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WO2024232570A1 - Composition pour prévenir ou traiter une maladie musculaire comprenant un extrait de fleur de centaurea cyanus - Google Patents

Composition pour prévenir ou traiter une maladie musculaire comprenant un extrait de fleur de centaurea cyanus Download PDF

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Publication number
WO2024232570A1
WO2024232570A1 PCT/KR2024/005660 KR2024005660W WO2024232570A1 WO 2024232570 A1 WO2024232570 A1 WO 2024232570A1 KR 2024005660 W KR2024005660 W KR 2024005660W WO 2024232570 A1 WO2024232570 A1 WO 2024232570A1
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Prior art keywords
composition
extract
muscle
preventing
improving
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English (en)
Korean (ko)
Inventor
김명석
정상훈
레 탐티
바오응옥 응우옌
이욱빈
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Korea Institute of Science and Technology KIST
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Korea Institute of Science and Technology KIST
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Priority claimed from KR1020230085742A external-priority patent/KR102786421B1/ko
Application filed by Korea Institute of Science and Technology KIST filed Critical Korea Institute of Science and Technology KIST
Publication of WO2024232570A1 publication Critical patent/WO2024232570A1/fr
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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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a composition for preventing or treating muscle disease comprising a cornflower extract.
  • Muscles are largely divided into skeletal muscle, cardiac muscle, and visceral muscle, and among them, skeletal muscle is the tissue that exists in the largest amount in the human body, accounting for 40-45% of body weight. Skeletal muscle is attached to bone through tendon and plays a role in creating movement or force of the bone.
  • One muscle is composed of numerous muscle fibers, and muscle fibers are in turn made of numerous myofibrils composed of actin and myosin. When actin and myosin overlap and move, the length of the muscle shortens or lengthens, causing overall muscle contraction and relaxation.
  • An increase in myofibril size means an increase in muscle fiber thickness, which results in muscle growth.
  • Muscle diseases progress through a process in which walking and movement functions become impaired due to weakening of skeletal muscles, and activities of daily living (ADL) become difficult, making independent living impossible. In addition, it causes cardiopulmonary dysfunction and other complications, so it is important to accurately understand the characteristics of each muscle disease and approach it accordingly.
  • the present inventors have made efforts to develop a natural product effective in preventing or treating muscle diseases, and as a result, have experimentally confirmed that a cornflower extract is useful for improving muscle strength and exercise performance, thereby completing the present invention.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating muscle disease, increasing muscle weight, and/or improving exercise ability, which contains a cornflower extract as an effective ingredient.
  • an object of the present invention is to provide a food composition for preventing or improving muscle disease, increasing muscle weight, and/or improving exercise ability, which contains a cornflower extract as an effective ingredient.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or improving muscle disease, increasing muscle weight, and/or improving exercise ability, which contains a cornflower extract as an effective ingredient.
  • the present invention provides a food composition for preventing or improving muscle disease, increasing muscle weight, and/or improving exercise ability, containing a cornflower extract as an effective ingredient.
  • the present invention provides a pharmaceutical composition for preventing or improving muscle disease, increasing muscle weight, and/or improving exercise ability, containing a cornflower extract as an effective ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle disease, increasing muscle weight, and/or improving exercise ability, containing a cornflower extract as an effective ingredient.
  • the above muscle disease may be at least one disease selected from the group consisting of sarcopenia, muscular atrophy, myasthenia, muscular dystrophy, myotonia, hypotonia, muscular weakness, muscular dystrophy, atony, amyotrophic lateral sclerosis, and inflammatory myopathy.
  • the above composition can enhance the strength of the teeth.
  • the above composition can increase muscle weight.
  • the composition can increase the expression of one or more genes selected from the group consisting of Myd1 , Myog , Ppargc1a , UCp3 and Tomm20 .
  • the above composition can be extracted with a solvent selected from the group consisting of water, organic solvents and mixtures thereof.
  • the above organic solvent may be one or more solvents selected from the group consisting of lower alcohols having 1 to 6 carbon atoms, nucleic acids, acetone, ethyl acetate, chloroform, and diethyl ether.
