WO2018128481A1 - Composition for preventing or treating muscular diseases, comprising indole-3-carbinol or pharmaceutically acceptable salt thereof as active ingredient - Google Patents

Composition for preventing or treating muscular diseases, comprising indole-3-carbinol or pharmaceutically acceptable salt thereof as active ingredient Download PDF

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WO2018128481A1
WO2018128481A1 PCT/KR2018/000304 KR2018000304W WO2018128481A1 WO 2018128481 A1 WO2018128481 A1 WO 2018128481A1 KR 2018000304 W KR2018000304 W KR 2018000304W WO 2018128481 A1 WO2018128481 A1 WO 2018128481A1
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muscle
indole
carbinol
active ingredient
composition
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PCT/KR2018/000304
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French (fr)
Korean (ko)
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박태선
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연세대학교 산학협력단
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    • 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
    • A23K20/116—Heterocyclic compounds
    • A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
    • 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 indole-3-carbinol 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 indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient, to promote muscle differentiation, muscle regeneration or muscle enhancement To provide a composition.
  • Still another object of the present invention is to provide a cosmetic composition for improving muscle function, including indole-3-carbinol 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 administering to or administering to a subject a pharmaceutical composition comprising indole-3-carbinol or a salt thereof as an active ingredient, It is to provide a method for promoting muscle differentiation, muscle regeneration or muscle strengthening.
  • Another object of the present invention to provide a method for preventing or treating muscle diseases, promoting muscle differentiation, muscle regeneration or muscle strengthening of a composition comprising indole-3-carbinol or a salt thereof as an active ingredient. will be.
  • 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 indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a health functional food composition for preventing muscle diseases or improving muscle function, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a health functional food composition for promoting muscle differentiation, muscle regeneration, or muscle strengthening, including indole-3-carbinol 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, which comprises indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a cosmetic composition for improving muscle function, comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for preventing or treating muscle diseases, comprising administering to or administering to a subject a pharmaceutical composition comprising indole-3-carbinol or a salt thereof as an active ingredient. .
  • the present invention provides a method for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising administering to or administering to a subject a composition comprising indole-3-carbinol or a salt thereof as an active ingredient. to provide.
  • the present invention provides a use for preventing or treating muscle diseases of a composition comprising indole-3-carbinol or a salt thereof as an active ingredient.
  • the present invention provides the use of indole-3-carbinol 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, which comprises indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • 3-carbinol 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, thus reducing muscle function, muscle wasting or muscle degeneration
  • muscle diseases caused by muscle differentiation, muscle regeneration, muscle mass increase effect can be exhibited, and can inhibit muscle loss, bar disease prevention or treatment, muscle differentiation, muscle regeneration and muscle mass increase or It can be used to improve muscle function.
  • FIG. 1 shows the thickness change of myotube in mouse myoblasts.
  • 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, and each value is the mean ⁇ standard error of three crystals in three independent wells. P ⁇ 0.05 indicates statistical significance.
  • FIG. 2 shows the expression changes of proteins involved in protein degradation and synthesis in mouse myoblasts treated with indole-3-carbinol.
  • FIG. 2A shows the protein levels of p-4E-BP1, Total 4E-BP1, p-p70S6K1, and Total p70S6K1, and
  • FIG. 2B shows gene expression levels of MaFbx and MuRF1. Each value is the mean ⁇ standard error of three determinations in three independent wells. P ⁇ 0.05 indicates statistical significance.
  • Figure 3 shows the changes in body weight (A), hanging time (B) and grip force (C) of the normal diet (Chow), high fat diet (HFD) and indole-3-carbinol mice This is a result of confirming the increase in muscle strength by indole-3-carbinol intake.
  • 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 indole-3-carbinol is a grayish white solid, which is an indole compound which is extremely unstable under acidic solution and is changed to another derivative by biological activity when exposed to gastric acid.
  • C 9 H 9 NO molecular weight is 147.17 g / mol.
  • Indole-3-carbinol may be represented by Formula 1 below, and the IUPAC name is 1H-Indol-3-ylmethanol.
  • composition according to the invention can increase the expression of p-4E-BP1 or p-p70S6K1 protein.
