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WO2018128478A1 - Composition, comprenant comme principe actif de l'ionone ou un sel pharmaceutiquement acceptable de celle-ci, destinée à la prévention ou au traitement de troubles musculaires - Google Patents

Composition, comprenant comme principe actif de l'ionone ou un sel pharmaceutiquement acceptable de celle-ci, destinée à la prévention ou au traitement de troubles musculaires Download PDF

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Publication number
WO2018128478A1
WO2018128478A1 PCT/KR2018/000297 KR2018000297W WO2018128478A1 WO 2018128478 A1 WO2018128478 A1 WO 2018128478A1 KR 2018000297 W KR2018000297 W KR 2018000297W WO 2018128478 A1 WO2018128478 A1 WO 2018128478A1
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Prior art keywords
muscle
ionone
composition
active ingredient
preventing
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English (en)
Korean (ko)
Inventor
박태선
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Industry Academic Cooperation Foundation of Yonsei University
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Industry Academic Cooperation Foundation of Yonsei University
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    • 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
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/316—Foods, ingredients or supplements having a functional effect on health having an effect on regeneration or building of ligaments or muscles

Definitions

  • the present invention relates to a composition for preventing or treating muscle diseases comprising ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the elderly population accounted for 7.2% of the total population in 2000 and entered an aging society.
  • the aged population is expected to enter an aging society (more than 20%).
  • Muscle mass in humans decreases with age (10-15% at 50-70 years, and more than 30% at 70-80 years), thereby weakening muscle strength and muscle function, called sarcopenia. do.
  • Geriatric muscular dystrophy is a major cause of limiting the independent living of the elderly by inducing activity disorder and gait disorder.
  • myopathy lowers metabolic rate, increases insulin resistance, promotes type 2 diabetes, and increases the risk of hypertension and cardiovascular disease by three to five times.
  • drug repositioning technology is being developed to apply myostatin inhibitor or other FDA-approved drugs to myopathy.
  • Muscles are divided into skeletal muscles, cardiac muscles, and smooth muscles, and skeletal muscles are the most abundant tissues in the human body, accounting for 40 to 45% of body weight. Skeletal muscles attach to bones through the tendons, creating bone movement or force.
  • One muscle is made up of numerous myofibers, which in turn are made up of numerous myofibers composed of actin and myosin. When actin and myosin overlap each other, they shorten or lengthen the muscles, causing the entire muscle to contract and relax.
  • An increase in myofibril size means an increase in myofiber thickness, resulting in an increase in muscle.
  • Type I muscle fibers that make up muscle are classified into Type I, Type IIA and Type IIB by the metabolic process and contraction rate that produce ATP.
  • Type I muscle fibers are slow in contraction and contain a large number of myoglobin and mitochondria, making them suitable for continuous, low-intensity aerobic activity.
  • Type II muscle fibers have a red color and are also called red muscles, and soleus is typical.
  • 'Type IIB muscle fibers' are very short but have high strength for anaerobic exercise due to their high contraction speed. They are white due to the low content of myoglobin, and the gastrocnemius is one of them.
  • Type IIA muscle fibers have the intermediate characteristics of the two muscle fibers mentioned above, and the rectus femoris. As the body ages, not only the composition of Type I and II muscle fibers varies by muscle area, but all types of muscle fibers decrease.
  • Skeletal muscles have the characteristics of being regenerated and maintained according to the environment, but these characteristics are lost with age, and consequently, as aging progresses, muscle mass is reduced and muscle strength is also lost.
  • Signaling systems involved in the growth and regeneration of muscle include signaling mediated by insulin like growth factor 1 (IGF-1) / AKT to regulate protein synthesis.
  • IGF-1 receptor IGF-1R
  • the activation of IGF-1 receptor (IGF-1R) in the muscle cell membrane increases AKT phosphorylation through IRS1 and PI3K phosphorylation, and the latter activates mTORC phosphorylation.
  • Activation of mTORC increases the phosphorylation of ribosomal protein S6 kinase beta-1 (p70S6K1), which increases mRNA translation and increases the activity of eukaryotic translation initiation factor 4 G (eIF4G), and eukaryotic translation initiation factor 4E binding protein Phosphorylate 1 (4E-BP1) protein.
