular formula of C 15 H 10 O 7 and a molecular weight of 302.2, and the IUPAC of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one can have a name.
  • the method for obtaining the compound may be chemically synthesized by a method known in the field to which the present invention pertains, or a commercially available material may be used, but is not limited thereto.
  • the extract or mixture may include one or more selected from the group consisting of Compounds 1 to 10 as an active ingredient, standard material, or active material, but is not limited thereto.
  • the extract or mixture may contain a high dose of the compound, but is not limited thereto.
  • influenza refers to an infectious disease caused by an influenza virus of the Orthomyxoviridae family among viruses that cause cold symptoms. Compared to the common cold, systemic symptoms such as fever, muscle pain, and headache appear distinctly, and the incubation period is about 1 to 3 days. Influenza is classified into A, B, and C types, and their overall structure and composition are the same. They have a diameter of 80 to 120 nm, and are filament-shaped in the early stage of infection, but become circular in the later stage.
  • Influenza virus the viral envelope surrounding the central nucleus is largely composed of glycoproteins that can be distinguished into two types, hemagglutinin (H) and neuraminidase (N), and the nucleus is composed of viral RNA (viral RNA). RNA) and viral proteins necessary to protect and activate it. Types B and C have low susceptibility and low genetic diversity, so there are almost no subtypes, and they appear infrequently and do not become prevalent. It is again divided into several subtypes according to the reaction. In nature, there are 18 H serotypes and 11 N serotypes, and mainly H1/2/3 and N1/2 are the subtypes that cause influenza in humans. According to one embodiment of the present invention, the influenza virus may be an influenza A type H1N1 virus, but is not limited thereto.
  • the term “molecular docking simulation” means structure-based drug design by predicting the binding suitability of a small molecule ligand to an appropriate target binding site based on the association between biologically relevant molecules such as proteins, peptides, nucleic acids, carbohydrates, and lipids.
  • influenza inhibitory activity was determined based on the ability to bind to influenza virus proteins.
  • the pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • the excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a moisturizer, a film-coating material, and a controlled release additive.
  • compositions according to the present invention are powders, granules, sustained-release granules, enteric granules, solutions, eye drops, elsilic agents, emulsions, suspensions, spirits, troches, perfumes, and limonadese, respectively, according to conventional methods.
  • tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusate It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta agents, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external agents are creams, gels, patches, sprays, ointments, and warning agents.
  • lotion, liniment, pasta, or cataplasma may have formulations such as the like.
  • Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Additives for the liquid formulation according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (tween esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, and the like may be used.
  • a solution of white sugar, other sugars, or a sweetener may be used, and aromatics, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as necessary.
  • Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.
  • tragacantha methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose, HPMC 1828, HPMC 2906, HPMC 2910, etc. and, if necessary, surfactants, preservatives, stabilizers, colorants, and fragrances may be used.
  • Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twins, nijuntinamide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; tonicity agents such as sodium chlor
  • the suppository according to the present invention includes cacao butter, lanolin, witapsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lannet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolen (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Buytyrum Tego-G -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxycote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hyde Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neos
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, etc. ) or by mixing lactose and gelatin.
  • excipients for example, starch, calcium carbonate, sucrose, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.
  • the pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, eg oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal insertion, vaginal It can be administered by intraoral insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.
  • the pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient together with various related factors such as the disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient.
  • subject means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, cow, etc. of mammals.
  • administration means providing a given composition of the present invention to a subject by any suitable method.
  • prevention refers to any action that suppresses or delays the onset of a desired disease
  • treatment means that the desired disease and its resulting metabolic abnormality are improved or improved by administration of the pharmaceutical composition according to the present invention. All actions that are advantageously altered are meant, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administration of the composition according to the present invention.
  • the present invention provides a food composition for preventing or improving influenza virus infection comprising a mixture of an extract of Agrimonia pilosa and an extract of galla rhois as an active ingredient.