  • the pharmaceutical composition for preventing or treating muscle diseases according to the present invention is not particularly limited as long as it contains indole-3-carbinol or a pharmaceutically acceptable salt thereof, preferably the indole-3-carbinol
  • the dose may include, but is not limited to, a concentration of 0.1 ⁇ M to 1000 ⁇ M.
  • the indole-3-carbinol is less than the concentration range, there is a problem that the protein synthesis and degradation activity in muscle cells is lowered, it is difficult to exhibit the effect of preventing or treating muscle disease, indole-3-carbinol in the concentration range If exceeded, there may be toxicity concerns, including cytotoxicity.
  • 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.
  • 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 present invention provides a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol 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.
  • indole-3-carbinol when indole-3-carbinol was treated to mouse myoblasts reduced by dexamethasone, myotubes of the mouse myoblasts were significantly increased. can confirm. That is, the indole-3-carbinol of the present invention can suppress muscle loss and promote muscle growth by increasing the thickness of myotubes in mouse myoblasts.
  • the present invention also provides a health functional food composition for promoting muscle differentiation, muscle regeneration, or muscle strengthening, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol are as described above.
  • the indole-3-carbinol when used as an additive for the health functional food, it may be added as it is or used together with other foods or food ingredients, Can be used accordingly.
  • 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 indole-3-carbinol 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.
  • the present invention provides a composition for animal feed for preventing or improving muscle diseases, which comprises indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a composition for animal feed for preventing or improving muscle diseases which comprises indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol 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 present invention provides a cosmetic composition for improving muscle function comprising indole-3-carbinol (Indole-3-carbinol) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • indole-3-carbinol indole-3-carbinol
  • a pharmaceutically acceptable salt thereof as an active ingredient.
  • the excipients include, but are not limited to, emollients, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners and solvents.
  • fragrances, pigments, fungicides, antioxidants, preservatives and moisturizing agents may be further included, and may include thickeners, inorganic salts, synthetic polymer materials and the like for the purpose of improving the properties.
  • the indole-3-carbinol may be easily added to the face wash and the soap base.
  • the cream When the cream is prepared, it may be prepared by adding indole-3-carbinol 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.
  • the content of indole-3-carbinol contained in the cosmetic composition of the present invention is not limited thereto, but is preferably 0.001 to 10% by weight, 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 to or administering to a subject a pharmaceutical composition comprising indole-3-carbinol or a salt thereof as an active ingredient, muscle differentiation Provide methods of palpation, muscle regeneration, or muscle strengthening.
  • 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 indole-3-carbinol or a salt thereof as an active ingredient.
  • 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).
  • 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).
  • Example 1 in Comparative Example 1, the thickness of the myotube was significantly reduced compared to that of normal cells, and in Example 1 treated with indole-3-carbinol, it was decreased by dexamethasone. Visually, the myotube thickness was increased again. In addition, as shown in Figure 1B, it was confirmed that even when treated with indole-3-carbinol quantified using the image J software, the myotube thickness reduced by dexamethasone increased 56% significantly. From this, it can be seen that indole-3-carbinol increases the thickness of myotube in mouse myoblasts, thereby inhibiting muscle loss and promoting muscle growth.
  • 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 expression of protein degradation and synthesis in mouse myoblasts treated with indole-3-carbinol.
  • FIG. 2A in Comparative Example 1, the amount of p-4E-BP1 and p-p70S6K1 proteins related to protein synthesis was significantly reduced compared to normal cells (Basal) (FIG. 2A). Genes MaFbx / atrogin1 and MuRF1 expression can be seen to increase significantly (Fig. 2B).
  • FIG. 2A shows that the amount of p-4E-BP1 and p-p70S6K protein reduced by dexamethasone was again significantly increased (FIG.
  • 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 in three groups (Chow, HFD, and Indole-) according to the ovary method. 8 animals per group were randomly placed in 3-carbinol group for 10 weeks.
  • the obesity induction diet used in this experiment was a high fat diet (HFD: 40% fat calorie, 17 g lard + 3% corn oil / 100 g diet) and an indole-3-carbinol supplement (Indole) -3-carbinol-supplemented high fat diet (Indole-3-carbinol) had the same composition as HFD but contained 0.2% of indole-3-carbinol (Table 2). Chow fed a commercial rodent chow. Indole-3-carbinol was purchased from Sigma-Aldrich.