  • the present invention provides a method for preventing, treating, or improving muscle disease, and/or a method for increasing muscle weight, and/or a method for improving exercise ability, comprising a step of administering or taking a composition containing a cornflower extract as an active ingredient to a subject.
  • the present invention provides a composition containing a cornflower extract as an effective ingredient for preventing, treating, or improving muscle disease, and/or for increasing muscle weight, and/or for improving exercise ability.
  • the cornflower extract of the present invention has the effect of enhancing grip strength, increasing muscle weight, improving exercise performance, etc.
  • the composition containing the cornflower extract of the present invention as an effective ingredient can be applied to various products such as pharmaceutical compositions, food compositions, and quasi-drug compositions for preventing, treating, or improving muscle diseases as a natural medicine.
  • Figure 1 is a schematic diagram of the design of an animal model created to confirm the effect of extracts of Chrysanthemum indicum on the treatment or improvement of sarcopenia.
  • Figure 2 shows the results of confirming the effect of the extract of Cornelian cherry on improving grip strength (Con: control group, Dex: Dexamethasone, Oxy: Oxymetholone, CC 100: Cornelian cherry extract 100 mg/kg, CC 50: Cornelian cherry extract 50 mg/kg, CC 10: Cornelian cherry extract 10 mg/kg; ** p ⁇ 0.01; ***, p ⁇ 0.001).
  • Figure 3 shows the results of confirming the effect of the extract of cornelian cherry on improving exercise performance.
  • a maximum running speed
  • b distance run to exhaustion
  • c time taken to exhaustion
  • Con control group
  • Dex dexamethasone
  • Oxy oxymetholone
  • CC 100 cornelian cherry extract 100 mg/kg
  • CC 50 cornelian cherry extract 50 mg/kg
  • CC 10 cornelian cherry extract 10 mg/kg
  • Figure 4 shows the results of confirming the effect of the extract of Cornelian cherry on increasing muscle weight.
  • a thigh muscle weight
  • b hamstring muscle weight
  • c calf muscle weight
  • d flounder muscle weight
  • Dex Dexamethasone
  • Oxy Oxymetholone
  • CC 100 Cornelian cherry extract 100 mg/kg
  • CC 50 Cornelian cherry extract 50 mg/kg
  • CC 10 Cornelian cherry extract 10 mg/kg
  • Figure 5 shows the results of confirming the effect of the extract of Cornelian cherry on the survival rate of myotube cells (Con: control group, Dex: dexamethasone, CC 10: Cornelian cherry extract 10 ug/ml, CC 20: Cornelian cherry extract 20 ug/ml, CC 40: Cornelian cherry extract 40 ug/ml; ***, p ⁇ 0.001).
  • Figure 6 shows the results of confirming the effect of the extract of Cornelian cherry on enhancing the expression of muscle cell differentiation markers (Con: control group, Dex: dexamethasone, CC 10: Cornelian cherry extract 10 ug/ml, CC 20: Cornelian cherry extract 20 ug/ml, CC 40: Cornelian cherry extract 40 ug/ml; *, p ⁇ 0.05; ** p ⁇ 0.01).
  • Figure 7 shows the results of confirming the effect of the extract of Chrysanthemum indicum on enhancing gene expression related to mitochondrial function (exercise performance ability)
  • Con control group
  • Dex dexamethasone
  • CC 10 10 ug/ml of Chrysanthemum indicum extract
  • CC 20 20 ug/ml of Chrysanthemum indicum extract
  • CC 40 40 ug/ml of Chrysanthemum indicum extract
  • the present inventors completed the present invention by experimentally confirming that an extract of the cornflower, a natural product with little or no side effects, is effective in increasing the expression of genes related to vascular cell differentiation and exercise performance, increasing muscle weight, and improving exercise performance, etc.
  • the present invention provides a composition for preventing, improving or treating muscle disease, increasing muscle weight and/or enhancing exercise ability, comprising an extract of Centaurea cyanusa as an effective ingredient.
  • the above muscle disease may be at least one disease selected from the group consisting of sarcopenia, muscular atrophy, myasthenia, muscular dystrophy, myotonia, hypotonia, muscular weakness, muscular dystrophy, atony, amyotrophic lateral sclerosis, and inflammatory myopathy.
