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WO2025110819A1 - Composition pour prévenir, soulager ou traiter des maladies respiratoires provoquées par de la poussière fine, comprenant un extrait de phlomis umbrosa - Google Patents

Composition pour prévenir, soulager ou traiter des maladies respiratoires provoquées par de la poussière fine, comprenant un extrait de phlomis umbrosa Download PDF

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Publication number
WO2025110819A1
WO2025110819A1 PCT/KR2024/018723 KR2024018723W WO2025110819A1 WO 2025110819 A1 WO2025110819 A1 WO 2025110819A1 KR 2024018723 W KR2024018723 W KR 2024018723W WO 2025110819 A1 WO2025110819 A1 WO 2025110819A1
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Prior art keywords
fine dust
extract
preventing
respiratory
hansokdan
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Pending
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PCT/KR2024/018723
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English (en)
Korean (ko)
Inventor
이영섭
마경호
김관우
이대영
박찬성
장세원
김지민
한윤영
조하늘
이재선
김보미
이용욱
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Natural Endotech Co Ltd
Korea Rural Development Administration
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Natural Endotech Co Ltd
Korea Rural Development Administration
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Publication of WO2025110819A1 publication Critical patent/WO2025110819A1/fr
Pending 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
    • 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
    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • 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
    • A23V2200/314—Foods, ingredients or supplements having a functional effect on health having an effect on lung or respiratory 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
    • 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

Definitions

  • the present invention was made under the support of the Rural Development Administration under the task number 1395070339, and the research management specialized institution of the task is the Rural Development Administration, the research project name is "Development of core technology for increasing useful components of crops”, the research project name is “Development of technology for producing Hansokdan for increasing useful components and processing and materialization technology of black ginseng", the main institution is Natural Endotech Co., Ltd., and the research period is from January 1, 2019 to December 31, 2023.
  • the present invention relates to a composition for preventing, improving or treating respiratory diseases caused by fine dust, containing an extract of Hansokdan as an effective ingredient.
  • the respiratory system is responsible for the respiratory function of inhaling and exhaling air into the body.
  • the trachea acts as a passage connecting the throat to the bronchial tubes and has a branched structure. This structure reduces the speed of air, so that foreign substances such as bacteria and dust do not reach the terminal part of the alveoli and are deposited on the inner wall of the bronchial tubes. These deposited foreign substances are moved out of the lungs and eliminated by the mucus secreted in the bronchial tubes and the movement of cilia.
  • Respiratory diseases which occur when the respiratory system does not function normally, are diseases that affect the organs related to breathing.
  • the main symptoms include coughing, hemoptysis, chest pain, sputum, and shortness of breath, and are caused by chronic inflammatory reactions in the respiratory tract and damage to the respiratory organs.
  • Fine dust is defined as particulate matter (PM) with a diameter of 10 ⁇ m or less among the total suspended particles (TSP) in the air, and is divided into fine dust (PM10) with a diameter of less than 10 ⁇ m and ultrafine dust (PM2.5) with a diameter of less than 2.5 ⁇ m.
  • Fine dust is a Group 1 carcinogen as defined by the International Agency for Research on Cancer (IARC) under the World Health Organization (WHO), and ultrafine dust (PM2.5) is known to be harmful to the human body, causing respiratory diseases, etc. by reaching the alveoli directly through the respiratory system.
  • IARC International Agency for Research on Cancer
  • WHO World Health Organization
  • PM2.5 ultrafine dust
  • fine dust occurs in high concentrations from winter to spring, causing many tangible and intangible damages and adverse effects on daily life, and Korea is experiencing many difficulties in managing fine dust due to the geographical influence of the westerly wind blowing from China and seasonal characteristics such as heavy rain concentrated in the summer.
  • Phlomoides umbrosa Turczaninow is a root of a perennial plant in the Labiatae family, and is commonly found in mountain foothills of Korea except for the northern mountainous regions. Phlomoides umbrosa Turczaninow has several long cylindrical or spindle-shaped roots, and has vertical wrinkles on its outer surface. Phlomoides umbrosa is known to be effective in relieving pain, anti-inflammation, and allergic diseases, and its roots and leaves are known to be usable as food ingredients.