  • HFD High fat Control diet
  • Indole-3-carbinol 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
  • tert-butyhydroquinone 0.04 0.04 Test substance (Indole-3-carbinol) - 2 Total (g) 1,000 1,000 1,000
  • grip strength was measured using the four feet of the mouse at 10 weeks of breeding.
  • the grip force measuring device equipped with a wire mesh (20 x 10 cm) (Daejong Equipment Industry, Korea) measured the force (N) of the wire mesh of the mouse a total of five times, and at least 1 minute rest between measurements. Gave time.
  • the experimental results were obtained by dividing the measured force (N) and weight (kg).
  • the muscle tissue of the mouse was extracted, fixed in 10% formalin, and then stained with Hematoxylin and eosin (H & E) by a Korean CFC (Gyeonggi-do, Korea) and observed using an optical microscope (IX71, Olympus, JPN). Pictures were taken using a camera (DP71, Olympus, JPN).
  • indole-3-carbinol was significantly reduced by 36% than the weight of the mice fed the high fat diet (Fig. 3A).
  • Indole-3-carbinol also significantly increased the holding impulse (FIG. 3B) and grip strength (FIG. 3C) of mice fed high fat diets by 169% and 38%, respectively. From these results, indole-3-carbinol was found to have a very good strength enhancing effect in high fat diet induced muscle loss animal model.
  • indole-3-carbinol was found in the rectus femoris (6%, FIG. 4A) and soleus (6%, FIG. 4B) of high-fat diet mice.
  • the fiber diameter was significantly increased. Therefore, it was found that indole-3-carbinol showed a very good skeletal muscle increase effect in the high fat diet induced muscle loss animal model.
  • the above ingredients were mixed and filled in an airtight cloth to prepare a powder.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the above components are dissolved in purified water according to a conventional preparation method, dissolved in purified water, and then lemon juice is added in an appropriate amount. After adjusting to 100 mL in total, sterilized and filled in a brown bottle to prepare a liquid formulation.
  • Vitamin B6 0.5 mg
  • composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method.
  • the granules may be prepared and used for preparing a health food composition according to a conventional method.
  • the resulting solution is filtered and obtained in a sterilized 2 L container, sealed sterilization and then refrigerated and stored Used to prepare the healthy beverage composition of the invention.
  • composition ratio is mixed with a component suitable for a favorite beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
  • the compounding ratio is mixed with a component suitable for nutritional longevity in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a conventional manufacturing method in the cosmetic field.
  • the above blending ratio is mixed composition of a component suitable for a flexible softener in a preferred embodiment, but the blending ratio may be arbitrarily modified, it can be prepared according to the manufacturing method in the general cosmetic field.
  • the compounding ratio is mixed with a component suitable for nourishing cream in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a conventional manufacturing method in the cosmetic field.
  • the compounding ratio is mixed with a component suitable for a massage cream in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a manufacturing method in the general cosmetic field.
  • the compounding ratio is mixed with a component suitable for a pack in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a manufacturing method in the general cosmetic field.
  • the compounding ratio is mixed with a component suitable for a gel in a preferred embodiment, the compounding ratio may be arbitrarily modified, and can be prepared according to a conventional manufacturing method in the cosmetic field.
  • the blending ratio is a relatively suitable composition for the cosmetic composition in a preferred embodiment, but can be applied to cosmetics of various uses, including other color cosmetics, according to the efficacy that can be applied to a thin coating on the human body, that is, Ointment may be used for manufacturing, and the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
  • composition 0.1-10%
  • Vitamin E 0.01 ⁇ 0.1%
  • a feed was prepared as follows.

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Abstract

The present invention relates to a composition for preventing or treating muscular diseases or for improving muscular function, comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

인돌-3-카비놀 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 치료용 조성물A composition for preventing or treating muscle diseases comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient
본 출원은 2017년 1월 6일 출원된 대한민국 특허출원 제10-2017-0002505호를 우선권으로 주장하고, 상기 명세서 전체는 본 출원의 참고문헌이다. This application claims the priority of Korean Patent Application No. 10-2017-0002505, filed January 6, 2017, the entirety of which is a reference of the present application.
