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WO2024096445A1 - Composition pour améliorer, prévenir ou traiter des maladies liées au stress et à la dépression, comprenant du talampanel - Google Patents

Composition pour améliorer, prévenir ou traiter des maladies liées au stress et à la dépression, comprenant du talampanel Download PDF

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Publication number
WO2024096445A1
WO2024096445A1 PCT/KR2023/016806 KR2023016806W WO2024096445A1 WO 2024096445 A1 WO2024096445 A1 WO 2024096445A1 KR 2023016806 W KR2023016806 W KR 2023016806W WO 2024096445 A1 WO2024096445 A1 WO 2024096445A1
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WO
WIPO (PCT)
Prior art keywords
stress
depression
talampanel
related diseases
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2023/016806
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English (en)
Korean (ko)
Inventor
박상기
우영식
유진영
김건화
홍신형
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.)
Korea Basic Science Institute KBSI
POSTECH Research and Business Development Foundation
Original Assignee
Korea Basic Science Institute KBSI
POSTECH Research and Business Development Foundation
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Publication of WO2024096445A1 publication Critical patent/WO2024096445A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
    • 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

Definitions

  • the present invention relates to a composition containing talampanel for improving, preventing or treating diseases related to stress and depression.
  • neuropsychiatric diseases including anxiety, depression, and schizophrenia are on the rise due to rapidly increasing stress.
  • the number of patients suffering from stress and depression is increasing due to various causes, including social and structural causes.
  • Talampanel acts as a non-competitive antagonist of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor, a type of ionotropic glutamate receptor in the central nervous system. It is a drug studied for the treatment of epilepsy, malignant glioma, traumatic brain injury, epilepsy, and amyotrophic lateral sclerosis (ALS).
  • AMPA alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • the present inventors confirmed that talampanel can be effectively used to improve and treat stress and depression by confirming the efficacy of talampanel in improving and treating stress and depression in a stress-induced depression model, and completed the present invention.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to stress and depression, comprising talampanel or a pharmaceutically acceptable salt thereof represented by the following formula (1).
  • the purpose of the present invention is to provide the use of talampanel in the treatment of diseases related to stress and depression.
  • the purpose of the present invention is to provide a method of treating stress and depression-related diseases by administering talampanel to an individual in need thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating diseases related to stress and depression, comprising talampanel or a pharmaceutically acceptable salt thereof represented by the following formula (1).
  • the talampanel has the structure of Formula 1 above.
  • Talampanel shows excellent improvement effects on stress and depression-related diseases.
  • the stress- and depression-related diseases mentioned above are a concept that includes symptoms in which cognitive, mental, and physical symptoms appear due to loss of motivation and persistent depression, leading to a decline in daily functioning. Stress and depression-related diseases related to the above symptoms, including persistent depression, decreased motivation, sleep disorders such as insomnia, weight changes related to decreased or increased appetite, repeated thoughts or attempts of suicide, negative thinking, excessive guilt, etc. means.
  • depression, stress, post-operative stress syndrome cluster headache due to stress, migraine due to stress, unexplained pain due to stress, insomnia due to stress, memory disorder, cognitive disorder, and attention disorder. It could be any one.
  • talampanel has excellent antidepressant and anti-stress efficacy in experiments conducted on animal models of stress-induced depression, and thus talampanel is useful for improving and treating diseases related to stress and depression. It was confirmed that it can be used.
  • prevention used in the present invention refers to all actions that suppress or delay the onset of diseases related to stress and depression by administering a composition.
  • treatment means any action in which the symptoms of the disease are improved or beneficially changed by administration of the composition.
  • pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, such as inorganic ionic salts made of calcium, potassium, sodium, magnesium, etc.; Inorganic acid salts made from hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid.
  • inorganic ionic salts made of calcium, potassium, sodium, magnesium, etc.
  • Inorganic acid salts made from hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid and sulfuric acid
  • Organic acid salts made from acids, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; Sulfonic acid salts made from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; Amino acid salts made from glycine, arginine, lysine, etc.; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are not limited by these salts listed.
  • talampanel represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier, and may be prepared in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, etc. according to conventional methods. It may be formulated in the form of a sterile injectable solution.
  • the pharmaceutically acceptable carriers include those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, Including, but not limited to, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition of the present invention may contain diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and other pharmaceutically acceptable additives, but is not limited thereto.
  • the pharmaceutical composition of the present invention when formulated as an oral solid preparation, it includes tablets, pills, powders, granules, capsules, etc., and such solid preparations contain at least one excipient, such as starch, calcium carbonate, It may contain sucrose or lactose, gelatin, etc., and includes, but is not limited to, lubricants such as magnesium stearate and talc.