  • eIF4G and 4E-BP1 are involved in the formation of the eIF4F complex, that is, eIF4G binds to eIF4A and eIF4E to form the eIF4F complex, while phosphorylation of 4E-BP1 inhibits its binding to eIF4E, leading to an increase in free eIF4E. do.
  • Akt / mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.Nature cell biology, 3, 1014-1019, 2001).
  • AKT phosphorylation stimulates muscle fiber growth by increasing eIF2B expression through glycogen synthase kinase 3 (GSK3) and also inhibits muscle loss by inhibiting the expression of forkhead box O (FOXO), a proteolytic transcription factor.
  • Muscle loss is regulated by signaling mediated by receptors of the TGF- ⁇ family, including myostatin, transforming growth factor beta (TGF- ⁇ ), and activin. Binding of the ligand to the TGF- ⁇ type II receptor phosphorylates the type I receptor, the latter phosphorylates the smad 2/3 complex and eventually activates FOXO.
  • the latter increases gene expression of muscle-specific ubiquitin-ligase, muscle RING-finger protein-1 (MURF1) and Muscle Atrophy F-Box (MAFbx) / atrogin-1, which attach ubiquitin to the lysine site of the target protein. Promote proteolysis and eventually induce muscle loss (Gumucio et al., Atrogin-1, MuRF-1, and sarcopenia. Endocrine, 43, 12-21, 2013).
  • MURF1 muscle RING-finger protein-1
  • MAFbx Muscle Atrophy F-Box
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating muscle diseases, promoting muscle differentiation, muscle regeneration or muscle strengthening, including ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is a health functional food composition for preventing or improving muscle function, promoting muscle differentiation, muscle regeneration or muscle strengthening, including ionone or a pharmaceutically acceptable salt thereof as an active ingredient, It is to provide a composition for livestock feed.
  • Still another object of the present invention is to provide a cosmetic composition for improving muscle function, including ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is a method for preventing or treating muscle disease, the method for promoting muscle differentiation, muscle regeneration, or muscle, comprising administering to or administering to a subject a pharmaceutical composition comprising ionone or a salt thereof as an active ingredient. It is to provide a strengthening method.
  • Still another object of the present invention is to provide a method for preventing or treating muscle diseases, promoting muscle differentiation, muscle regeneration, or muscle strengthening of a composition comprising ionone or a salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle diseases comprising ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition may increase the expression of p-4E-BP1 or p-p70S6K1 protein.
  • the composition may reduce the expression of a MuRF1 (Muscle Ring-Finger Protein) or MaFbx (Muscle atrophy F-box).
  • MuRF1 Muscle Ring-Finger Protein
  • MaFbx Muscle atrophy F-box
  • the muscle disease may be a muscle disease due to muscle function decline, muscle reduction, muscle wasting or muscle degeneration.
  • the muscle disease is atony, muscular atrophy, muscular dystrophy, myasthenia, cachexia, rigid spinesyndrome, muscular dystrophy At least one selected from the group consisting of sclerosis (amyotrophic lateral sclerosis), Charcot-Marie-Tooth disease, and sarcopenia.
  • the present invention provides a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening including ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for preventing muscle diseases or improving muscle function, including ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for promoting muscle differentiation, muscle regeneration or muscle strengthening including ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a composition for animal feed for preventing or improving muscle diseases, including ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a composition for promoting animal differentiation, muscle regeneration or muscle strengthening, comprising ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a cosmetic composition for improving muscle function comprising ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for preventing or treating muscle diseases, comprising administering to or administering to a subject a pharmaceutical composition comprising ionone or a salt thereof as an active ingredient.
  • the present invention also provides a method for promoting muscle differentiation, muscle regeneration, or muscle strengthening, comprising administering to or administering to a subject a composition comprising ionone or a salt thereof as an active ingredient.
  • the present invention provides a use for preventing or treating muscle diseases of a composition comprising ionone or a salt thereof as an active ingredient.
  • the present invention provides a muscle differentiation promotion, muscle regeneration or muscle strengthening use of the composition comprising ionone (ionone) or a salt thereof as an active ingredient.