  • the present invention is any one selected from the group consisting of flavonoid compounds represented by the following formula (1) or triterpenoid compounds represented by the following formula (2), isomers thereof, and food-acceptable salts thereof. It provides a food composition for preventing or improving influenza virus infection comprising one or more as active ingredients:
  • R 1 is H or OH
  • R 2 is any one selected from the group consisting of ⁇ -L-rhamnopyranosyl, H, ⁇ -D-glucopyranosyl, rutinosyl, and OH;
  • R 3 is H or ⁇ -D-glucuronosyl
  • "food” means a natural product or processed product containing one or more nutrients, preferably means a state that can be eaten directly through a certain degree of processing process, and usually means As, it means to include all health functional foods, beverages, food additives and beverage additives.
  • the food composition may be a health functional food composition, but is not limited thereto.
  • the "functional food” is the same term as food for special health use (FoSHU), medicine processed to efficiently display bioregulatory functions in addition to nutritional supply, It means a food with high medical effect, and can be manufactured into tablets, capsules, pills, granules, powders, liquids, flakes, pastes, syrups, gels, jellies, bars, or film formulations.
  • “functionality” means obtaining useful effects for health purposes, such as adjusting nutrients for the structure and function of the human body or physiological functions.
  • Seonhakcho of the present invention Agrimonia pilosa ) Extract and nut gall ( Galla rhois )
  • the mixture of the extract and its derived compound can be added as it is or used together with other food or food ingredients, according to conventional methods can be used
  • the mixing amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
  • the freshwater extract of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less based on the raw material.
  • the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.
  • Examples of foods to which the above substances can be added include meat, sausages, bread, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice creams, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and includes all health functional foods in a conventional sense.
  • the health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional components, like conventional beverages.
  • the aforementioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used.
  • the proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
  • the composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, A carbonation agent used in carbonated beverages and the like may be contained.
  • the composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination. The ratio of these additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the present invention provides a quasi-drug composition for preventing or suppressing influenza virus infection comprising a mixture of an extract of Agrimonia pilosa and an extract of galla rhois as an active ingredient.
  • the present invention is any one selected from the group consisting of flavonoid compounds represented by the following formula (1) or triterpenoid compounds represented by the following formula (2), isomers thereof, and pharmaceutically acceptable salts thereof.
  • a quasi-drug composition for preventing or inhibiting influenza virus infection comprising at least one as an active ingredient:
  • R 1 is H or OH
  • R 2 is any one selected from the group consisting of ⁇ -L-rhamnopyranosyl, H, ⁇ -D-glucopyranosyl, rutinosyl, and OH;
  • R 3 is H or ⁇ -D-glucuronosyl
  • the quasi-drug is a preparation used for sterilization, insecticide, and similar purposes for the prevention of infectious diseases described in Article 2, Subparagraph 7, Item C of the Pharmaceutical Affairs Act, and is used for human or animal It may refer to repellents, repellents, preventives, pesticides, or attracting insecticides such as flies and mosquitoes used for the health of people.
  • the quasi-drug may include external skin preparations and personal hygiene products.
  • it may be a disinfectant cleanser, shower foam, gargreen, wet tissue, detergent soap, hand wash, or ointment, but is not limited thereto.
  • the quasi-drug composition according to the present invention When used as a quasi-drug additive, the composition may be added as it is or used together with other quasi-drugs or quasi-drug ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient may be appropriately determined depending on the purpose of use.
  • the quasi-drug composition of the present invention may be prepared in the form of, for example, a general emulsified formulation and a solubilized formulation.
  • a general emulsified formulation for example, it may have formulations such as emulsions, creams, ointments, sprays, oil gels, gels, oils, aerosols, and smokers such as lotions, but it may be used without limitation as long as it exhibits the pest control inducing effect of the present invention. .
  • the quasi-drug composition appropriately blends oil, water, surfactant, moisturizer, lower alcohol having 1 to 4 carbon atoms, a thickener, a chelating agent, a colorant, a preservative, or a flavoring agent, etc., which are generally formulated in quasi-drug compositions, in each dosage form, as necessary. and can be used.
  • the MDCK cell line used in the experiment was cultured under conditions of 37°C, 5% CO 2 and MEM (Minimum essential) containing 10% fetal bovine serum (FBS, Hyclone Thermo Scientific) and 1% penicillin/streptomycin (P/S, Gibco). medium, Gibco) medium.