  • Hansokdan extract for preventing, improving, or treating respiratory diseases caused by fine dust is unknown, and no research on its mechanism has been conducted.
  • the inventors of the present invention conducted a direct efficacy study on the prevention, improvement or treatment of respiratory diseases induced by fine dust possessed by the extract of Hansokdan, and as a result, it was confirmed that the extract of Hansokdan increased antioxidant enzyme activity and decreased the levels of Th2 (T helper type 2) cytokines such as interleukin 4 (IL-4), interleukin 5 (IL-5) and interleukin 13 (IL-13) and the concentration of leukotrienes and prostaglandin E2, which are respiratory disease factors.
  • Th2 Th2
  • cytokines such as interleukin 4 (IL-4), interleukin 5 (IL-5) and interleukin 13 (IL-13)
  • the concentration of leukotrienes and prostaglandin E2 which are respiratory disease factors.
  • the thickness and degree of contraction of the alveolar wall were improved, and it was confirmed that the expression of factors related to inflammation induction in lung tissue was suppressed in a concentration-dependent manner.
  • the purpose of the present invention is to provide a food composition containing an extract of Hansokdan for preventing or improving respiratory diseases caused by fine dust.
  • the present invention aims to provide a pharmaceutical composition for preventing or treating respiratory diseases caused by fine dust, including an extract of Hansokdan.
  • the present invention provides a food composition for preventing or improving respiratory disease caused by fine dust, which contains an extract of Hansokdan.
  • the present invention provides a pharmaceutical composition for preventing or treating respiratory diseases caused by fine dust, including an extract of Hansokdan.
  • the extract of Hansokdan of the present invention increases antioxidant activity in the bronchi and lungs, reduces inflammatory factors caused by fine dust, and has expectorant activity, so it has excellent effects in preventing, improving, and treating respiratory diseases caused by fine dust. Therefore, it can be used as a food composition for preventing or improving respiratory diseases caused by fine dust or a pharmaceutical composition for preventing or treating respiratory diseases caused by fine dust.
  • Figure 1 is a graph showing the results of measuring cell viability of Hansokdan extract.
  • Figure 2 is a graph showing the results of analysis of the expression of inflammatory cytokines in a cell model of the extract of Hansokdan.
  • Figure 3 is a graph showing the results of analysis of the expression regulation of proteins that regulate inflammation-inducing signaling pathways in a cell model of the extract of Hansokdan.
  • Figure 4 is a graph measuring the antioxidant activity of the extract of Hansokdan in an animal model.
  • Figure 5 is a graph showing the results of analysis of the expression of inflammatory cytokines in an animal model of the extract of Hansokdan.
  • Figure 6 is a photograph showing the results of an analysis of the regulation of alveolar wall thickness in an animal model of a Korean herb extract.
  • Figure 7 is a graph showing the results of protein expression regulation analysis of the inflammatory signaling pathways in bronchial and lung tissues in an animal model of Hansokdan extract.
  • Figure 8 is a graph showing the results of analysis of the regulation of the expression of leukotrienes and prostaglandin E2 related to the inflammatory mechanism in an animal model of the extract of Hansokdan.
  • Figure 9 is a graph analyzing the expectorant activity of the extract of Hansokdan in an animal model.
  • a food composition for preventing or improving respiratory diseases caused by fine dust comprising an extract of Hansokdan.
  • prevention used in the present invention means any act of inhibiting or delaying the occurrence, development, and recurrence of respiratory diseases caused by fine dust by administering the composition according to the present invention.
  • improvement used in the present invention means any action that reduces a parameter related to a respiratory disease caused by fine dust, for example, the degree of symptoms, by administering a composition according to the present invention.
  • treatment means all acts that improve or beneficially change the symptoms of respiratory diseases and complications caused by fine dust by administering the composition according to the present invention.
  • Treatment means all acts that improve or beneficially change the symptoms of respiratory diseases and complications caused by fine dust by administering the composition according to the present invention.
  • anyone with ordinary knowledge in the technical field to which the present invention pertains will be able to know the exact criteria for diseases to which the composition of the present invention is effective and determine the degree of improvement, enhancement, and treatment by referring to materials presented by the Korean Medical Association, etc.
