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WO2018128483A1 - Composition pour la prévention ou le traitement de maladies musculaires, comprenant de l'ocimène, de l'eugénol ou un sel pharmaceutiquement acceptable de ceux-ci en tant que principe actif - Google Patents

Composition pour la prévention ou le traitement de maladies musculaires, comprenant de l'ocimène, de l'eugénol ou un sel pharmaceutiquement acceptable de ceux-ci en tant que principe actif Download PDF

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Publication number
WO2018128483A1
WO2018128483A1 PCT/KR2018/000306 KR2018000306W WO2018128483A1 WO 2018128483 A1 WO2018128483 A1 WO 2018128483A1 KR 2018000306 W KR2018000306 W KR 2018000306W WO 2018128483 A1 WO2018128483 A1 WO 2018128483A1
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muscle
eugenol
composition
active ingredient
ocimene
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PCT/KR2018/000306
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English (en)
Korean (ko)
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박태선
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연세대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47B—TABLES; DESKS; OFFICE FURNITURE; CABINETS; DRAWERS; GENERAL DETAILS OF FURNITURE
    • A47B77/00—Kitchen cabinets
    • A47B77/04—Provision for particular uses of compartments or other parts ; Compartments moving up and down, revolving parts
    • A47B77/14—Provision for particular uses of compartments or other parts ; Compartments moving up and down, revolving parts by incorporation of racks or supports, other than shelves, for household utensils
    • 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
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47B—TABLES; DESKS; OFFICE FURNITURE; CABINETS; DRAWERS; GENERAL DETAILS OF FURNITURE
    • A47B45/00—Cabinets, racks or shelf units, characterised by features enabling enlarging in height, length, or depth
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47B—TABLES; DESKS; OFFICE FURNITURE; CABINETS; DRAWERS; GENERAL DETAILS OF FURNITURE
    • A47B46/00—Cabinets, racks or shelf units, having one or more surfaces adapted to be brought into position for use by extending or pivoting
    • 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
    • A61K31/01—Hydrocarbons
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K8/31—Hydrocarbons
    • 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
    • A61K8/34—Alcohols
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16B—DEVICES FOR FASTENING OR SECURING CONSTRUCTIONAL ELEMENTS OR MACHINE PARTS TOGETHER, e.g. NAILS, BOLTS, CIRCLIPS, CLAMPS, CLIPS OR WEDGES; JOINTS OR JOINTING
    • F16B12/00—Jointing of furniture or the like, e.g. hidden from exterior
    • F16B12/10—Jointing of furniture or the like, e.g. hidden from exterior using pegs, bolts, tenons, clamps, clips, or the like
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47B—TABLES; DESKS; OFFICE FURNITURE; CABINETS; DRAWERS; GENERAL DETAILS OF FURNITURE
    • A47B2220/00—General furniture construction, e.g. fittings
    • A47B2220/0036—Brackets