본 발명은 인돌-3-카비놀 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a composition for preventing or treating muscle diseases, comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
대한민국은 2000년 노인인구가 전체인구의 7.2%를 차지하여 고령화 사회에 진입하였으며, 2050년에는 초고령화사회(20% 이상)에 진입할 것으로 예측된다(2013년 고령자 통계, 통계청). 사람의 근육양은 나이가 들면서 감소하고(50 ~ 70세에 10 ~ 15% 정도, 그리고 70 ~ 80세에서 30% 이상 감소), 이에 따라 근력과 근기능도 약화되는데, 이를 노인성 근감소증(sarcopenia)이라 한다. 노인성 근감소증은 활동장애와 보행장애를 유발하여 노인들의 독립적인 생활을 제한하는 주요 원인이 된다. 또한, 근감소증은 기초대사율을 저하시켜 인슐린 저항성을 높이고 2형 당뇨병 발생을 촉진하며, 고혈압 및 심혈관계 질환 발생위험을 3 ~ 5배 증가시킨다. 현재 근감소증 치료용도로 승인된 의약품은 전무한 실정이며, myostatin 억제물질 또는 기존 FDA 승인을 받은 타질환 치료제를 근감소증에 적용하는 약물재배치(drug repositioning) 기술이 개발 중에 있다.In Korea, the elderly population accounted for 7.2% of the total population in 2000 and entered an aging society. In 2050, 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. In addition, 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. Currently, no drug has been approved for the treatment of myopathy, and drug repositioning technology is being developed to apply myostatin inhibitor or other FDA-approved drugs to myopathy.
근육은 크게 골격근(skeletal muscle), 심장근(cardiac muscle), 평활근(visceral muscle)으로 구분되고, 이 중 골격근은 인체에서 가장 많은 양으로 존재하는 조직으로, 체중의 40 ~ 45%를 차지한다. 골격근은 건(tendon)을 통해 뼈(bone)에 붙어서 뼈의 움직임 또는 힘을 만들어 내는 역할을 한다. 하나의 근육은 수많은 근섬유로 구성되어 있으며, 다시 근섬유는 액틴과 미오신으로 구성된 수많은 근원섬유로 만들어진다. 액틴과 미오신이 서로 겹쳐서 움직이면 근육의 길이가 짧아지거나 길어지면서 전체적인 근육의 수축과 이완을 유발하게 된다. 근원섬유 크기의 증가는 근섬유 두께의 증가를 의미하고, 그 결과 근육의 증가가 일어나게 된다.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.
근육을 구성하는 근섬유의 유형은 ATP를 발생시키는 대사과정과 수축속도에 의해 주로 Type Ⅰ, Type ⅡA 그리고 Type ⅡB로 구분된다. 'Type Ⅰ 근섬유'는 수축속도가 느리고 많은 수의 미오글로빈과 미토콘드리아를 함유하고 있어 지속적이면서 낮은 강도의 유산소 활동을 하는데 적절하다. Type Ⅱ 근섬유는 적색을 띄고 있어서 적색근이라고도 일컬어지며 대표적으로 가자미근(soleus)이 이에 속한다. 반면, 'Type ⅡB 근섬유'는 수축속도가 빨라 매우 짧지만 높은 강도의 무산소 운동을 하는데 쓰이며, 미오글로빈의 함량이 적어 백색을 띄고 있으며 대표적으로 장딴지근(gastrocnemius)이 이에 속한다. 'Type ⅡA 근섬유'는 앞서 언급한 두 가지 근섬유의 중간적인 특성을 띄며 대퇴직근(rectus femoris)가 이에 속한다. 나이가 듦에 따라 근육의 부위별 Type Ⅰ, Ⅱ 근섬유의 조성이 달라질 뿐 아니라 모든 타입의 근섬유가 감소하게 된다.The types of 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. On the other hand, '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.