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin
  • the leaves of Agrimonia pilosa and Galla rhois were purchased from BioKorea Co., LTd (Seoul), and voucher specimens (BMRI-AP-1601, BMRI-RG-1602) were purchased from Biomedical Research Center, Kyunghee University, Yongin, Korea. deposited in A dried sample (20 kg) was extracted with 50% ethanol at 80 ⁇ 2° C. for 6 hours and then filtered. Then, it was concentrated using a rotary evaporator and freeze-dried to obtain 1.57 kg of Seonhakcho extract and 11.59 kg of nut gall extract. A mixture of Seonhakcho extract and gall nut extract was used in a ratio of 6:4, respectively, and was abbreviated as APRG64. All samples were stored at 4°C until use.
  • CPE cytopathic effect
  • IAV-induced CPE inhibitory activity of APRG64 confirmed in Experimental Example 1-2 is not a virus-independent cell death but a virus-dependent cell death effect, it was confirmed whether the same effect appears under an apoptosis inducer.
  • MDCK cells infected with IAV were treated with 200 nM of staurosporine (STS), an apoptosis inducer, and then additionally treated with 10 ⁇ g/ml APRG64 to determine cell death (cell viability).
  • STS staurosporine
  • 10 ⁇ g/ml APRG64 1% crystal violet staining was used, the images were processed with ImageJ software to quantify the cells attached to the plate, and all graphs were made based on the average of three repetitions.
  • IAV-induced CPE inhibitory activity of APRG64 confirmed in Experimental Example 1 was based on the inhibition of viral replication. To confirm this, MDCK cells infected with IAV were treated with APRG64, and RT-qPCR and Western blot experiments were performed on the production of influenza virus mRNA, protein, and infectious particles.
  • MDCK cells cultured in MEM medium were infected with IAV at a multiplicity of infection (MOI) of 0.1 for 1 hour, then treated with APRG64 (10 ⁇ g/ml), and after 6 hours, M1, which forms the structure of influenza virus, And the expression level of viral nucleoprotein (NP) was analyzed by RT-qPCR.
  • NucleoZOL Macherey-Nagel, Duren, Germany
  • ReverTraAce qPCR RT kit Toyobo, Osaka, Japan
  • a cDNA synthesis kit RevertraAce qPCR RT kit, Toyobo
  • CFX Connect real-time system Bio-Rad, Hercules, CA, USA
  • Classification (Content) direction order SEQ ID NO: 1 (M1 primer) forward 5′-AAGACCAATCCTGTCACCTCTG-3′ SEQ ID NO: 2 (M1 primer) reverse 5'-CAAAACGTCTACGCTGCAGTCC-3' SEQ ID NO: 3 (NP primer) forward 5′-CCAGATCAGTGTGCAGCCTA-3′ SEQ ID NO: 4 (NP primer) reverse 5′-CTCTGGCTTTGCACTTTCC-3′ SEQ ID NO: 5 (GAPDH primer) forward 5′-AACATCATCCCTGCTTCCAC-3′ SEQ ID NO: 6 (GAPDH primer) reverse 5′-GACCACCTGGTCCTCAGTGT-3′
  • M1 and NS1 proteins of IAV were analyzed by Western blot, and actin was used as a loading control.
  • cells were lysed using NP-40 buffer (ELPIS Biotech, Daejeon, Korea) in the presence of a protease inhibitor (Thermo Scientific).
  • Cell extracts were loaded on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel and then transferred to a nitrocellulose membrane (GE Healthcare, Chicago, IL, USA), and then the membrane was incubated in TBST solution for blocking.
  • % BSA for 1 hour followed by incubation with primary antibodies (Abcam, Cambridge, UK) overnight at 4°C.
  • HRP horseradish peroxidase
  • APRG64 treatment was shown to strongly suppress the expression of IAV M1 (Fig. 3a, left graph) and NP (Fig. 3a, center graph) mRNA expression, and consistent with these results, M1 and non-structural protein 1 (NS1 ) was found to be substantially inhibited by APRG64 treatment (Fig. 3a, right picture).