  • One aspect of the present invention is a food composition for preventing or improving respiratory disease caused by fine dust, comprising an extract of Hansokdan.
  • Phlomoides umbrosa Turczaninow is a perennial herbaceous plant belonging to the Labiatae family, and its main physiologically active components include flavonol glycosides, phenylethanoid glycosides, amino acids, umbrosides, etc., and these components are known to exhibit anti-inflammatory, antioxidant, and immunomodulatory activities.
  • the extract of Hansokdan used in the present invention can be obtained using various organs, tissues (e.g., roots, leaves, flowers, stems, fruits, seeds, etc.) of Hansokdan, and most preferably, it is an extract obtained from the roots of Hansokdan.
  • organs, tissues e.g., roots, leaves, flowers, stems, fruits, seeds, etc.
  • the extract of Hansokdan according to the present invention can be obtained by extracting and separating from nature using extraction and separation methods known in the art, and the "extract" defined in the present invention is extracted from Hansokdan using an appropriate solvent, and includes, for example, a crude extract, a polar solvent-soluble extract, or a non-polar solvent-soluble extract.
  • any organic solvent acceptable in the fields of food science/pharmaceutics/cosmetics may be used, and water or an organic solvent may be used, but is not limited thereto, for example, water; straight-chain or branched alcohols having 1 to 4 carbon atoms, including methanol, ethanol, propanol, isopropanol, and butanol; acetone; ether; benzene; chloroform; Ethyl acetate; Methylene chloride; Hexane; and Cyclohexane, etc., may be used alone or in combination.
  • the extract may be extracted with one or more solvents selected from the group consisting of water and linear or branched alcohols having 1 to 4 carbon atoms. More preferably, the extract may be extracted with water as a solvent. Any one of the following extraction methods may be selected and used: hot water extraction, cold immersion extraction, reflux cooling extraction, solvent extraction, steam distillation, ultrasonic extraction, extraction, and pressing.
  • the desired extract may additionally undergo a conventional fractionation process and may be purified using a conventional purification method.
  • the extract included in the composition of the present invention can be produced in a powder form by additional processes such as reduced pressure distillation and freeze drying or spray drying of the primary extract extracted by the above-mentioned hot water extraction or solvent extraction method.
  • the primary extract can be obtained by further purifying fractions using various chromatography such as silica gel column chromatography, thin layer chromatography, high performance liquid chromatography, etc. Therefore, in the present invention, the extract is a concept including all extracts, fractions, and purified products obtained at each stage of extraction, fractionation, or purification, and their dilutions, concentrates, or dried products.
  • the extract of the present invention includes an extract using the above-described extraction solvent.
  • the extract of the present invention can be prepared in a powder form by additional processes such as reduced pressure distillation and freeze drying or spray drying.
  • the amount of the extract of Hansokdan as an effective ingredient in the composition of the present invention is 0.10-90 wt% with respect to the total weight of the composition.
  • the composition suppresses an inflammation-related signal pathway caused by fine dust
  • the inflammation-related signal may be at least one selected from the group consisting of ERK (Extracellular signal-regulated kinases), JNK (c-jun N-terminal kinase), NF- ⁇ B (nuclear factor kappa-light-chain-enhancer of activated B cells) p65, PI3K/AKT, and STAT6.
  • the signal may be ERK (Extracellular signal-regulated kinases), JNK (c-jun N-terminal kinase), NF- ⁇ B (nuclear factor kappa-light-chain-enhancer of activated B cells) p65, PI3K/AKT, and STAT6, but is not limited thereto.
  • the composition suppresses a signal pathway related to inflammation caused by fine dust, and the signal related to inflammation may be STAT6.
  • composition increases antioxidant enzyme activity
  • the antioxidant enzyme may be, but is not limited to, superoxide dismutase, catalase, and glutathione peroxidase.
  • composition may reduce the secretion of inflammatory factors caused by fine dust or inflammatory cytokines caused by fine dust.
  • the inflammatory factor may be at least one selected from the group consisting of leukotrienes, prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), and for example, may be, but is not limited to, leukotrienes, prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and iNOS.
  • PGE2 prostaglandin E2
  • COX-2 cyclooxygenase-2
  • iNOS inducible nitric oxide synthase
  • the inflammatory cytokine may be at least one selected from the group consisting of interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13), and interferon gamma (IFN- ⁇ ), and for example, interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13), and interferon gamma (IFN- ⁇ ), but is not limited thereto.
