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WO2018128480A1 - Composition destinée à la prévention ou au traitement de maladies musculaires, comprenant de l'acide géranique ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif - Google Patents

Composition destinée à la prévention ou au traitement de maladies musculaires, comprenant de l'acide géranique ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif Download PDF

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WO2018128480A1
WO2018128480A1 PCT/KR2018/000301 KR2018000301W WO2018128480A1 WO 2018128480 A1 WO2018128480 A1 WO 2018128480A1 KR 2018000301 W KR2018000301 W KR 2018000301W WO 2018128480 A1 WO2018128480 A1 WO 2018128480A1
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Prior art keywords
muscle
geranic acid
active ingredient
composition
preventing
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Korean (ko)
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • 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
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • 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 geranic acid 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.
  • myotropia decreases basal metabolic rate, increases insulin resistance, promotes type 2 diabetes, and increases the risk of hypertension and cardiovascular disease by 3-5 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, comprising geranic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a functional food composition for preventing or improving muscle function, promoting muscle differentiation, muscle regeneration or muscle strengthening, including geranic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a functional food composition for preventing or improving muscle function, promoting muscle differentiation, muscle regeneration or muscle strengthening including geranic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a cosmetic composition for improving muscle function, including geranic acid 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 diseases, comprising the steps of administering or taking a pharmaceutical composition comprising geranic acid or a salt thereof as an active ingredient, promoting muscle differentiation, muscle regeneration, or It is to provide muscle strengthening methods.
  • 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 geranic acid or a salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle diseases comprising geranic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition may increase the expression of p-AKT 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 comprising geranic acid (geranic acid) 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 geranic acid 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 comprising geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a composition for animal feed for preventing or improving muscle diseases, including geranic acid 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 geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a cosmetic composition for improving muscle function comprising geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for preventing or treating muscle diseases, comprising administering or taking a pharmaceutical composition comprising geranic acid or a salt thereof as an active ingredient to an individual.
  • the present invention also provides a method for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising administering or taking a composition comprising geranic acid or a salt thereof as an active ingredient to an individual.
  • the present invention provides a use for preventing or treating muscle diseases of a composition comprising geranic acid or a salt thereof as an active ingredient.
  • the present invention also provides the use of geranic acid or a salt thereof as an active ingredient to promote muscle differentiation, muscle regeneration or muscle strengthening.
  • the present invention relates to a composition for preventing or treating muscle diseases, or improving muscle function, comprising geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as the active ingredient, wherein the geranic acid is used to synthesize muscle protein in muscle cells. And increase the expression of a protein associated with an increase in muscle mass and inhibit the expression of enzymes involved in muscle protein degradation from the mRNA level, so muscle differentiation and muscle regeneration in muscle diseases due to muscle function degradation, muscle wasting or muscle degeneration. Increasing muscle mass may have an effect of strengthening muscles and may inhibit muscle loss, and may 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 the synthesis and protein degradation in mouse myoblasts treated with geranic acid.
  • FIG. 2A shows the protein levels of p-AKT and Total AKT
  • FIG. 2B shows the 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 ingesting geranic acid from changes in body weight (A), hanging time (B) and grip force (C) of normal diet group (Chow), high fat diet group (HFD) and geranic acid intake group (Geranic acid) mice This is the result of checking.
  • Figure 4 is a result of confirming the fiber diameter of the muscle tissue of the mouse by ingesting geranic acid 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 have completed the present invention by confirming that the monoterpene-based compound geranic acid has an effect on muscle enhancement and muscle loss improvement 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 geranic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the geranic acid is a colorless or pale yellow light oily liquid, insoluble in water, dissolved in alcohol or propylene glycol, and is a monoterpene-based compound used for industrial taste and aroma.
  • Structural formula is C 10 H 16 O 2
  • molecular weight is 168 g / mol.
  • Geranic acid may be represented by the following formula (1), IUPAC name is (2E) -3,7-dimethyl-2,6-octadienoic acid [(2E) -3,7-Dimethyl-2,6-octadienoic acid] And a stereoisomer of nerolic acid.
  • the geranic acid may include geranic acid hydrate, geranic acid derivative, and the like, and may also include a solvent compound and stereoisomer thereof.
  • the method for obtaining the geranic acid is not particularly limited, and it can be separated from the plant containing the geranic acid, chemically synthesized using a known production method, or commercially available.
  • composition according to the invention can increase the expression of p-AKT 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 (Muscle atrophy F-box) and MuRF1 (muscle RING finger 1) are muscle-specific ubiquitin-ligases that attach ubiquitin to the lysine site of the target protein to promote protein degradation and ultimately reduce muscle loss. It is a representative gene to induce. These two genes are regulated by higher AKT and FOXO. FOXO migrates into the nucleus and acts as a transcription factor to increase the expression of MaFbx / atrogin1 and MuRF1. In conclusion, phosphorylated AKT phosphorylates FOXO and phosphorylated FOXO fails to migrate into the nucleus, reducing the expression of MaFbx / Atrogin-1 and MuRF1.
  • the composition of the present invention may inhibit muscle loss by increasing the phosphorylation of AKT.