  • infectious virus particles were titrated through plaque assay. Specifically, MDCK cells were infected with IAV at an MOI of 0.1 for 1 hour and then treated with 10 ⁇ g/ml APRG64 for 36 hours, followed by 0.3% BSA and 0.5% agarose (Affymetrix, Santa Clara, CA, USA). It was incubated for 2 days with MEM containing. Cells were then fixed with 3.5% formaldehyde and removed from an agarose gel, and plaques were identified by staining the cells with a 1% crystal violet solution.
  • Immunocytochemical analysis was performed to confirm the effect of APRG64 on reducing IAV NP-expressing cells. Specifically, MDCK cells were infected with IAV at an MOI of 0.1 for 1 hour, then treated with 10 ⁇ g/ml APRG64 for 6 hours, fixed with 4% formaldehyde, and then treated with 0.5% Triton X-100 (Sigma-Aldrich). permeabilized. After treatment with an anti-IAV NP antibody (Abcam), cells were incubated with Alexa Fluor 488-conjugated secondary antibody (Thermo Scientific) and DAPI (4',6-diamidino-2-phenylindole) solution (Sigma-Aldrich) was used to detect nuclei.
  • the anti-IAV activity was confirmed.
  • the anti-IAV activity was confirmed through the expression levels of M1 and viral nucleoprotein (NP), which form the structure of influenza virus, after each compound was treated with IAV-infected cells.
  • MDCK cells were infected with IAV at an MOI of 0.1 for 1 hour, and then treated with afgeline (Compound 1, 10 ⁇ g/ml), apigenin (Compound 2, 5 ⁇ g/ml), and apigenin 7-O-glu.
  • Curonide (Compound 3, 10 ⁇ g/ml), Astragaline (Compound 4, 10 ⁇ g/ml), Nicotiflorin (Compound 5, 10 ⁇ g/ml), Quercetin (Compound 6, 2.5 ⁇ g/ml), Quercetin (Compound 6, 2.5 ⁇ g/ml)
  • Relative expression levels of M1 and NP mRNAs of IAV were measured by RT -Analyzed by qPCR. RT-qPCR analysis was performed in the same manner as in Example 2-1 except for the concentration of each compound.
  • MDCK cells were infected with IAV at an MOI of 0.1 and then treated with 0.625, 1.25, 2.50 or 5.00 ⁇ g/ml of apigenin, and after 24 hours, the cells were incubated with 1% crystal violet solution. Adherent cells were analyzed by staining. In addition, the EC 50 of apigenin was calculated by quantifying the attached cells at 24 hpi, and CPE analysis was performed in the same manner as in Experimental Example 1-2 except for this.
  • apigenin was additionally treated after treatment with the apoptosis inducer to confirm cell death.
  • MDCK cells were treated with 5 ⁇ g/ml of apigenin and then additionally treated with 200 nM of staurosporine (STS) to perform CPE analysis to confirm cell viability.
  • STS staurosporine
  • the image was processed with ImageJ software to quantify the cells attached to the plate, and the graph showed the average of three repetitions, and the experiment was performed in the same manner as in Experimental Example 1-3 except for this.
  • RT-qPCR analysis and Western blotting were performed. Specifically, MDCK cells were infected with IAV at an MOI of 0.1 for 1 hour and then treated with 5 ⁇ g/ml apigenin, and after 6 hours, the expression levels of M1 and NP mRNA of IAV were analyzed by RT-qPCR, Virus M1 and NS1 protein expression levels were analyzed by Western blot. The experimental method and conditions were performed in the same manner as in Experimental Example 2-1.
  • MDCK cells were infected with IAV at an MOI of 0.1 for 1 hour, then treated with 5 ⁇ g/ml apigenin, and plaque assay was performed at 36 hpi to measure the infectious virus titer and presented in a graph. At this time, the plaque analysis method and conditions were performed in the same manner as in Experimental Example 2-2.
  • Immunocytochemical analysis was performed to confirm the increase or decrease of IAV NP-expressing cells (IAV-NP) by apigenin. Specifically, MDCK cells were infected with IAV at an MOI of 0.1 for 1 hour and then treated with 5 ⁇ g/ml apigenin for 6 hours, and then the reduction of IAV-NP expressing cells was confirmed by immunocytochemical analysis, At this time, immunocytochemical analysis was performed in the same manner as in Experimental Example 2-3.