  • the present invention relates to a composition for preventing or treating muscle diseases, or improving muscle function, comprising ionone or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the ionone is used for synthesizing muscle protein in muscle cells and It is possible to increase the expression of proteins associated with increased muscle mass and inhibit the expression of enzymes involved in muscle protein degradation from the mRNA level, so muscle differentiation, muscle regeneration, Muscle strength can be increased through increasing muscle mass, and can inhibit muscle loss, and can be used for preventing or treating muscle diseases, muscle differentiation, muscle regeneration, and muscle mass increase or muscle function improvement.
  • FIG. 1 is a graph showing changes in thickness, length, and fusion index of myotubes in mouse myoblasts.
  • FIGS. 1B-1D show the diameter (B), fusion index (C), and length (D) of myotubes.
  • Each value is the mean ⁇ standard error of three determinations in three independent wells. P ⁇ 0.05 indicates statistical significance.
  • FIG. 2 shows the change in the expression of proteins involved in protein degradation and synthesis in mouse myoblasts treated with ionone.
  • FIG. 2A shows the protein levels of p-4E-BP1, Total 4E-BP1, p-p70S6K1, and Total p70S6K1, and
  • FIG. 2B shows gene expression levels of MaFbx and MuRF1. Each value is the mean ⁇ standard error of three determinations in three independent wells. P ⁇ 0.05 indicates statistical significance.
  • Figure 3 shows the increase in muscle strength by ion intake from changes in body weight (A), hanging time (B) and grip force (C) of normal diet group (Chow), high-fat diet group (HFD) and ionone group (Ionone) mice. The result is confirmed.
  • Figure 4 is the result of confirming the fiber diameter of the muscle tissue of the mouse by ion intake in the rectus femoris (A) and soleus (B). Quantitative values represent the fiber diameter of each muscle for 8 rats as mean ⁇ standard error. P ⁇ 0.05 indicates statistical significance.
  • the present inventors completed the present invention by confirming that the ketone-based compound ionone is effective in improving muscle and improving muscle loss by inhibiting the degradation of muscle protein and promoting synthesis.
  • muscle refers to tendons, muscles, and tendons in general
  • muscle function means the ability to exert a force by contraction of muscles, muscles can exert maximum contraction force to withstand resistance Muscle strength, which is the ability to be present, muscle endurance, which is how long or how many times a muscle can repeat contraction and relaxation, and quickness, which is the ability to exert a strong force in a short time.
  • Muscle functions are subjective to the liver, proportional to muscle mass, and “muscle improvement” means better muscle function.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle diseases comprising ionone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the ionone is Rubus idaeus (Raspberry), Daucus carota subsp. Sativus (Carrot, Carrot), Prunus dulcis (Almond, almond), Menta, and (Herb, herbs) mainly ketone (ketone), mainly that the flower fragrance aroma component-based compound that contains the, following structural formula is C 13 H 20 O, molecular weight of 192.3 g / mol.
  • Ionone includes isomers of alpha-ionone, beta-ionone, and gamma-ionone represented by the following Chemical Formulas 1, 2, and 3, respectively, Especially beta isomers are preferred, but are not limited thereto.
  • it may include an ionone hydrate, an ionone derivative, and the like, and may also include a solvent compound or stereoisomer thereof.
  • the method for obtaining the ionone is not particularly limited, and may be isolated from the plant containing the ionone, chemically synthesized using a known manufacturing method, or commercially available.
  • composition according to the invention can increase the expression of p-4E-BP1 or p-p70S6K1 protein.
  • composition according to the present invention can reduce the expression of the MuRF1 (Muscle Ring-Finger Protein) or MaFbx (Muscle atrophy F-box).
  • MuRF1 Muscle Ring-Finger Protein
  • MaFbx MaFbx
  • representative molecules related to protein synthesis include p70S6K1, 4E-BP1, and eIF members, and these three molecules are regulated by higher mTORCs.
  • Activation of mTORc phosphorylates p70S6K1 and activated p70S6K1 phosphorylates 40S ribosomal protein S6 to increase mRNA translation.