골격근은 환경에 따라 재생되어 유지되는 특징을 가지고 있으나, 이러한 특징은 나이가 듦에 따라 소실되고 결과적으로 노화가 진행되면서 근육양이 감소될 뿐 아니라 근력 역시 상실된다. 근육의 성장 및 재생에 관여하는 신호전달체계로는 insulin like growth factor 1(IGF-1)/AKT에 의해 매개되어 단백질 합성을 조절하는 신호전달이 있다. 근육세포막에 존재하는 IGF-1 receptor(IGF-1R)가 활성화되면 IRS1 및 PI3K 인산화를 통해 AKT 인산화가 증가되고 후자는 mTORC 인산화를 활성화시킨다. mTORC의 활성화는 ribosomal protein S6 kinase beta-1(p70S6K1)의 인산화를 증가시켜 mRNA 번역(translation)을 증가시키는 동시에 eukaryotic translation initiation factor 4 G(eIF4G)의 활성을 증가시키고, eukaryotic translation initiation factor 4E binding protein 1(4E-BP1) 단백질을 인산화시킨다. eIF4G와 4E-BP1은 eIF4F 복합체를 형성하는 데 관여하는데 즉, eIF4G는 eIF4A 및 eIF4E와 결합하여 eIF4F 복합체를 형성하는 한편, 4E-BP1은 인산화되면 eIF4E와의 결합능이 저해되어 유리상태의 eIF4E를 증가시키게 된다. 후자는 다른 translation initiation factor들(eIF4G 및 eIF4A)와 결합하여 eIF4F 복합체를 형성하고, 이렇게 형성된 eIF4F 복합체는 리보솜 구조를 안정화시킴으로써 번역개시(translation initiation)를 촉진하여 궁극적으로 단백질 합성을 증가시키게 된다(Bodine et al., 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).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. 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. 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 (Bodine et al., 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).
또한 AKT 인산화는 glycogen synthase kinase 3 (GSK3)를 통해 eIF2B 발현을 증가시켜 근섬유 성장을 촉진시키는 한편 단백질 분해 관련 전사인자인 forkhead box O(FOXO)의 발현을 억제함으로써 근 손실을 억제하기도 한다. 근손실은 myostatin, transforming growth factor beta(TGF-β), 그리고 activin을 포함하는 TGF-β family의 receptor에 의해 매개되는 신호전달에 의해 조절된다. TGF-β type II receptor에 리간드가 결합하면 type I receptor를 인산화시키고, 후자는 smad 2/3 complex를 인산화시켜 결국 FOXO를 활성화시킨다. 후자는 muscle-specific ubiquitin-ligase인 muscle RING-finger protein-1(MURF1), Muscle Atrophy F-Box(MAFbx)/atrogin-1의 유전자 발현을 증가시키고, 이는 ubiquitin을 표적단백질의 lysine 부위에 부착시켜 단백질 분해를 촉진시키고, 결국 근육의 감소를 유도한다(Gumucio et al., Atrogin-1, MuRF-1, and sarcopenia. Endocrine, 43, 12-21, 2013). In addition, 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-β family, including myostatin, transforming growth factor beta (TGF-β), and activin. Binding of the ligand to the TGF-β 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).
우수한 근 기능 조절 활성을 가지며 안전하게 적용될 수 있는 물질의 탐색이 계속 요구되고 있으나, 아직까지 근 기능 개선 조성물로서 천연물 유래 단독 성분이 많이 개발되지 않은 실정이다. 따라서 본 발명자는 부작용이 적은 천연물에서 근육 단백질의 분해작용을 억제하고 합성을 촉진시킴으로써 근육의 증강 및 근손실 개선에 효과가 있는 식품 소재를 개발하고자 하였다.There is a continuing need for the search for a substance having excellent muscle function regulating activity and which can be safely applied. However, a lot of natural ingredients derived from natural products have not been developed as a muscle function improving composition. Therefore, the present inventors have attempted to develop a food material that is effective in improving muscles and improving muscle loss by inhibiting the degradation of muscle proteins and promoting synthesis in natural products with few side effects.
본 발명의 목적은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 치료용, 근육 분화 촉진, 근육 재생 또는 근육 강화용 약학적 조성물을 제공하는 것이다.An object of the present invention is to prevent or treat muscle diseases, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient, to promote muscle differentiation, muscle regeneration or muscle enhancement To provide a composition.