  • apigenin is the main antiviral component of APRG64.
  • the antiviral activity of APRG64 and apigenin against other strains of IAV was investigated.
  • MDCK cells were infected with another influenza strain, A/PR/8/34 (H1N1), at an MOI of 0.1 for 1 hour, and treated with APRG64 (10 ⁇ g/ml) or apigenin (5 ⁇ g/ml), respectively.
  • APRG64 10 ⁇ g/ml
  • apigenin 5 ⁇ g/ml
  • APRG64 and apigenin were confirmed to strongly reduce viral protein expression in PR8-infected cells, respectively (FIG. 8a).
  • the anti-IAV activity of APRG64 and apigenin was similar to that of oseltamivir phosphate (Tamiflu), an antiviral neuraminidase inhibitor clinically used for the treatment of IAV infection, influenza virus It was confirmed that the treatment effect was remarkably good.
  • IAV replication begins when the virus attaches to and enters the host cell. Whether APRG64 and apigenin target this early stage of viral replication to inhibit IAV replication was analyzed.
  • MDCK cells were treated with 10 ⁇ g/ml APRG64 or 5 ⁇ g/ml apigenin for 1 hour at 4° C., respectively, and infected with IAV at an MOI of 0.1. Then, the mRNA expression levels of M1 and NP of IAV were analyzed by RT-qPCR at 6 hpi. In addition, the mRNA expression levels of M1 and NP of IAV after treatment with APRG64 or apigenin at 1, 2 or 4 hours (hpi) after infection were analyzed.
  • APRG64 and apigenin significantly inhibited the expression of M1 and NP RNA of IAV, respectively (FIG. 8b).
  • treatment with APRG64 or apigenin at 1, 2 or 4 hours post infection (hpi) also reduced the expression levels of M1 and NP RNA of IAV (Fig. 8c). According to these results, it was confirmed that APRG64 and apigenin inhibit the early stages of IAV replication including viral attachment and entry.
  • RdRP IAV RNA-dependent RNA polymerase
  • IAV M1 and NP IAV M1 and NP (+) It can be measured by the expression level of the RNA strand. Therefore, by analyzing the expression levels of (+) RNA strands of IAV M1 and NP according to APRG64 and apigenin treatment, it was confirmed whether or not IAV RdRP activity was affected. Specifically, MDCK cells were infected with IAV at 0.1 MOI for 1 hour.
  • IAV infection dramatically induced phosphorylation of ERK and SAPK, but this increase was not observed in cells treated with APRG64 or apigenin (FIG. 8e).
  • APRG64 and apigenin were intranasally administered to a mouse model to confirm antiviral effects.
  • dpi the number of infectious viral particles in the lungs was measured by plaque assay. Other than that, it was performed under the same conditions as the plaque analysis method according to Experimental Example 2-2.
  • APRG64 was orally administered to mice, it was confirmed whether the killing effect caused by IAV was suppressed. Specifically, wild-type C57BL/6 mice prepared as described above were orally administered with 0, 25 or 50 mg/kg of APRG64 for 3 days, and then infected with 1 ⁇ 10 3 pfu of IAV. In addition, APRG64 was orally administered to the mice for an additional 5 days, and mouse survival was monitored for 14 days.
  • mice were significantly protected from IAV-induced death in a dose-dependent manner (FIG. 10c). Specifically, all of the mouse group not administered with APRG64 died on day 10, whereas all of the group treated with APRG64 maintained survival for 14 days. In particular, the survival rate of mice administered with 50 mg/kg of APRG64 was 80% or more, confirming that the antiviral effect against IAV was remarkably excellent.
  • RNA, cytokines, and infectious viral particles in mouse lungs were analyzed by RT-qPCR or plaque assay.
  • wild-type C57BL/6 mice prepared for oral administration of Experimental Example 8-3 were orally treated with 50 mg/kg of APRG64 for 3 days, and then the mice were infected with 1 ⁇ 10 3 pfu of IAV, and then 5 The same amount of APRG64 was additionally treated for 10 days.