  • IL-4 interleukin 4
  • IL-5 interleukin 5
  • IL-13 interleukin 13
  • IFN- ⁇ interferon gamma
  • the respiratory disease may be at least one disease selected from the group consisting of respiratory inflammatory lung disease, chronic obstructive pulmonary disease, allergic rhinitis, sinusitis, upper respiratory tract infection, lower respiratory tract infection, chronic bronchitis, bronchiectasis, pneumonia, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome, cystic fibrosis, otitis media, pulmonary fibrosis, asthma, emphysema, pharyngitis, laryngitis, and tonsillitis, but is not limited thereto.
  • the extract of the invention can be added to food for the purpose of preventing or improving respiratory diseases caused by fine dust.
  • the extract of the invention can be used as a food additive
  • the extract of the invention can be added as it is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method.
  • the amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
  • the composition of the invention is added in an amount of 15 wt% or less, preferably 10 wt% or less, based on the raw material.
  • the amount can be below the above range, and since there is no problem in terms of safety, the active ingredient can also be used in an amount greater than the above range.
  • foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and all foods in the conventional sense are included.
  • the health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages.
  • the above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • a natural sweetener such as thaumatin and stevia extract, or a synthetic sweetener such as saccharin and aspartame can be used.
  • the proportion of the natural carbohydrate is generally about 0.01-0.20 g, preferably about 0.04-0.10 g, per 100 mL of the composition of the present invention.
  • composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
  • composition of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These components may be used independently or in combination. The proportion of these additives is not particularly important, 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.
  • Another aspect of the present invention is a pharmaceutical composition for preventing or treating respiratory diseases caused by fine dust, comprising an extract of Hansokdan.
  • composition according to the present invention may contain a pharmaceutically effective amount of the extract of Hansokdan alone or may contain one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the pharmaceutically effective amount as mentioned above means an amount sufficient to prevent, improve and treat symptoms of respiratory diseases.
  • pharmaceutically acceptable as mentioned above means a composition that is physiologically acceptable and does not typically cause allergic reactions such as gastrointestinal disorders, dizziness or similar reactions when administered to humans.
  • composition of the present invention can be administered orally or parenterally during clinical administration, and can be used in the form of a general pharmaceutical preparation.
  • the dosage form can be oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., ocular), transdermal, or transcutaneous, but is not limited thereto.
  • Examples of the dosage form include tablets; caplets; capsules such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; Liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions); solutions and elixirs; liquid dosage forms suitable for injection into a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solid preparations (e.g., crystalline or amorphous solids) which can be reconstituted to provide liquid dosage forms suitable for injection into a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil
  • a dosage form used for the acute treatment of a disease may contain a greater amount of active ingredient than a dosage form used for the chronic treatment of the same disease.
  • a parenteral dosage form may contain a lesser amount of active ingredient than an oral dosage form used to treat the same disease.
  • the dosage forms and methods encompassed by the present invention are very diverse, as will be apparent to those skilled in the art to which the present invention pertains.
  • composition containing a pharmaceutically acceptable carrier can be in various oral or parenteral dosage forms. When formulated, it can be prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants that are commonly used.
  • the above carrier, excipient and diluent may be at least one selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, saline, methyl hydroxybenzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil, dextrin, calcium carbonate, propylene glycol and liquid paraffin, but is not limited thereto, and all conventional carriers, excipients or diluents can be used.
  • the above components may be added independently or in combination to the effective ingredient, the Hansokdan extract.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the dosage varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
  • solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid preparations may be prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included.
  • preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, gelatin, etc.
  • the pharmaceutical composition of the present invention can be used parenterally in the form of an aseptic solution or suspension injection with water or other pharmaceutically acceptable liquids, as needed.
  • it can be formulated by mixing it appropriately with a pharmacologically acceptable carrier or medium, specifically, sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, excipient, vehicle, preservative, binder, etc., in a unit dosage form required for generally recognized pharmaceutical practice.
  • the amount of the active ingredient in the above formulation can be such that an appropriate dosage within the indicated range can be obtained.