  • the pharmaceutical composition of the present invention when formulated in liquid form for oral use, it includes suspensions, oral solutions, emulsions, syrups, etc., and includes, but is not limited to, diluents such as water and liquid paraffin, humectants, sweeteners, fragrances, preservatives, etc.
  • the pharmaceutical composition of the present invention when formulated for parenteral use, it includes sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, and olive. Includes, but is not limited to, vegetable oils such as oil, injectable esters such as ethyl oleate, etc.
  • As a base for suppositories witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used, but are not limited to these.
  • composition can be administered singly or multiple times in a pharmaceutically effective amount.
  • pharmaceutically effective amount of the present invention means an amount sufficient to prevent or treat a disease with a reasonable benefit/risk ratio applicable to medical prevention or treatment, and the effective dose level is determined by the severity of the disease, the activity of the drug, Including the patient's age, weight, health, gender, patient's sensitivity to drugs, administration time, administration route and excretion rate of the composition of the present invention used, treatment period, and drugs mixed or used simultaneously with the composition of the present invention used. It can be determined according to factors well known in the medical field and other factors. For example, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof can be administered at 0.0001 to 100 mg/kg per day, and the administration may be administered once a day or in divided doses.
  • the pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans by various routes, for example, by oral administration, intrathecium, inner ear, abdominal cavity or vein, muscle, subcutaneous, intrauterine dura, sublingual or cerebrovascular administration. It may be administered by injection, but is not limited to this.
  • the pharmaceutical composition of the present invention may contain 0.01 to 95% by weight, preferably 1 to 80% by weight, of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Additionally, the pharmaceutical composition of the present invention can be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
  • subject of the present invention includes animals or humans whose symptoms can be improved by administration of the pharmaceutical composition according to the present invention.
  • diseases related to stress and depression can be effectively prevented and treated.
  • administration means introducing a predetermined substance into a human or animal by any appropriate method, and the route of administration of the therapeutic composition according to the present invention is through any general route as long as it can reach the target tissue. It may be administered orally or parenterally. Additionally, the therapeutic composition according to the present invention can be administered by any device that can move the active ingredient to target cells.
  • Another aspect of the present invention is the prevention of stress and depression-related diseases, comprising administering a therapeutically effective amount of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. Or provide a treatment method.
  • the term "individual" of the present invention refers to any animal that has developed or can develop diseases related to stress and depression, and is typically treated with a compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof. It may be an animal that can show beneficial effects, but any animal that has symptoms of stress or depression-related diseases or is likely to have these symptoms is included without limitation. As described above, the stress- and depression-related diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual.
  • Another aspect of the present invention provides the use of the compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, for manufacturing a medicine for preventing or treating diseases related to stress and depression.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of diseases related to stress and depression.
  • the present invention provides a food composition for preventing or improving diseases related to stress and depression, comprising talampanel or a foodologically acceptable salt thereof represented by the following formula (1).
  • improvement in the present invention refers to any action in which stress- and depression-related diseases are improved or beneficially changed by administration of the composition of the present invention.
  • the talampanel and its salt are preferably contained in an amount of 0.00001 to 0.01% by weight relative to the food composition. If it is less than 0.00001% by weight, the effect is insignificant, and if it exceeds 0.01% by weight, the increase in effect compared to the amount used is minimal, making it uneconomical.
  • Foodologically acceptable salts may apply mutatis mutandis to pharmaceutically acceptable salts.
  • Food compositions of the present invention include, for example, noodles, gums, dairy products, ice cream, meat, grains, caffeinated beverages, general beverages, chocolate, bread, snacks, confectionery, candy, pizza, jelly, alcoholic beverages, alcohol, and vitamin complexes. and other health supplements, but is not necessarily limited thereto.
  • the food composition of the present invention when used as a food additive, it can be added as is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods.
  • the food composition includes health functional foods.
  • health functional food refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and “functionality” refers to the structure of the human body. It means ingestion for the purpose of controlling nutrients for function or obtaining useful effects for health purposes such as physiological effects.
  • the food composition and health functional food of the present invention may contain additional ingredients.
  • it may include biotin, folate, panthotenic acid, vitamins A, C, D, E, B1, B2, B6, B12, niacin, etc.
  • minerals such as chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), zinc (Zn), iron (Fe), and calcium (Ca).
  • amino acids such as cysteine, valine, lysine, and tryptophan.
  • preservatives potassium sorbate, sodium benzoate, salicylic acid, sodium dihydroacetate, etc.
  • colorants tar color, etc.
  • coloring agents sodium nitrite, sodium nitrite, etc.
  • bleaching agents sodium sulfite
  • disinfectants bleaching powder, high-level bleaching powder, Sodium hypochlorite, etc.
  • swelling agents alum, D-potassium hydrogen tartrate, etc.