  • 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, Charcot-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 geranic acid or a pharmaceutically acceptable salt thereof, preferably the dose of geranic acid is 0.1 ⁇ M to 1000 ⁇ M. It may include a concentration, but is not limited thereto. At this time, when the geranic acid is less than the concentration range, there is a problem that the protein synthesis and degradation activity in muscle cells is lowered, so that it is difficult to exert the effect of preventing or treating muscle diseases, and if the geranic acid exceeds the concentration range, cytotoxicity 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 with the geranic acid.
  • 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 comprising geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the geranic acid 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 geranic acid of the present invention can suppress muscle loss and promote muscle growth by increasing the thickness of myotubes in mouse myoblasts.
  • the geranic acid of the present invention can increase the amount of muscle by increasing the phosphorylation of AKT 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 geranic acid or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the geranic acid 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 comprising geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the geranic acid are as described above.
  • the geranic acid when used as an additive of the health functional food, it may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method Can be.
  • 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 geranic acid 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 also provides a composition for animal feed for preventing or improving muscle diseases, including geranic acid or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the geranic acid are as described above.
  • the present invention provides a composition for promoting animal differentiation, muscle regeneration or muscle strengthening, comprising geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the geranic acid 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 comprising geranic acid (geranic acid) or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the geranic acid are as described above.
  • the cosmetic composition of the present invention contains geranic acid as an active ingredient and, together with a dermatologically acceptable excipient, 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
  • 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.
  • thickeners inorganic salts, synthetic polymer materials and the like for the purpose of improving the properties.
  • the cream When the cream is prepared, it can be prepared by adding geranic acid or a salt thereof to a cream base of a general oil-in-water type (O / W). To this, synthetic or natural materials, such as proteins, minerals, vitamins, etc., for the purpose of improving physical properties, such as flavors, chelating agents, pigments, antioxidants, and preservatives, may be added.
  • synthetic or natural materials such as proteins, minerals, vitamins, etc.
  • synthetic or natural materials such as proteins, minerals, vitamins, etc.
  • for the purpose of improving physical properties such as flavors, chelating agents, pigments, antioxidants, and preservatives
  • the content of geranic acid contained in the cosmetic composition of this invention is not limited to this, it is preferable that it is 0.001-10 weight% with respect to the total weight of the whole composition, and it is more preferable that it is 0.01-5 weight%. 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
  • the present invention is a method for preventing or treating muscle diseases, comprising the steps of administering or taking a pharmaceutical composition comprising geranic acid or a salt thereof as an active ingredient to an individual, promoting muscle differentiation, muscle regeneration or muscle strengthening Provide a method.
  • 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 geranic acid or a salt thereof as an active ingredient.
  • the composition comprising the geranic acid of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient increases AKT protein phosphorylation in myoblasts and inhibits the expression of MuRF1 and MaFbx / atrogin1 genes, thereby reducing muscle function, muscle In muscle diseases caused by depletion or muscle degeneration, muscle differentiation, muscle regeneration, and muscle mass can be shown to strengthen muscle strength, and can inhibit muscle loss, for preventing or treating muscle diseases, promoting muscle differentiation, and muscle regeneration. And for increasing muscle mass or improving muscle function.
  • 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 (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).
  • FIG. 1A in Comparative Example 1, myotube thickness and length of mouse myoblasts were significantly reduced compared to normal cells, and in Example 1 treated with geranic acid, dexamethasone was used. Visually, the reduced thickness and length of the myotube increased again. In quantitatively confirming the results, geranic acid significantly reduced myotube thickness (62%, FIG. 1B), fusion index (37%, FIG. 1C) and myotube length (126%, FIG. 1D), which were significantly reduced by dexamethasone. Significantly increased. From this, geranic acid was found to increase the thickness of myotube in mouse myoblasts, thereby inhibiting muscle loss and promoting muscle growth.
  • 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 the expression changes of proteolytic molecules in mouse myoblasts treated with geranic acid.
  • the amount of p-AKT protein that can inhibit the expression of MaFbx / Atrogin-1 and MuRF1 related to proteolysis was significantly reduced compared to that of normal cells (Basal) ( 2A), MaFbx / atrogin1 and MuRF1 expression, which are proteolytic genes below, were significantly increased (FIG. 2B).
  • Example 1 treated with geranic acid the amount of p-AKT protein decreased by dexamethasone was significantly increased again (FIG. 2A), and the expression of MuRF1 and MaFbx / atrogin1 was significantly decreased (FIG. 2B).
  • geranic acid is thought to be involved in ultimately increasing muscle mass by increasing AKT 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 on a commercial rodant chow, and then three groups (Chow, HFD, and geranic acid) were obtained according to the ingot method. 8 animals per group were randomly placed and 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 supplemented with geranic acid (geranic acid-supplemented).
  • high fat diet, geranic acid was the same composition as HFD but contained 0.2% geranic acid (Table 2).
  • HFD High fat Control diet
  • Geranic acid geranic acid
  • dietary supplement g / kg diet
  • Casein 200 200 DL-Methionine 3 3
  • Corn starch 111 109 Sucrose 370 370 cellulose 50 50 Corn oil 30
  • Mineral complex 42 Choline Bitartrate 2
  • cholesterol 10
  • 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).
  • mice fed geranic acid was significantly reduced by 21% than the weight of the mice fed high fat diet (FIG. 3A).
  • Geranic acid also significantly increased the holding impulse (FIG. 3B) and grip strength (FIG. 3C) of mice fed high fat diets by 111% and 28%, respectively. From these results, geranic acid was found to have a very good strength enhancing effect in high fat diet induced muscle loss animal model.
  • geranic acid was significant in the fiber diameter of the rectus femoris (8%, Figure 4A) and soleus (4%, Figure 4B) of mice fed a high-fat diet Increased by enemy. Therefore, geranic acid was found to have a 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%
  • the feed additive of Preparation Example 7 was used as an active ingredient to prepare a feed having the following composition.