  • a sterile composition for injection can be prescribed according to the usual formulation practice using a vehicle such as distilled water for injection.
  • aqueous solution for injection examples thereof include saline solution, isotonic solutions containing glucose or other auxiliary agents, for example, D-sorbitol, D-mannose, D-mannitol, sodium chloride, and may be used in combination with appropriate solubilizing agents, for example, alcohols, specifically ethanol, polyalcohols, for example, propylene glycol, polyethylene glycol, nonionic surfactants, for example, polysorbate 80(TM), HCO-50.
  • auxiliary agents for example, D-sorbitol, D-mannose, D-mannitol, sodium chloride
  • solubilizing agents for example, alcohols, specifically ethanol, polyalcohols, for example, propylene glycol, polyethylene glycol, nonionic surfactants, for example, polysorbate 80(TM), HCO-50.
  • oily liquid sesame oil and soybean oil can be mentioned, and can be used together with benzyl benzoate and benzyl alcohol as solubilizing agents.
  • it can be mixed with a buffer, for example, phosphate buffer, sodium acetate buffer, analgesic, for example, procaine hydrochloride, stabilizer, for example, benzyl alcohol, phenol, and antioxidant.
  • the prepared injection solution can usually be filled into a suitable ampoule.
  • the pharmaceutical composition of the present invention may have any one dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • a base for the suppository witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, gelatin, and the like can be used.
  • the effective dosage for the human body of the pharmaceutical composition containing the extract of Hansokdan of the present invention may vary depending on the patient's age, body weight, sex, dosage form, health condition, and disease severity.
  • the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the prevention or treatment of respiratory diseases caused by fine dust.
  • the pharmaceutical composition of the present invention contains the above-described Hansokdan extract, descriptions of the overlapping contents with the above-described Hansokdan extract of the present invention are omitted in order to avoid excessive complexity of the present specification due to descriptions of overlapping contents.
  • the RAW264.7 cells used in this experiment were obtained from the American Type Culture Collection (ATCC; Rockville, MD, USA).
  • the medium used was Roswell Park Memorial Institute (RPMI-1640) medium containing 10% Fetal Bovine Serum (FBS) and 1% Penicillin-Streptomycin (100 units/mL), and the cells were cultured in an incubator (Thermo Fisher Scientific Inc., Pittsburgh, PA, USA) controlled at 37°C, 5% CO 2 , and 95% humidity.
  • RPMI-1640 Roswell Park Memorial Institute
  • FBS Fetal Bovine Serum
  • Penicillin-Streptomycin 100 units/mL
  • Dexamethasone (Sigma-Aldrich, Korea) was used as a positive control (PC).
  • mice 6-week-old male Balb/c mice weighing approximately 20 g were supplied by Saeron Bio Co., Ltd. (Uiwang-si, Korea). After a 1-week adaptation period under the conditions of 12-hour light/dark cycle, 23 ⁇ 2°C, and 50 ⁇ 5% relative humidity, they were used in the experiment. During the adaptation period, food and drinking water were freely available, and they were randomly divided into 5 groups of 8 mice each so that the average body weights were similar, and the experiment was conducted for each experimental group under the conditions in Table 1 below.
  • the intake and body weight of each experimental group were measured every week.
  • Low-dose OVA and Alum were injected intraperitoneally on days 1, 8, and 15 from the start of the test.
  • Hansokdan extract (PU) was orally administered at different concentrations every day for 7 days starting from one week before the end of the test, and high-dose OVA was injected intranasally (INT) for 3 days before the end of the test to induce airway and lung damage and inflammation.
  • INT was performed by securing the airway of the mouse and allowing it to enter the lungs through the trachea while breathing through the nose. After fasting for 12 hours, the experimental animals were anesthetized, opened, and blood was collected through the abdominal aorta. 1-5. Histopathological observation (H&E staining)
  • Lung tissues obtained by sacrificing animals were fixed in 10% neutral formalin for 24 hours, then embedded in paraffin after going through a general tissue processing process, and sectioned into 4 ⁇ m thick sections using a tissue sectioner (RM2125, Leica, Wützlar, Germany) and mounted on polylysine-coated slides. Paraffin was removed from the tissue sections using xylene, and they were soaked in alcohol and distilled water for 10 minutes, washed with distilled water, and then stained with H&E (Hematoxylin & Eosin) to observe the size of fat globules.