  • mice lungs were collected and viral RNA, titers and production of inflammatory cytokines were analyzed to determine the relative mRNA expression levels and infectious virus titers of M1 and NP of IAV, and the inflammatory cytokines IFN- ⁇ , TNF- ⁇ and The relative expression level of IL-6 was analyzed by RT-qPCR.
  • Classification (Content) direction order SEQ ID NO: 7 (IFN- ⁇ primer) forward 5′-GGCCATCAGCAACAACATAAGCGT-3′ SEQ ID NO: 8 (IFN- ⁇ primer) reverse 5′-TGGGTTGTTGACCTCAAACTTGGC-3′ SEQ ID NO: 9 (TNF- ⁇ primer) forward 5′-GCCTCTTCTCATTCCTGCTTG-3′ SEQ ID NO: 10 (TNF- ⁇ primer) reverse 5′-CTGATGAGAGGGAGGCCATT-3′ SEQ ID NO: 11 (IL-6 primer) forward 5′-ACGGCCTTCCCTACTTCACA-3′ SEQ ID NO: 12 (IL-6 primer) reverse 5'-CATTTCCACGATTTCCCAGA-3'
  • APRG64 can be used to treat IAV infection as a drug that can be administered intranasally and orally, which is safe and exhibits remarkably excellent effects.
  • a molecular docking simulation was performed on the influenza virus for the APRG64-derived compound to evaluate the virus inhibitory ability.
  • influenza A/H1N1 the compound continuously binds to the subunit viral RdRp (PA, PB1, PB2) that affects replication and transcription in the virus. Therefore, in the present invention, blind docking was performed for the subunit viral RdRp (PA, PB1, PB2).
  • molecular docking simulation was performed for the C-terminal domain, middle domain, and Cap binding domain.
  • Influenza virus also has a Receptor binding domain (RBD) like the spike protein of coronavirus (SARS-CoV-2). RBD; and A pocket, which plays a major role in the process of cell membrane fusion after RBD enters the cell and before exporting its RNA into the cell.
  • RBD Receptor binding domain
  • a composition for preventing, treating, or improving influenza virus infection containing a mixture of an extract of Agrimonia pilosa and an extract of Galla rhois as an active ingredient has no side effects on the human body and is safe, while antiviral through a virus-dependent route activity is excellent.
  • antiviral effects have been confirmed in vivo, and the active ingredients of the mixed extracts also have remarkably excellent antiviral activities, so it is expected that they can be usefully used as a composition for preventing, treating, or improving influenza virus infectious diseases.
  • the industrial applicability of the present invention is recognized.

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Abstract

La présente invention concerne une composition, de prévention, de traitement ou de soulagement d'une infection par le virus de la grippe, comprenant un mélange d'un extrait d'Agrimonia pilosa et d'un extrait de Galla rhois en tant que principes actifs, qui ne provoque pas d'effets secondaires sur un corps humain et présente ainsi une sécurité optimale, et a également une excellente activité antivirale due à un effet de lésion cellulaire par l'intermédiaire d'une voie dépendante du virus, d'un effet de réduction de gène associé au virus de la grippe, et analogues. En outre, la présente invention non seulement est confirmée avec un effet antiviral in vivo, mais présente également une excellente activité antivirale dans le principe actif des extraits mélangés, et peut ainsi être utilisé pour une composition en vue de prévenir, de traiter ou de soulager une infection par le virus de la grippe.
PCT/KR2022/013577 2021-09-08 2022-09-08 Composition pour la prévention, le traitement ou le soulagement d'une infection par le virus de la grippe, comprenant un mélange d'extrait d'agrimonia pilosa et d'extrait de galla rhois en tant que principes actifs Ceased WO2023038480A1 (fr)

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KR1020220113158A KR20230039782A (ko) 2021-09-08 2022-09-07 선학초(Agrimonia pilosa) 추출물과 오배자(Galla rhois) 추출물의 혼합물을 유효성분으로 포함하는 인플루엔자 바이러스 감염증 예방, 치료 또는 개선용 조성물
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