  • strengthening agents emulsifiers, thickeners (greasing), coating agents, antioxidants (butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), etc.) , seasonings (MSG monosodium glutamate, etc.), sweeteners (dulcine, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), food additives such as gum base agents, anti-foam agents, solvents, improvers, etc. can be added
  • Talampanel of the present invention has excellent anti-depressant and anti-stress effects and can be usefully used to improve and treat stress- and depression-related diseases.
  • Figure 1 is a diagram showing an outline of an experiment to verify the antidepressant effect of talampanel administration at different concentrations in a chronic movement-restricted stress-based depression mouse model over 15 days.
  • Figure 2 is a diagram showing an outline of an experiment to verify the antidepressant effect of talampanel administration at different concentrations in a chronic movement-restricted stress-based depression mouse model over 28 days.
  • Figure 3 is a diagram showing the amount of change in body weight of mice following administration of talampanel at each concentration along with movement restriction stress over 15 days.
  • Figure 4 is a diagram analyzing the level of despair behavior of depression through a forced swimming test in mice following the administration of talampanel at different concentrations along with movement restriction stress over 15 days.
  • Figure 5 is a diagram analyzing the level of despair behavior of depression through a forced swimming test in mice following movement restriction stress over 28 days and administration of talampanel at various concentrations.
  • Figure 6 is a diagram analyzing the level of despair behavior of depression through a tail hanging test in mice following administration of talampanel at different concentrations along with movement restriction stress over 28 days.
  • Figure 7 is a diagram analyzing the level of anhedonia in depression through a sugar preference test in mice following the administration of talampanel at different concentrations along with movement restriction stress over 28 days.
  • Example 1 Evaluation of the efficacy of improving depression by administration of talampanel in a mouse model of depression induced by chronic movement restriction stress
  • mice 8-9 week old male C57BL6/J mice were provided through Hyochang Science. Mice were provided with food and water to consume ad libitum under diurnal lighting conditions (12 hours light, 12 hours dark). All animal experiment procedures were approved by the Pohang University of Science and Technology Animal Experiment Ethics Committee (IACUC), and all experiments were performed in accordance with approved guidelines.
  • IACUC Pohang University of Science and Technology Animal Experiment Ethics Committee
  • talampanel showed an improvement effect on weight loss due to stress and depression by preventing weight loss due to continuous stress.
  • a cylindrical tank measuring 20 cm in diameter x 30 cm in height was filled with water at 25-28°C until the height was 15 cm. Afterwards, each mouse was carefully placed in water, and its activity was recorded by video recording for 6 minutes. Up to four mice were conducted simultaneously at a time, and a partition was installed to prevent the mice from seeing each other. The water in the tank was freshly prepared after each test session.
  • the movement of the mouse was defined as any movement other than the minimum required to maintain body balance and keep the head above water, and immobile time was measured.
  • the forced swim test is an experiment in which water is placed in a cylindrical, obstacle-free container and the rat is placed in it, and the time taken to determine the movement of the rat is determined. It is a representative measure of depressive behavior. The longer the immobile time, the more depressed the individual is judged to be.
  • mice's tail was fixed with tape, and the mouse's head was placed on the ceiling of a 25 cm wide x 25 cm long x 40 cm high white box with its head about 15 cm above the ground. The length was adjusted so that it fell apart, and the tail was attached.
  • mice The activity of each mouse was recorded by video recording for 6 minutes. Up to four mice were treated at the same time, and the immobile time of the mice was measured for a total of 6 minutes. The movement of the mouse was defined as a state in which all limbs did not move based on whether the mouse had limb movement, and the immobile time was measured.
  • the tail suspension test measures the time it takes for an animal to stop moving to escape by suspending the tail off the ground. As with FST, the longer the immobile time, the more depressed the individual is judged to be. Since the FST may be due to the immobility of the animal due to the impact of falling into the water, a TST test may be required for a more accurate test. In other words, the TST is characterized by being more sensitive to antidepressants than the FST because animals remain immobile for a longer period of time in the FST.
  • mice were deprived of food and water for 18 hours on the first day of the experiment (food and water deprivation), and then provided with food on the second and third days. % sugar solution and water were provided simultaneously, providing experience with 2% sugar. Afterwards, on the 4th day, food and water were withheld for 18 hours, and then on the 5th day of the experiment, 2% sugar solution and water were provided simultaneously for 3 hours, allowing free choice. To measure the mouse's intake, the weight of the solution and bottle were recorded before and after the 3-hour test.
  • the sugar preference test is a measure of anhedonia caused by depression. This was an experiment in which rats were given regular water and a 1% sugar solution to see which liquid they preferred. Normal rats tended to prefer the sugar solution, but depressed/anhedonic rats had a preference for the sugar solution. There was little difference in preference.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition pour améliorer, prévenir ou traiter des maladies liées au stress et à la dépression, la composition contenant du talampanel. Le talampanel selon la présente invention présente d'excellents effets antidépresseurs et antistress et peut ainsi être efficacement utilisé dans l'amélioration et le traitement de maladies associées au stress et à la dépression.
PCT/KR2023/016806 2022-11-03 2023-10-26 Composition pour améliorer, prévenir ou traiter des maladies liées au stress et à la dépression, comprenant du talampanel Ceased WO2024096445A1 (fr)