  • H&E Hematoxylin & Eosin
  • the effect on antioxidant enzymes in the bronchoalveolar lavage fluid (BALF) of mice induced with OVA was measured.
  • the animals were sacrificed and the absorbance was measured at 450 nm in the BALF using SOD, GPx kits (BioVison Inc., Mountain View, CA, USA), and CAT (Biomax Inc., Seoul, Korea) with an ELIAS plate reader (Bio-Rad Laboratories Headquarters, Hercules, CA, USA).
  • RAW264.7 cells were seeded in a 96-well plate at 5 ⁇ 10 5 cells/well and stabilized. After that, samples were treated at various concentrations in each well, and LPS was treated together at a concentration of 1 ⁇ g/mL. After 24 hours, the supernatant was used to measure the secretion of IL-4, IL-5, IL-13, and TNF- ⁇ using a Duoset ELISA kit (R&D system, Minneapolis, MN, USA) at 655 nm with an ELIAS plate reader (Bio-Rad Laboratories Headquarters, Hercules, CA, USA).
  • the effect of Hansokdan extract on cytokine secretion in an animal model induced by OVA-induced immune hypersensitivity was measured in the same manner as in the cell experiment. Specifically, the secretion amounts of IL-4, IL-5, IL-13, and IFN- ⁇ were measured using a Duoset ELISA kit (R&D system, Minneapolis, MN, USA) at 655 nm with an ELIAS plate reader (Bio-Rad Laboratories Headquarters, Hercules, CA, USA) using bronchoalveolar lavage fluid (BALF) obtained by sacrificing the animals.
  • a Duoset ELISA kit R&D system, Minneapolis, MN, USA
  • ELIAS plate reader Bio-Rad Laboratories Headquarters, Hercules, CA, USA
  • RAW264.7 cells were seeded at 1 ⁇ 10 6 cells/well in a 6-well plate and stabilized, then treated with Hansokdan extract at concentrations of 100 and 500 ⁇ g/mL and co-treated with LPS at a concentration of 1 ⁇ g/mL.
  • Protein quantification was performed using the protein quantification method (Bradford) using BSA and bio-rad protein assay Dye Reagent Concentrate (Bio-Rad, Hercules, CA USA).
  • NF- ⁇ B pathway and MAPK pathway proteins were measured via western blot in the same manner as in the cell experiment.
  • Lung tissue was homogenized by adding lysis buffer containing protease inhibitor, kept on ice for a certain period of time, and centrifuged (12,000 rpm, 20 min, 4°C) to isolate proteins. Protein quantification was performed using BSA and bio-rad protein assay Dye Reagent Concentrate (Bio-Rad, Hercules, CA USA) by the protein quantification method (Bradford).
  • bronchial constrictors, bronchitis and asthma-inducing factors present in bronchoalveolar lavage fluid (BALF) using an animal model was performed using a competitive ELISA assay kit (Invitrogen USA).
  • the expectorant effect was measured using an animal model according to the phenol red excretion method.
  • Ambroxol 250 mg/kg known as an expectorant drug, was used as a positive control (Amb).
  • PU Hansokdan extract
  • 500 mg/kg phenol red was injected intraperitoneally. 30 minutes later, the subject was anesthetized, bled through the abdominal aorta, and the entire bronchial tube was cut.
  • the isolated bronchial tube was washed in 1 mL of saline for 30 minutes, centrifuged at 10,000 rpm for 5 minutes at room temperature, and 1 N caustic soda (NaOH) was added to the supernatant (0.1 mL of 1 N NaOH per 1 mL of supernatant). The absorbance was measured at 546 nm to measure the expectorant activity as the phenol red concentration.
  • the experiment was analyzed using the SPSS (Statistical Package for the Social Science) version 22 program, and the measurement results of all experiments were expressed as the mean ⁇ standard deviation (SD). Statistical significance between groups was tested using Duncan's multiple range test, and significance was verified at the p ⁇ 0.05 level.
  • the macrophages When macrophages are activated for the primary removal of antigens that have entered the lungs, the macrophages stimulate B cells to produce antibodies specific to the antigen and secrete IgE specific to the antigen.