  • Activation of mTORC also increases the activity of eIF4G and simultaneously phosphorylates 4E-BP1, both molecules involved in forming the eIF4F complex.
  • eIF4G binds to eIF4A and eIF4E to form an eIF4F complex, while when 4E-BP1 is phosphorylated, its binding ability with eIF4E is inhibited to increase the free eIF4E.
  • the latter combines with other translation initiation factors (eIF4G and eIF4A) to form an eIF4F complex, which in turn promotes translation initiation by stabilizing ribosomal structures, ultimately increasing protein synthesis.
  • MAFbx / Atrogin-1 and MuRF1 are muscle-specific ubiquitin-ligase, and are representative proteins that promote protein degradation and induce muscle reduction by attaching ubiquitin to the lysine site of the target protein, and the composition of the present invention is MuRF1 (Muscle).
  • MuRF1 Muscle
  • muscle disease is a disease reported in the art as a muscle disease caused by muscle function decrease, muscle loss, muscle wasting or muscle degeneration, and specifically, the muscle disease is atony, muscular atrophy. (muscular atrophy), muscular dystrophy, myasthenia gravis, cachexia, rigid spinesyndrome, amyotrophic lateral sclerosis, Charco-Marie-Tooth disease Tooth disease) and sarcopenia may be any one or more selected from the group consisting of, but is not limited thereto.
  • the muscle wasting or degeneration occurs due to the whole factor, acquired factors, aging, etc., muscle wasting is characterized by a gradual loss of muscle mass, weakening and degeneration of the muscle, in particular skeletal or veterinary and heart muscle.
  • the pharmaceutical composition for preventing or treating muscle diseases according to the present invention is not particularly limited as long as it contains ionone or a pharmaceutically acceptable salt thereof.
  • the dose of the ionone is in a concentration of 0.1 ⁇ M to 1000 ⁇ M. It may include, but is not limited to such.
  • the ionone is less than the concentration range, there is a problem that the protein synthesis and degradation activity in the muscle cells is lowered, so that it is difficult to exert the effect of preventing or treating muscle diseases, and if the ionone exceeds the concentration range, cytotoxic There may be toxicity concerns, including.
  • the pharmaceutical composition for preventing or treating muscle diseases according to the present invention is in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral formulations, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. It may be formulated and used, and may include suitable carriers, excipients or diluents commonly used in the manufacture of pharmaceutical compositions for formulation.
  • the carrier or excipient or diluent may be lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicide, cellulose, methyl cellulose, undetermined. And various compounds or mixtures including vaginal cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
  • diluents or excipients such as fillers, weights, binders, wetting agents, disintegrating agents, surfactants.
  • Solid preparations for oral administration may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like in the ionone.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin and the like.
  • lubricants such as magnesium stearate and talc may also be used.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin. .
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol gelatin and the like can be used.
  • the preferred dosage of the pharmaceutical composition for preventing or treating muscle diseases according to the present invention depends on the patient's condition, weight, degree of disease, drug form, route of administration, and duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, it may be administered at 0.0001 to 2,000 mg / kg, preferably at 0.001 to 2,000 mg / kg. Administration may be once a day or may be divided several times. However, the scope of the present invention is not limited by the above dosage.
  • the pharmaceutical composition for preventing or treating muscle diseases according to the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes. All modes of administration may be administered, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the present invention provides a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening including ionone or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the ionone are as described above.
  • Muscle growth can occur by increasing the fiber size and / or by increasing the number of fibers.
  • the growth of the muscle can be measured by A) increase in wet weight, B) increase in protein content, C) increase in number of muscle fibers, and D) increase in diameter of muscle fibers.
  • An increase in muscle fiber growth can be defined as an increase in diameter when the diameter is defined as the shortening of the ellipsoid in cross section.
  • Useful therapeutic agents include, but are not limited to, wetting gain, protein content, and / or in animals with muscle degeneration at least 10% compared to control animals previously treated similarly (ie, animals with degenerated muscle tissue not treated with muscle growth compounds). Increasing the diameter by at least 10%, more preferably at least 50%, and most preferably at least 100%.