  • the above composition can enhance the strength of the teeth.
  • the above composition can increase exercise performance.
  • the above composition can increase muscle weight.
  • the composition can increase the expression of one or more genes selected from the group consisting of Myd1 , Myog , Ppargc1a , UCp3 and Tomm20 .
  • the above composition may be a food composition, a health functional food composition, a pharmaceutical composition or an over-the-counter drug composition.
  • prevention means any action that delays the onset of a muscle disease by administering the composition of the present invention
  • treatment and “improvement” mean any action that improves or beneficially changes the symptoms of a muscle disease by administering the composition of the present invention.
  • the above cornflower extract can be extracted using a polar solvent or/and a nonpolar solvent.
  • the above polar solvent may include at least one selected from the group consisting of (i) water, (ii) alcohol (preferably, methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, 2-butoxyethanol or ethylene glycol), (iii) acetic acid, (iv) dimethyl-formamide (DMFO), and (v) dimethyl sulfoxide (DMSO).
  • alcohol preferably, methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, 2-butoxyethanol or ethylene glycol
  • acetic acid preferably, methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, 2-butoxyethanol or ethylene glyco
  • the above nonpolar solvent may include at least one selected from the group consisting of acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1-pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethyl sulfide, chloroform, dichloromethane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrachloride, and THF.
  • the extract can be extracted using water, an organic solvent, or a mixture thereof as a solvent, and according to a specific embodiment of the present invention, the extract of the present invention can be obtained by treating water to cornflower.
  • the above organic solvent may include one or more solvents selected from the group consisting of lower alcohols having 1 to 6 carbon atoms (methanol, ethanol, propanol, butanol, etc.), hexanes, acetone, ethyl acetate, chloroform, and diethyl ether.
  • lower alcohols having 1 to 6 carbon atoms methanol, ethanol, propanol, butanol, etc.
  • hexanes acetone, ethyl acetate, chloroform, and diethyl ether.
  • the above-described cornelian cherry extract can be prepared into fractions according to a method commonly used in the decomposition of the present technology, and as a solvent used to fractionate the above-described cornelian cherry extract, at least one selected from the group consisting of water, lower alcohols having C1 to C4, n-hexane, ethyl acetate, acetone, acetonitrile, butyl acetate, 1,3-butylene glycol, methylene chloride, and mixed solvents thereof can be used, but is not limited thereto. However, a butanol fraction may be more preferable.
  • the term 'extract' used herein has the meaning commonly used in the art as a crude extract as described above, but in a broad sense, it also includes a fraction obtained by further fractionating an extract. That is, the cornflower extract includes not only one obtained by using the above-described extraction solvent, but also one obtained by additionally applying a purification process thereto. For example, fractions obtained by passing the extract through an ultrafiltration membrane having a certain molecular weight cut-off value, fractions obtained through various additional purification methods such as separation by various chromatographies (designed for separation according to size, charge, hydrophobicity, or affinity) are also included in the natural product extract of the present invention.
  • the extract used in the present invention can be manufactured into a powder state by additional processes such as reduced pressure distillation and freeze drying or spray drying.
  • the extract can be extracted by adding water, an organic solvent or a mixture thereof to the cornelian cherry blossom in an amount of 5 to 50 times the weight of the cornelian cherry blossom, more preferably 10 to 30 times, but is not limited thereto.
  • the extraction temperature can be 10 °C to 150 °C, more preferably 15 °C to 120 °C, but is not limited thereto.
  • the extraction time is preferably 1 to 20 hours, more preferably 2 to 8 hours, but is not limited thereto.
  • the extraction method can be any of a cold steeping, an ultrasonic extraction or a reflux cooling extraction method, but is not limited thereto.
  • the number of extractions is preferably 1 to 5 times, and it is more preferably 2 to 3 times of repeated extraction, but is not limited thereto.
  • the extract can be diluted, concentrated, or purified and dried after being diluted or concentrated for use.
  • the term "comprising as an effective ingredient” in this specification means including a sufficient amount to achieve the efficacy or activity of the extract of the cornflower.