  • the produced IgE activates mast cells, and when degranulated from mast cells through binding to the antigen, symptoms of respiratory diseases such as bronchoconstriction are induced.
  • the absolute total cell number of granulocytes and lymphocytes in the bronchoalveolar lavage fluid (BALF) increases and infiltrates the airways and alveoli.
  • BALF bronchoalveolar lavage fluid
  • inflammatory cytokines such as TNF- ⁇ , IL-4, IL-5, and IL-13 secreted from inflammatory cells such as eosinophils, Th2 cells, and mast cells increase the size of mucus cells and the amount of mucus, thereby inducing an inflammatory response.
  • mitogen-activated protein kinases include, in addition to ERK1/2, p38 MAPK and jun N-terminal kinase (JNK), and most of their target genes play an important role in producing hormones that promote cell division or growth necessary for cell growth and in regulating inflammatory substances.
  • NF- ⁇ B like MAPKs, regulates various biological functions including cell proliferation and differentiation, and PTEN, as a tumor suppressor gene, induces cell cycle arrest and apoptosis through the PI3K/AkT signal pathway.
  • MMPs are proteolytic enzymes secreted by neutrophils, and in the case of MMP-9 (Matrix metalloproteinase-9), it activates TGF- ⁇ to promote the decomposition of lung tissue and fibrosis around the small airways, and macrophages stimulated by allergens express iNOS (inducible nitric oxide synthase) within the cells, promoting the production of a large amount of NO (Nitric oxide) from L-arginine and oxygen molecules.
  • iNOS inducible nitric oxide synthase
  • the extract of Hansokdan showed consistent and significant differences in antioxidant activity compared to the control group (C) at a high concentration of Hansokdan extract (PU-H) of 200 mg/kg for all antioxidant enzymes SOD, CAT, and GPx (Fig. 4).
  • the anti-inflammatory effect of the extract of Hansokdan was cross-validated with the type 2 cytokines IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF) and IFN- ⁇ , which cross-inhibits type 2 cytokines among type 1 cytokines, to determine whether similar results were obtained in animal experiments.
  • BALF bronchoalveolar lavage fluid
  • IFN- ⁇ bronchoalveolar lavage fluid
  • Leukotrienes are factors related to bronchial constriction, and when asthma and bronchitis occur, they are overproduced and act as a factor that worsens the symptoms, and prostaglandin E2 (PGE2) is known to be an important substance that cyclically induces inflammation in the inflammatory mechanism. Therefore, the two factors were measured in an animal model to confirm the improvement effect of respiratory inflammation induced by Hansokdan extract and fine dust, and the results are shown in Fig. 8 of the present invention.
  • the extract of Hansokdan can be used to prevent and treat respiratory diseases caused by fine dust through the expectorant activity of the extract of Hansokdan.
  • the purpose of the present invention is to provide a food composition containing an extract of Hansokdan for preventing or improving respiratory diseases caused by fine dust.
  • the present invention aims to provide a pharmaceutical composition for preventing or treating respiratory diseases caused by fine dust, including an extract of Hansokdan.

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Abstract

La présente invention concerne une composition pour prévenir, soulager ou traiter des maladies respiratoires provoquées par de la poussière fine, la composition comprenant un extrait de Phlomis umbrosa. L'extrait de Phlomis umbrosa selon la présente invention améliore l'activité antioxydante dans les bronches et les poumons, réduit les facteurs inflammatoires provoqués par de la poussière fine, et présente une activité expectorante, et peut ainsi être utilisé en tant que composition alimentaire pour prévenir ou soulager des maladies respiratoires provoquées par de la poussière fine, ou en tant que composition pharmaceutique pour prévenir ou traiter des maladies respiratoires provoquées par de la poussière fine.
PCT/KR2024/018723 2023-11-23 2024-11-25 Composition pour prévenir, soulager ou traiter des maladies respiratoires provoquées par de la poussière fine, comprenant un extrait de phlomis umbrosa Pending WO2025110819A1 (fr)

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KR102234040B1 (ko) * 2018-03-16 2021-04-01 주식회사 헬릭스미스 호흡기 질환의 예방 또는 치료용 생약 조성물
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