  • Compounds that increase growth by increasing the number of muscle fibers are useful as therapeutic agents when they increase the number of muscle fibers in diseased tissues by at least 1%, more preferably at least 20%, and most preferably at least 50%. These percentage values are relative to the basal level in untreated and disease-free comparative mammals or when the compound is administered locally and in contrast to disease-free muscle.
  • Muscle regeneration refers to the process by which new muscle fibers are formed from myoblasts.
  • Useful therapeutic agents for regeneration increase the number of new fibers at least about 1%, more preferably at least 20%, and most preferably at least 50%, as described above.
  • Myocyte differentiation refers to the induction of muscle developmental programs that specify components of muscle fibers such as contractile organs (myofibril).
  • Useful therapeutic agents for differentiation may comprise at least about 10%, more preferably at least 50%, and most preferably at least 100% of all myofiber components in diseased tissues, as compared to equivalent tissues in similarly treated control animals. Increase.
  • the myotubes of the mouse myoblasts significantly increased.
  • the ionone of the present invention can suppress muscle loss and promote muscle growth by increasing the thickness of myotubes in mouse myoblasts.
  • ionone of the present invention can increase the amount of muscle by increasing the phosphorylation of 4E-BP1 and p70S6K protein in mouse myoblasts and inhibiting MuRF1 and Mafbx / atrogin1 gene expression.
  • the present invention provides a health functional food composition for preventing muscle diseases or improving muscle function, including ionone or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the ionone and muscle diseases are as described above.
  • the present invention provides a health functional food composition for promoting muscle differentiation, muscle regeneration or muscle strengthening including ionone or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the ionone are as described above.
  • the ionone when used as an additive of the health functional food, it may be added as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient can be appropriately determined depending on the purpose of use, such as prevention, health or treatment.
  • Formulations of dietary supplements may be in the form of powders, granules, pills, tablets, capsules, as well as in the form of general foods or beverages.
  • the foodstuff which can add the said substance is a dairy product including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, etc.
  • Various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexes, etc. may include all foods in a conventional sense.
  • the ionone may be added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less based on 100 parts by weight of the raw material in the manufacture of food or beverage.
  • the amount may be below the above range, and the present invention has no problem in terms of safety in terms of using fractions from natural products. The above amount can also be used.
  • the beverage in the health functional food according to the present invention may contain various flavors or natural carbohydrates, etc. as an additional ingredient, as in general drinks.
  • the above-mentioned natural carbohydrates may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol.
  • sweetening agent natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame, and the like can be used.
  • the ratio of the natural carbohydrate may be about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 mL of the beverage according to the present invention.
  • composition for improving sleep of the present invention may contain fruit flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components can be used independently or in combination.
  • the ratio of such additives is not limited, but is generally selected from the range of 0.01 to 0.1 parts by weight relative to 100 parts by weight of the health functional food of the present invention.
  • the present invention provides a composition for animal feed for preventing or improving muscle diseases, including ionone or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the ionone are as described above.
  • the present invention provides a composition for promoting animal differentiation, muscle regeneration or muscle strengthening, comprising ionone or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the ionone are as described above.
  • the livestock is preferably one kind of livestock selected from the group consisting of cattle, pigs, chickens, ducks, goats, sheep and horses, but is not limited thereto.
  • the feed composition may include a feed additive.
  • the feed additive of the present invention corresponds to a feed supplement in the Feed Control Act.
  • feed may refer to any natural or artificial diet, one meal, or the like, or a component of the one meal, for the animal to eat, ingest, and digest.
  • the kind of the feed is not particularly limited, and may be used a feed commonly used in the art.
  • Non-limiting examples of the feed may include plant feeds such as cereals, fruits, food processing by-products, algae, fibres, pharmaceutical by-products, oils, starches, gourds or grain by-products; And animal feeds such as proteins, minerals, fats and oils, minerals, fats and oils, single cell proteins, zooplankton or foods. These may be used alone or in combination of two or more thereof.
  • the feed additive may additionally contain a carrier that is acceptable to the unit animal.
  • the feed additive may be added as it is, or a known carrier, stabilizer, or the like. If necessary, various nutrients such as vitamins, amino acids, minerals, antioxidants, and other additives may be added. Powders, granules, pellets, suspensions and the like may be in a suitable state.