Applications Claiming Priority (2)

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KR10-2022-0145184 2022-11-03
KR1020220145184A KR102787292B1 (ko) 2022-11-03 2022-11-03 탈람파넬을 포함하는 스트레스 및 우울증 관련 질환의 개선, 예방 또는 치료용 조성물

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120156260A1 (en) * 2009-07-31 2012-06-21 Ascendis Pharma A/S Prodrugs Containing an Aromatic Amine Connected By an Amido Bond to a Linker
US20160022642A1 (en) * 2014-07-25 2016-01-28 Yale University Compounds Useful for Promoting Protein Degradation and Methods Using Same
WO2018169798A1 (fr) * 2017-03-11 2018-09-20 The Regents Of The University Of California Atténuation de troubles du snc par polythérapie faisant intervenir des neurostéroïdes, et des bloqueurs ampa
WO2021259304A1 (fr) * 2020-06-23 2021-12-30 Antengene (Hangzhou) Biologics Co., Ltd. Anticorps et méthodes de traitement de maladies associées à la claudine
WO2022159506A1 (fr) * 2021-01-19 2022-07-28 Merit Therapeutics, Inc. Composés de cannabidiol deutérés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120156260A1 (en) * 2009-07-31 2012-06-21 Ascendis Pharma A/S Prodrugs Containing an Aromatic Amine Connected By an Amido Bond to a Linker
US20160022642A1 (en) * 2014-07-25 2016-01-28 Yale University Compounds Useful for Promoting Protein Degradation and Methods Using Same
WO2018169798A1 (fr) * 2017-03-11 2018-09-20 The Regents Of The University Of California Atténuation de troubles du snc par polythérapie faisant intervenir des neurostéroïdes, et des bloqueurs ampa
WO2021259304A1 (fr) * 2020-06-23 2021-12-30 Antengene (Hangzhou) Biologics Co., Ltd. Anticorps et méthodes de traitement de maladies associées à la claudine
WO2022159506A1 (fr) * 2021-01-19 2022-07-28 Merit Therapeutics, Inc. Composés de cannabidiol deutérés

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KR102787292B1 (ko) 2025-03-31
KR20240063495A (ko) 2024-05-10

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