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Abstract

La présente invention concerne une composition destinée à la prévention ou au traitement de maladies musculaires, ou à l'amélioration de la fonction musculaire, comprenant de l'acide géranique ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif.
PCT/KR2018/000301 2017-01-06 2018-01-05 Composition destinée à la prévention ou au traitement de maladies musculaires, comprenant de l'acide géranique ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif Ceased WO2018128480A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060189566A1 (en) * 2003-02-26 2006-08-24 Miho Komatsu Muscle building agent and preventive or remedy for muscle weakening
US20110028549A1 (en) * 2007-05-11 2011-02-03 Aisa Therapeutics Use of a monoterpene to treat or prevent stress
KR20150024586A (ko) * 2013-08-27 2015-03-09 (주)네오팜 근육 분화 촉진 및 근육 강화용 조성물 및 외용제
KR20150071932A (ko) * 2013-12-19 2015-06-29 이화여자대학교 산학협력단 Taz 단백질 활성화 유도 성분을 포함하는 근육 분화 및 근육재생용 약학적 조성물
KR20150142536A (ko) * 2014-06-12 2015-12-22 한국생명공학연구원 부틸 피리디늄 또는 이의 유도체를 포함하는 근력약화 관련 질환의 예방 또는 치료용 약학적 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060189566A1 (en) * 2003-02-26 2006-08-24 Miho Komatsu Muscle building agent and preventive or remedy for muscle weakening
US20110028549A1 (en) * 2007-05-11 2011-02-03 Aisa Therapeutics Use of a monoterpene to treat or prevent stress
KR20150024586A (ko) * 2013-08-27 2015-03-09 (주)네오팜 근육 분화 촉진 및 근육 강화용 조성물 및 외용제
KR20150071932A (ko) * 2013-12-19 2015-06-29 이화여자대학교 산학협력단 Taz 단백질 활성화 유도 성분을 포함하는 근육 분화 및 근육재생용 약학적 조성물
KR20150142536A (ko) * 2014-06-12 2015-12-22 한국생명공학연구원 부틸 피리디늄 또는 이의 유도체를 포함하는 근력약화 관련 질환의 예방 또는 치료용 약학적 조성물

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