Definitions

  • the present invention relates to a composition for the prevention or treatment of muscle diseases, comprising an ocimen, eugenol 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 prevent or treat muscle diseases, including ocimene, eugenol or pharmaceutically acceptable salts thereof as an active ingredient, to promote muscle differentiation, muscle regeneration or strengthening muscle composition To provide.
  • Still another object of the present invention is to prevent or improve muscle disease, promote muscle differentiation, promote muscle differentiation, muscle regeneration, or strengthen muscles, including ocimene, eugenol, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a composition for livestock feed is provided.
  • Still another object of the present invention is to provide a cosmetic composition for improving muscle function, including ocimene, eugenol, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is a method for preventing or treating muscle diseases, comprising the step of administering to or administering to a subject a pharmaceutical composition comprising ocimene, eugenol or a salt thereof as an active ingredient, muscle differentiation It is to provide a method of palpation, muscle regeneration or muscle strengthening.
  • 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 ocimene, eugenol, or a salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle diseases, including ascimene, eugenol, 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 comprising an ocimene (eumenol), eugenol (eugenol) 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 asocimen (eumenol), eugenol (eugenol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • asocimen eumenol
  • eugenol eugenol
  • 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 an ocimene, eugenol 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 as ocimene (eumenol), eugenol (eugenol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a composition for promoting animal differentiation, muscle regeneration, or muscle strengthening, comprising ocimene, eugenol, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a cosmetic composition for improving muscle function comprising an ocimene, eugenol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a method for preventing or treating muscle diseases, which comprises administering or administering to a subject a pharmaceutical composition comprising ocimene, eugenol, 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 ocimene, eugenol, or a salt thereof as an active ingredient. .
  • the present invention provides a use for the prevention or treatment of muscle diseases of the composition comprising an ocimene (eumenol), eugenol (eugenol) or salts thereof as an active ingredient.
  • the present invention provides a muscle differentiation, muscle regeneration or muscle strengthening use of the composition comprising an ocimene (eumenol), eugenol 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 ocimene, eugenol, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Knol can increase the expression of proteins involved in muscle protein synthesis and muscle mass in muscle cells, and the expression of enzymes involved in muscle protein degradation can be suppressed from the mRNA level, thereby reducing muscle function, muscle exhaustion or muscle degeneration.
  • muscle differentiation, muscle regeneration, and muscle mass increase effect can be strengthened, and the muscle reduction can be suppressed, for the prevention or treatment of muscle diseases, muscle differentiation, muscle regeneration and muscle mass increase or muscle function improvement It can be used to.
  • FIG. 1 shows the change in the thickness of myotube in mouse myoblasts treated with osmenene.
  • FIG. 1A is a microscopic image of Giemsa-Wright stained root canal cells.
  • FIG. 1B is a result of measuring the diameter of the root canal cells. Each value is the mean ⁇ standard error of three crystals 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 ossimens.
  • 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 is a result of confirming the increase in muscle strength by the intake of oscimen from the change in body weight (A), hanging time (B) and grip force (C) of the high-fat diet group (HFD) and Ocimene intake group (Ocimene) mice.
  • FIG. 4 shows the thickness change of myotube in eugenol-treated mouse myoblasts.
  • FIG. 4A is a microscopic image of Giemsa-Wright stained myotubes
  • FIG. 4B is a result of measuring the diameter of myotubes.
  • Each value is the mean ⁇ standard error of three crystals in three independent wells. P ⁇ 0.05 indicates statistical significance.
  • Figure 5 shows the expression changes of the protein-related synthesis and synthesis in eugenol-treated mouse myoblasts.
  • 5A shows the protein levels of p-4E-BP1, Total 4E-BP1, p-p70S6K1, and Total p70S6K1, and
  • FIG. 5B 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 6 is a result of confirming the increase in muscle strength by the eugenol intake from the weight (A), hanging time (B) and grip force (C) changes of the high-fat diet group (HFD) and eugenol intake group (Eugenol) mice.
  • Figure 7 is a result of confirming the fiber diameter of the muscle tissue of the mouse by eugenol intake in the rectus femoris (A), soleus (B) and the gastrocnemius (gastronecmius). 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 shown that the eugenol, which is a monoterpene-based compound or phenylpropanoid-based compound, inhibits the degradation of muscle protein and promotes the synthesis, thereby improving muscle growth and muscle loss. By confirming, the present invention was completed.
  • 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, including ascimene, eugenol, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the five cement is as a colorless, clear liquid or pale yellow, water is not melted, soluble in oil and ethanol, as monoterpenes (monoterpene) based compound as a component constituting the floral fragrance of many plants, the structural formula is C 10 H 16 , molecular weight is 136.2 g / mol.
  • Osmenene may be represented by the following Chemical Formula 1, and the IUPAC name is (3E) -3,7-dimethylocta-1,3,6-triene, (E) -beta-ocimene, trans-beta-ocimene, beta- ocimene, (3E) -3,7-dimethylocta-1,3,6-triene, beta-ocimene and others.
  • osmenene within the range having the same efficacy as the above-mentioned osmenene, it may include an osmenene hydrate, an osmenene derivative, and the like, and may also include a solvent compound or stereoisomer thereof.
  • the method for obtaining the osmenene is not particularly limited, and may be isolated from the plant containing the osmenene, chemically synthesized using a known manufacturing method, or commercially available.
  • the plant containing the ossimen is Ocimum belonging to the Lamiaceae basilicum L., Evodia belonging to the Tangerine rutaecarpa , Fruit, Agathosma Betulina , Pimenta dioica ( Allspice ), Mentha arvensis piperascens (mint), Psidium guajava (Guava), Lavandula latifolia (spike lavender), Annona squamosa (custard apple), Tagetes minuta (Lanxian), Lantana camara (Lantana), Lavandula x intermedia (Lavantin), Laurus nobilis (laurel), Pimenta acris (bay), Perilla frutescens (leaf), Citrus
  • the eugenol is a pale yellow liquid with a strong aroma, Syzygium aromaticum (Clove, Clove), Cinnamomum zeylanicum (Cinnamon, cinnamon), Ocimum gratissimum (Basil, basil), Anethum graveolens (Dill), Pimpinella anisum (Anise, Anise), Laurus Nobilis (Bay laurel, laurel), Apium graveolens (Celery, celery), Melissa officinalis (Lemon balm, Melissa), Pimenta racemosa (Bay) and other ingredients mainly contained in phenylpropanoid compounds , Structural formula is C 10 H 12 O 2 , molecular weight is 164.20 g / mol.
  • Eugenol may be represented by the following formula (2), has a nickname such as aldehyde C-10, caprinaldehyde, decyl aldehyde, eugenoldehyde.
  • eugenol may include a eugenol hydrate, eugenol derivatives, and the like, and may also include a solvent compound or stereoisomer thereof.