  • the unit animal may be supplied alone or mixed with the feed.
  • the present invention provides a cosmetic composition for improving muscle function, including ionone (Ionone) or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the ionone are as described above.
  • the cosmetic composition of the present invention contains ionone as an active ingredient and a dermatologically acceptable excipient with a basic cosmetic composition (washing agents such as cosmetics, creams, essences, cleansing foams and cleansing water, packs, body oils), color cosmetic compositions (Foundation, lipstick, mascara, makeup base), hair product composition (shampoo, rinse, hair conditioner, hair gel) and soap and the like.
  • a basic cosmetic composition washing agents such as cosmetics, creams, essences, cleansing foams and cleansing water, packs, body oils
  • color cosmetic compositions Fraundation, lipstick, mascara, makeup base
  • hair product composition shampoo, rinse, hair conditioner, hair gel
  • soap and the like soap and the like.
  • the excipients include, but are not limited to, emollients, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners and solvents.
  • fragrances, pigments, fungicides, antioxidants, preservatives and moisturizing agents may be further included, and may include thickeners, inorganic salts, synthetic polymer materials and the like for the purpose of improving the properties.
  • the ionone may be easily added to the face wash and the soap base.
  • the cream may be prepared by adding ionone or a salt thereof to a cream base of a general oil-in-water type (O / W).
  • the content of ionone contained in the cosmetic composition of the present invention is not limited thereto, but is preferably 0.001 to 10% by weight, and more preferably 0.01 to 5% by weight based on the total weight of the composition. If the content is less than 0.001% by weight, the desired anti-aging or anti-wrinkle effect may not be expected, and when the content is more than 10% by weight, there may be difficulty in preparing a safety or formulation.
  • the present invention is a method for preventing or treating muscle diseases, the method for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising administering or taking a pharmaceutical composition comprising ionone or a salt thereof as an active ingredient to an individual.
  • a pharmaceutical composition comprising ionone or a salt thereof as an active ingredient to an individual.
  • the present invention also provides a use for preventing or treating muscle diseases, promoting muscle differentiation, muscle regeneration or muscle strengthening of a composition comprising ionone or a salt thereof as an active ingredient.
  • the composition comprising the ionone of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient increases 4E-BP1 and p70S6K1 protein phosphorylation in myoblasts, and inhibits MuRF1 and MaFbx / atrogin1 gene expression.
  • muscle diseases caused by muscle function deterioration muscle wasting or muscle degeneration, muscle differentiation, muscle regeneration, and muscle mass can be shown to enhance muscle strength, and can inhibit muscle loss, for preventing or treating muscle diseases, muscle differentiation It can be used for palpation, muscle regeneration and muscle mass increase or muscle function improvement.
  • Mouse myoblast cell lines (C2C12 cells) were purchased from ATCC (Manassas, VA, USA), and the cells were purchased at 37 ° C., 5% CO using 10% fetal bovine serum media (Gibco-BRL). Incubated in 2 incubators. When the cultured cells became 80% confluent, they were differentiated into myotubes using 2% horse serum media (Gibco-BRL).
  • dexamethasone distalmethasone, dexa; Sigma
  • beta-ionone CAS Number 14901-07-6, Sigma
  • Dexamethasone (dexamethasone, dexa; Sigma) 50 ⁇ M was treated in the same manner as in Example 1.
  • the myotube according to Example 1 was washed twice with PBS (Phosphate buffered saline) and fixed with 100% methanol for 10 minutes. When the fixation was completed, the resultant was dried for 10 minutes at room temperature and then stained for 30 minutes by dropping Giemsa-wright staining solution (Asan Pharmaceutical, Seoul) that specifically stained myotubes.
  • PBS Phosphate buffered saline
  • the stained myotubes were taken at X100 and X40 magnification using a fluorescence microscope (IX 71, Olympus) and analyzed using image J software (USA). Six sections of each well were randomly selected and micrographed. At least 100 myoblast thickness, length and fusion index were analyzed from each well (3 replicates / Group).