  • the present invention is a composition extracted from the natural plant material, cornflower, and the quantitative upper limit of the cornflower extract included in the composition of the present invention can be selected and implemented within an appropriate range by those skilled in the art.
  • composition for preventing or treating muscle disease, increasing muscle weight and/or improving exercise capacity containing cornflower extract as an active ingredient
  • composition of the present invention can be prepared as a pharmaceutical composition.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the composition of the present invention may be a pharmaceutical composition comprising (a) a pharmaceutically effective amount of the cornflower extract of the present invention described above; and (b) a pharmaceutically acceptable carrier.
  • pharmaceutically effective amount as used herein means an amount sufficient to achieve the efficacy or activity of the cornflower extract described above.
  • Pharmaceutically acceptable carriers are those commonly used in the formulation, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition of the present invention may further contain, in addition to the above components, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, a sorbitol, a sorbitol, a sorbitol, a sorbitol, mannitol, mannitol, manni
  • composition of the present invention can be administered orally or parenterally.
  • the suitable dosage of the pharmaceutical composition of the present invention can be prescribed variously depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity.
  • the general dosage of the effective ingredient included in the pharmaceutical composition of the present invention is within the range of 0.001-100 mg/kg/day, preferably 0.01-35 mg/kg/day, based on adults. Administration may be once a day or divided into several times. However, the scope of the present invention is not limited by the above dosage.
  • the pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and by putting it in a multi-dose container.
  • the formulation may be in the form of a solution, suspension, syrup or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet or capsule, and may additionally contain a dispersant or stabilizer.
  • composition of the present invention can be provided as a pharmaceutical composition.
  • the above cornflower extract can be added as is, or used together with other pharmaceutical ingredients, and can be used appropriately according to a conventional method.
  • the amount of active ingredients mixed can be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment).
  • the above pharmaceutical composition can be used in the manufacture of external preparations, patches, ointments, etc., but is not limited thereto.
  • the composition of the present invention can be provided as a food composition or a health functional food composition.
  • the composition containing the cornflower extract of the present invention as an effective ingredient is manufactured as a food composition, it includes not only the cornflower extract as an effective ingredient, but also components that are usually added during food manufacturing, such as proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents.
  • the carbohydrates described above are monosaccharides such as glucose, fructose, etc.; disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents [thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)] and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
  • citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, Eucommia extract, jujube extract, licorice extract, etc. may be additionally included in addition to the natural product extract of the present invention.
  • the formulation of the above food composition or health functional food composition may be in the form of powder, granules, pills, tablets, capsules, or any other form of general food or beverage.
  • foods to which the above substance 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 can be included.
  • the cornflower extract when manufacturing food or beverage, can be added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less, per 100 parts by weight of the raw material.
  • the amount in the case of long-term intake for the purpose of health and hygiene or health control, can be less than the above range, and since the present invention does not have any safety issues since it utilizes a natural substance, it can be used in an amount greater than the above range.
  • Centaurea cyanus was purchased from Herb Village Co., Ltd., cut into an appropriate size, and 2 kg of the aerial parts of Centaurea cyanus and 10 L of water were added to an extraction vessel, and cold-extracted for 3 days, and the precipitate was removed using a centrifuge, and impurities were filtered to obtain the filtrate. Thereafter, the solvent was concentrated under reduced pressure and dried to obtain 290 g of an extract.
  • the present inventors created a sarcopenia mouse model, and measured grip strength using control mice and the sarcopenia mouse model.
  • mice used to confirm the efficacy of the extract of Cornelian cherry were prepared through the following process.
  • C57BL/6J mice male, 12 weeks old
  • the diet, administration dose, and administration method administered to the experimental groups are shown in Table 2 below.
  • the test substance was prepared in the form of a liquid suspension using 0.5% CMC and the test substance was administered for 4 weeks. To compensate for the placebo effect of 0.5% CMC and the weight loss effect due to administration stress, 0.5% CMC was orally administered daily to the vehicle control group.