본 발명의 또 다른 목적은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 근 기능 개선용, 근육 분화 촉진, 근육 재생 또는 근육 강화용 건강기능성 식품 조성물, 가축 사료용 조성물을 제공하는 것이다.Still another object of the present invention is to prevent or improve muscle disease, promote muscle differentiation, promote muscle regeneration, or include indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a health functional food composition, composition for livestock feed for muscle strengthening.
본 발명의 또 다른 목적은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근 기능 개선용 화장료 조성물을 제공하는 것이다.Still another object of the present invention is to provide a cosmetic composition for improving muscle function, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 염을 유효성분으로 포함하는 약학적 조성물을 개체에 투여 또는 복용시키는 단계를 포함하는 근육 질환 예방 또는 치료 방법, 근육 분화 촉진, 근육 재생 또는 근육 강화 방법을 제공하는 것이다.Another object of the present invention is a method for preventing or treating muscle diseases, comprising administering to or administering to a subject a pharmaceutical composition comprising indole-3-carbinol or a salt thereof as an active ingredient, It is to provide a method for promoting muscle differentiation, muscle regeneration or muscle strengthening.
본 발명의 또 다른 목적은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 염을 유효성분으로 포함하는 조성물의 근육 질환 예방 또는 치료, 근육 분화 촉진, 근육 재생 또는 근육 강화 용도를 제공하는 것이다.Another object of the present invention to provide a method for preventing or treating muscle diseases, promoting muscle differentiation, muscle regeneration or muscle strengthening of a composition comprising indole-3-carbinol or a salt thereof as an active ingredient. will be.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating muscle diseases, comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 양상에 따르면, 상기 조성물은 p-4E-BP1 또는 p-p70S6K1 단백질의 발현을 증가시킬 수 있다.According to an aspect of the present invention, the composition may increase the expression of p-4E-BP1 or p-p70S6K1 protein.
본 발명의 일 양상에 따르면, 상기 조성물은 MuRF1(Muscle Ring-Finger Protein) 또는 MaFbx(Muscle atrophy F-box)의 발현을 감소시킬 수 있다.According to an aspect of the present invention, the composition may reduce the expression of a MuRF1 (Muscle Ring-Finger Protein) or MaFbx (Muscle atrophy F-box).
본 발명의 일 양상에 따르면, 상기 근육 질환은 근 기능 저하, 근육 감소, 근육 소모 또는 근육 퇴화로 인한 근육 질환일 수 있다.According to one aspect of the invention, the muscle disease may be a muscle disease due to muscle function decline, muscle reduction, muscle wasting or muscle degeneration.
본 발명의 바람직한 일 양상에 따르면, 상기 근육 질환은 긴장감퇴증(atony), 근위축증(muscular atrophy), 근이영양증(muscular dystrophy), 근무력증, 악액질(cachexia), 경직성 척추 증후군(rigid spinesyndrome), 근위축성 측삭경화증(루게릭병, amyotrophic lateral sclerosis), 샤르코-마리-투스병(Charcot-Marie-Tooth disease) 및 근육 감소증(sarcopenia)으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다.According to one preferred aspect of the present invention, 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.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 근 기능 개선용 건강기능성 식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing muscle diseases or improving muscle function, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 건강기능성 식품 조성물을 제공한다.The present invention also provides a health functional food composition for promoting muscle differentiation, muscle regeneration, or muscle strengthening, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 개선용 가축 사료용 조성물을 제공한다.In addition, the present invention provides a composition for animal feed for preventing or improving muscle diseases, which comprises indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 가축 사료용 조성물을 제공한다.The present invention also provides a composition for animal feed for promoting muscle differentiation, muscle regeneration or muscle enhancement, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근 기능 개선용 화장료 조성물을 제공한다.In addition, the present invention provides a cosmetic composition for improving muscle function, comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 염을 유효성분으로 포함하는 약학적 조성물을 개체에 투여 또는 복용시키는 단계를 포함하는 근육 질환 예방 또는 치료 방법을 제공한다.In another aspect, the present invention provides a method for preventing or treating muscle diseases, comprising administering to or administering to a subject a pharmaceutical composition comprising indole-3-carbinol or a salt thereof as an active ingredient. .