  • Trizol solution 334 ⁇ l was added per 1 X 10 7 cells of mouse myoblasts, and then centrifuged at 12,000 X g for 10 minutes. After transferring the supernatant to a new tube, 67 ⁇ l of chloroform was added and vortexed. Again, the supernatant was transferred to a new tube and isopropanol was added so that the ratio of the supernatant to isopropanol was 1: 1.
  • RNA samples extracted from mouse myoblasts were synthesized by reverse transcription using oligo dT primers and superscript reverse transcriptase (GIBCO BRL, Gaithersburg, MD, USA). PCR was performed using 5 'and 3' flanking sequences of the gene cDNA to be amplified as a template and cDNA obtained through reverse transcription, and the primer sequences used are shown in Table 1 below. 1 ⁇ l of the amplified PCR product was electrophoresed on a 1% agarose gel to confirm the DNA band.
  • p70S6K1, phopho-p70S6K1 (p-p70S6K1), 4E-BP1, phospho-4E-BP1 (p-4E-BP1) and GAPDH were used as primary antibodies.
  • the proteins were visualized on an X-ray film using an ECL Western blot detection kit (RPN2106, Amersham, Arlington Heights, IL, USA). Bands visualized on the X-ray film were scanned and quantified using Quantity One analysis software (Bio-Rad).
  • FIG. 2 is a graph showing changes in the expression of molecules related to protein degradation and synthesis in mouse myoblasts treated with ionone.
  • FIG. 2A in Comparative Example 1, the amount of p-4E-BP1 and p-p70S6K1 proteins related to protein synthesis was significantly reduced compared to normal cells (Basal) (FIG. 2A). Genes MaFbx / atrogin1 and MuRF1 expression can be seen to increase significantly (Fig. 2B).
  • FIG. 2A For Example 1 treated with ionone, the amount of p-4E-BP1 and p-p70S6K protein reduced by dexamethasone was significantly increased again (FIG. 2A), and the expression of MuRF1 and MaFbx / atrogin1 was significantly reduced.
  • ionone may be involved in ultimately increasing muscle mass by increasing 4E-BP1 and p70S6K1 protein phosphorylation in mouse myoblasts and inhibiting MuRF1 and MaFbx / atrogin1 gene expression.
  • mice Twenty five-week-old male C57BL / 6N mice (mating, Korea) were adapted to a laboratory environment for one week as a commercial rodant chow, and then three groups (Chow, HFD, and Ionone) according to the ingot method. 8 animals per group were randomly reared for 10 weeks.
  • the obesity induction diet used in this study was a high fat diet (HFD: 40% fat calorie, 17 g lard + 3% corn oil / 100 g diet) and was supplemented with ionone-supplemented high. fat diet, Ionone) had the same composition as HFD but contained 0.2% ionone (Table 2). Chow fed a commercial rodent chow. Ion was purchased from Sigma-Aldrich.
  • HFD High fat Control diet
  • Ionon ionone Supplementary diet
  • Casein 200 200 DL-Methionine 3 3 Corn starch 111 109 Sucrose 370 370 cellulose 50 50 Corn oil 30 30 Laad 170 170 Vitamin complex 12 12 Mineral complex 42 42 Choline Bitartrate 2 2 cholesterol 10 10 tert-butyhydroquinone 0.04 0.04 Test substance (ionone) - 2 Total (g) 1,000 1,000
  • grip strength was measured using the four feet of the mouse at 10 weeks of breeding.
  • the grip force measuring device equipped with a wire mesh (20 x 10 cm) (Daejong Equipment Industry, Korea) measured the force (N) of the wire mesh of the mouse a total of five times, and at least 1 minute rest between measurements. Gave time.
  • the experimental results were obtained by dividing the measured force (N) and weight (kg).
  • the muscle tissue of the mouse was extracted, fixed in 10% formalin, and then stained with Hematoxylin and eosin (H & E) by a Korean CFC (Gyeonggi-do, Korea) and observed using an optical microscope (IX71, Olympus, JPN). Pictures were taken using a camera (DP71, Olympus, JPN).
  • Ionone significantly observed the fiber diameters of the rectus femoris (7%, FIG. 4A) and soleus (5%, FIG. 4B) in mice fed high fat diet. Increased by enemy. Therefore, Ionon showed very good skeletal muscle increase effect in high fat diet induced muscle loss animal model.