  • mice Two weeks after administration of the test substance, the experimental group was administered dexamethasone via intraperitoneal injection for 2 weeks to induce sarcopenia, and the normal control group was administered saline via intraperitoneal injection. All mice were fed the same AIN76 diet (Research Diets) and the test substances were administered for an additional 2 weeks, for a total of 4 weeks. The dark:light cycle was maintained at a 12 hour:12 hour interval, and water was allowed to be consumed freely. As a result of the experiment, as shown in Fig.
  • Test group feedstuff Sarcopenia inducer Oral administration substances Dosage and method of administration Dosage period 1(Con) AIN76 diet Saline Vehicle - After oral administration of the test substance for 2 weeks 2 weeks of test substance and inducer administration (4 weeks total) 2(Dex) Dexamethasone (25 mg/kg, once daily, for 2 weeks) Vehicle - 3 (Dex+Oxy) Oxymetholone 50 mg/kg, Once a day, 4 (Dex+ CC 100) Cornflower extract 100 mg/kg, Once a day 5 (Dex+ CC 50) 50 mg/kg, Once a day 6 (Dex+ CC 10) 10 mg/kg, once daily
  • Myoblasts derived from C2C12 mice (CRL1772; American type cell collection, USA) were cultured in Dulbecco's Modified Eagle's Medium (DMEM) medium supplemented with 10 (v/v)% FBS, and after reaching 90% confluence, they were transferred to DMEM medium containing 2 (v/v)% horse serum and cultured for 7 days to differentiate into myotubes.
  • DMEM Dulbecco's Modified Eagle's Medium
  • myoatrophy was induced by treating the cells with 100 ⁇ M Dexamethasone for 24 hours, and the myoatrophy alleviation effect was confirmed by treating with cornflower extract (CC) at concentrations of 10, 20, and 40 ug/ml.
  • CC cornflower extract
  • Example 5 Effect of the extract of the cornflower on muscle cell differentiation and gene expression related to exercise performance in C2C12 myotube cells induced by dexamethasone treatment
  • the primer sequences are as follows:
  • Myd1 and Myog genes which are muscle cell differentiation markers that were reduced by dexamethasone treatment, was increased by the treatment with the cornflower extract, and the expression of Ppargc1a , UCp3 , and Tomm20 genes, which are mitochondrial function-related genes (exercise performance markers), was confirmed to be increased by the treatment with the cornflower extract.

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Abstract

La présente invention concerne une composition pour prévenir, améliorer ou traiter une maladie musculaire, comprenant un extrait de fleur de Centaurea cyanus. L'extrait de fleur de Centaurea cyanus de la présente invention a pour effet d'améliorer la force de préhension, d'augmenter le poids musculaire et d'améliorer les performances sportives et analogues. De plus, une composition comprenant l'extrait de fleur de Centaurea cyanus comme principe actif, selon la présente invention, est un médicament naturel et peut être appliquée à divers produits tels que des compositions pharmaceutiques, des compositions alimentaires et des compositions de quasi-médicament pour la prévention, le traitement, l'amélioration ou similaire de maladies musculaires.
PCT/KR2024/005660 2023-05-11 2024-04-26 Composition pour prévenir ou traiter une maladie musculaire comprenant un extrait de fleur de centaurea cyanus Pending WO2024232570A1 (fr)

Applications Claiming Priority (4)

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KR10-2023-0061095 2023-05-11
KR20230061095 2023-05-11
KR1020230085742A KR102786421B1 (ko) 2023-05-11 2023-07-03 수레국화 추출물을 포함하는 근육질환 예방 또는 치료용 조성물
KR10-2023-0085742 2023-07-03

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KR20140000767A (ko) * 2012-06-25 2014-01-06 연세대학교 원주산학협력단 치커리 추출물의 근육 손상 예방, 치료 또는 개선을 위한 용도
KR20180079174A (ko) * 2016-12-30 2018-07-10 연세대학교 산학협력단 3,5-디카페오일퀴닉에시드 또는 국화 추출물을 함유하는 근육 질환 예방 및 치료용 또는 근 기능 개선용 조성물
KR20220064641A (ko) * 2020-11-12 2022-05-19 주식회사 코리아나화장품 수레국화꽃과 당아욱꽃의 혼합 추출물을 함유하는 피부 자극 완화용 및 피부 보습용 화장료 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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