  • the method for obtaining the eugenol is not particularly limited, and may be isolated from the plant containing the eugenol, 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, 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 an omenmen, eugenol or a pharmaceutically acceptable salt thereof. It may include a concentration of 0.1 ⁇ M to 1000 ⁇ M, but is not limited thereto.
  • concentration range a concentration of 0.1 ⁇ M to 1000 ⁇ M, but is not limited thereto.
  • the ocimen, yugeol is less than the concentration range, there is a problem that the protein synthesis and degradation activity in the muscle cells is lowered, it is difficult to exhibit the effect of preventing or treating muscle diseases, and the ocimen, yugeol exceeds the concentration range In such cases, there may be concerns of toxicity, including cytotoxicity.
  • 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 oscimen and eugenol.
  • 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 an ocimene (eumenol), eugenol (eugenol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • an ocimene eumenol
  • eugenol eugenol
  • a pharmaceutically acceptable salt thereof as an active ingredient.
  • 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 ocimen and eugenol of the present invention when treated with ocymen and eugenol in mouse myoblasts reduced by dexamethasone, dexamethasone significantly increased myotubes of the mouse myoblasts You can check it. That is, the ocimen and eugenol of the present invention can suppress muscle loss and promote muscle growth by increasing the thickness of myotubes in mouse myoblasts.
  • the present invention provides a health functional food composition for preventing muscle diseases or improving muscle function, including asocimen (eumenol), eugenol (eugenol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • asocimen eumenol
  • eugenol eugenol
  • 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 an ocimene, eugenol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a health functional food composition for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising an ocimene, eugenol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Specific details of the osmenene, eugenol are as described above.
  • the acemen and eugenol as an additive of the health functional food, it may be added as it is or used with other food or food ingredients, It can be used properly.
  • 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 acemen and eugenol 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.
  • 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 as ocimene (eumenol), eugenol (eugenol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • ocimene eumenol
  • eugenol eugenol
  • a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a composition for promoting animal differentiation, muscle regeneration, or muscle strengthening, comprising ocimene, eugenol, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a composition for promoting animal differentiation, muscle regeneration, or muscle strengthening comprising ocimene, eugenol, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • osmenene, eugenol 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 an ocimene (eumene), eugenol (eugenol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a cosmetic composition for improving muscle function comprising an ocimene (eumene), eugenol (eugenol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cosmetic composition of the present invention contains an ocimen, eugenol 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 compositions (shampoo, rinse, hair conditioner, hair gel) and soaps 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 foundation, lipstick, mascara, makeup base
  • hair product compositions shampoo, rinse, hair conditioner, hair gel
  • soaps and the like soaps 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.
  • thickeners inorganic salts, synthetic polymer materials and the like for the purpose of improving the properties.
  • the cream it may be prepared by adding oscimen, eugenol, or a salt thereof to a cream base of a general oil-in-water type (O / W).
  • 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.
  • the content of the acimen and eugenol 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 comprising the step of administering or taking a pharmaceutical composition comprising an ocimene, eugenol or a salt thereof as an active ingredient to an individual, promoting muscle differentiation, Provides muscle regeneration or muscle strengthening methods.
  • the present invention provides a use for preventing or treating muscle diseases, promoting muscle differentiation, muscle regeneration, or muscle strengthening of a composition comprising ocimene, eugenol, or a salt thereof as an active ingredient.
  • the composition comprising an oscimen, eugenol or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient increases 4E-BP1 and p70S6K1 protein phosphorylation in myoblasts and expresses MuRF1 and MaFbx / atrogin1 genes.
  • By inhibiting the muscle function caused by muscle function deterioration, muscle wasting or muscle degeneration, muscle differentiation, muscle regeneration, muscle mass increase effect can be exhibited, and muscle reduction can be suppressed, for preventing or treating muscle diseases. It can be used for promoting muscle differentiation, muscle regeneration and 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 (dexxathasone, dexa; Sigma) was treated in the same manner as in Example 1, and was used independently for the osmenene and eugenol experiments.
  • 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 X20 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, and at least 100 myoblast thicknesses 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).
  • Figure 2 is a graph showing the change in the expression of protein degradation and synthesis in the mouse myoblast treated mice.
  • 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).
  • Example 1 treated with osmenene the amount of p-4E-BP1 and p-p70S6K protein reduced by dexamethasone was again significantly increased (FIG. 2A), and the expression of MuRF1 and MaFbx / atrogin1 was significantly reduced. It can be confirmed (Fig.
  • osmenene 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 Sixteen-week-old male C57BL / 6N mice (mating, Korea) were acclimated to a laboratory environment for one week as a commercial rodant chow, and then grouped into two groups (HFD group, Ocimene group) according to the egg mass method. 8 dogs were randomly placed and kept 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 orcimene-supplemented high.
  • the fat diet (ocimene) had the same composition as HFD but contained 0.2% of osmenene (Table 2).
  • HFD High fat Control diet
  • Oshimen ocimene
  • Supplementary diet 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).
  • FIG. 5 is a graph showing changes in the expression of proteolytic and synthetic molecules in eugenol-treated mouse myoblasts.
  • FIG. 5A the amount of p-4E-BP1 and p-p70S6K1 proteins related to protein synthesis was significantly reduced compared to normal cells (Basal) (FIG. 5A).
  • FIG. 5B Genes MaFbx / atrogin1 and MuRF1 expression was found to increase significantly (Fig. 5B).
  • FIG. 5A For example 2 treated with eugenol, again significantly increased the amount of p-4E-BP1 and p-p70S6K proteins reduced by dexamethasone (FIG. 5A) and significantly reduced the expression of MuRF1 and MaFbx / atrogin1.
  • eugenol is thought to 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.
  • the experimental diet was bred in the same manner as in Experiment 3 except that Eugenol was used as a diet supplemented with Eugenol (Eugenol-supplemented high fat diet, Eugenol).
  • 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). The photograph was taken using a digital camera (DP71, Olympus, JPN).
  • 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 with the following composition.