  • the above ingredients were mixed and filled in an airtight cloth to prepare a powder.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the above components are dissolved in purified water according to a conventional preparation method, dissolved in purified water, and then lemon juice is added in an appropriate amount. After adjusting to 100 mL in total, sterilized and filled in a brown bottle to prepare a liquid formulation.
  • Vitamin B6 0.5 mg
  • composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method.
  • the granules may be prepared and used for preparing a health food composition according to a conventional method.
  • the resulting solution is filtered and obtained in a sterilized 2 L container, sealed sterilization and then refrigerated and stored Used to prepare the healthy beverage composition of the invention.
  • composition ratio is mixed with a component suitable for a favorite beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
  • the compounding ratio is mixed with a component suitable for nutritional longevity in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a conventional manufacturing method in the cosmetic field.
  • the above blending ratio is mixed composition of a component suitable for a flexible softener in a preferred embodiment, but the blending ratio may be arbitrarily modified, it can be prepared according to the manufacturing method in the general cosmetic field.
  • the compounding ratio is mixed with a component suitable for nourishing cream in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a conventional manufacturing method in the cosmetic field.
  • the compounding ratio is mixed with a component suitable for a massage cream in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a manufacturing method in the general cosmetic field.
  • the compounding ratio is mixed with a component suitable for a pack in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a manufacturing method in the general cosmetic field.
  • the compounding ratio is mixed with a component suitable for a gel in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a conventional manufacturing method in the cosmetic field.
  • the blending ratio is a relatively suitable composition for the cosmetic composition in a preferred embodiment, but can be applied to cosmetics of various uses, including other color cosmetics, according to the efficacy that can be applied to a thin coating on the human body, that is, Ointment may be used for manufacturing, and the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
  • composition 0.1-10%
  • Vitamin E 0.01 ⁇ 0.1%
  • a feed was prepared as follows.

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Abstract

La présente invention concerne une composition, comprenant comme principe actif de l'Ionone ou un sel pharmaceutiquement acceptable de celle-ci, destinée à la prévention ou au traitement de troubles musculaires, ou à l'amélioration de la fonction musculaire.
PCT/KR2018/000297 2017-01-06 2018-01-05 Composition, comprenant comme principe actif de l'ionone ou un sel pharmaceutiquement acceptable de celle-ci, destinée à la prévention ou au traitement de troubles musculaires Ceased WO2018128478A1 (fr)

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Citations (4)

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US20060240131A1 (en) * 2002-08-15 2006-10-26 Warrenburg William S Process for effecting the relaxation of muscles of a human by means of fragrance
US7507425B2 (en) * 2005-09-27 2009-03-24 The Quigley Corporation Method for the treatment of cachexia
KR20100015184A (ko) * 2008-08-04 2010-02-12 (주)에이치케이바이오텍 항암효과를 가지는 버섯균사체배양 추출물 및 이것의제조방법
KR20160138926A (ko) * 2015-05-26 2016-12-06 연세대학교 산학협력단 근육 질환 예방, 개선 또는 치료용 또는 근 기능 개선용 조성물

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KR102175466B1 (ko) * 2013-11-29 2020-11-06 (주)아모레퍼시픽 아이오논(ionone) 유도체 화합물
JP6728344B2 (ja) * 2015-05-26 2020-07-22 ニュートゥリー カンパニー リミテッド 桔梗抽出物を含有する筋肉疾患の予防及び治療用又は筋機能改善用組成物

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US20060240131A1 (en) * 2002-08-15 2006-10-26 Warrenburg William S Process for effecting the relaxation of muscles of a human by means of fragrance
US7507425B2 (en) * 2005-09-27 2009-03-24 The Quigley Corporation Method for the treatment of cachexia
KR20100015184A (ko) * 2008-08-04 2010-02-12 (주)에이치케이바이오텍 항암효과를 가지는 버섯균사체배양 추출물 및 이것의제조방법
KR20160138926A (ko) * 2015-05-26 2016-12-06 연세대학교 산학협력단 근육 질환 예방, 개선 또는 치료용 또는 근 기능 개선용 조성물

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