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Abstract

La présente invention concerne une composition pour la prévention ou le traitement de maladies musculaires ou l'amélioration de la fonction musculaire, comprenant de l'ocimène, de l'eugénol ou un sel pharmaceutiquement acceptable de ceux-ci en tant que principe actif.
PCT/KR2018/000306 2017-01-06 2018-01-05 Composition pour la prévention ou le traitement de maladies musculaires, comprenant de l'ocimène, de l'eugénol ou un sel pharmaceutiquement acceptable de ceux-ci en tant que principe actif WO2018128483A1 (fr)

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KR102223248B1 (ko) 2019-03-29 2021-03-05 콜마비앤에이치 주식회사 당귀 추출물, 천궁 추출물 및 작약 추출물을 포함하는 근력 개선 또는 근감소증 예방, 개선 또는 치료용 조성물
KR102752074B1 (ko) * 2020-10-30 2025-01-10 (주)휴온스 차즈기 추출물을 유효성분으로 하는 근 위축증 또는 근 감소증 예방 또는 치료용 조성물
KR102750257B1 (ko) * 2021-09-28 2025-01-03 동의대학교 산학협력단 로즈마리 추출물을 유효 성분으로 포함하는 근감소증 예방 또는 개선용 조성물
KR102750301B1 (ko) * 2021-09-28 2025-01-03 동의대학교 산학협력단 허브 추출물 및 맥주 효모 분말을 유효 성분으로 포함하는 근감소증 예방 또는 개선용 조성물
KR102748036B1 (ko) * 2021-09-28 2024-12-27 동의대학교 산학협력단 라벤더 추출물을 유효 성분으로 포함하는 근감소증 예방 또는 개선용 조성물
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