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 염을 유효성분으로 포함하는 조성물을 개체에 투여 또는 복용시키는 단계를 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화 방법을 제공한다.In addition, the present invention provides a method for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising administering to or administering to a subject a composition comprising indole-3-carbinol or a salt thereof as an active ingredient. to provide.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 염을 유효성분으로 포함하는 조성물의 근육 질환 예방 또는 치료 용도를 제공한다.In addition, the present invention provides a use for preventing or treating muscle diseases of a composition comprising indole-3-carbinol or a salt thereof as an active ingredient.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol)또는 이의 염을 유효성분으로 포함하는 조성물의 근육 분화 촉진, 근육 재생 또는 근육 강화 용도를 제공한다.In addition, the present invention provides the use of indole-3-carbinol or a salt thereof as an active ingredient to promote muscle differentiation, muscle regeneration or muscle strengthening.
본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 치료용, 또는 근 기능 개선용 조성물에 관한 것으로, 상기 인돌-3-카비놀은 근육 세포에서 근단백질 합성 및 근육량 증가와 관련된 단백질의 발현을 증가시킬 수 있고, 근 단백질 분해에 관여하는 효소의 발현은 mRNA 수준에서부터 억제할 수 있으므로 근기능 저하, 근육 소모 또는 근육 퇴화로 인한 근육 질환에 있어서 근육 분화, 근육 재생, 근육량 증가를 통해 근력 강화 효과를 나타낼 수 있으며, 근육 감소를 억제할 수 있는 바, 근육 질환 예방 또는 치료용, 근육 분화, 근육 재생 및 근육량 증가용 또는 근 기능 개선에 이용될 수 있다. The present invention relates to a composition for preventing or treating muscle diseases or improving muscle function, which comprises indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. 3-carbinol 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, thus reducing muscle function, muscle wasting or muscle degeneration In muscle diseases caused by muscle differentiation, muscle regeneration, muscle mass increase effect can be exhibited, and can inhibit muscle loss, bar disease prevention or treatment, muscle differentiation, muscle regeneration and muscle mass increase or It can be used to improve muscle function.
도 1은 마우스 근아세포에서 myotube의 두께 변화를 나타낸 것이다. 도 1A는 Giemsa-wright 염색한 근관세포를 현미경으로 촬영하여 시각화한 것이고, 도 1B는 근관세포의 직경을 측정한 결과이며 각 값들은 세 개의 독립된 well에서 세 번의 결정 값의 평균±표준오차이다. P < 0.05는 통계적 유의성을 나타낸다. 1 shows the thickness change of myotube in mouse myoblasts. FIG. 1A is a microscopic image of Giemsa-wright stained root canal cells, and FIG. 1B is a result of measuring the diameter of the root canal cells, and each value is the mean ± standard error of three crystals in three independent wells. P <0.05 indicates statistical significance.
도 2는 인돌-3-카비놀을 처리한 마우스 근아세포에서 단백질 분해 및 합성 관련 분자들의 발현 변화를 나타낸 것이다. 도 2A는 p-4E-BP1, Total 4E-BP1, p-p70S6K1, 및 Total p70S6K1의 단백질 수준을 나타낸 것이고, 도 2B는 MaFbx 및 MuRF1의 유전자 발현 수준을 나타낸 것이다. 각 값들은 세 개의 독립된 well에서 세 번의 결정 값의 평균±표준오차이다. P <0.05는 통계적 유의성을 나타낸다.Figure 2 shows the expression changes of proteins involved in protein degradation and synthesis in mouse myoblasts treated with indole-3-carbinol. 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.
도 3은 정상식이군(Chow), 고지방식이군(HFD) 및 인돌-3-카비놀 섭취군(Indole-3-carbinol) 마우스의 체중(A), 매달리는 시간(B) 및 악력(C) 변화로부터 인돌-3-카비놀 섭취에 의한 근력 증가를 확인한 결과이다. Figure 3 shows the changes in body weight (A), hanging time (B) and grip force (C) of the normal diet (Chow), high fat diet (HFD) and indole-3-carbinol mice This is a result of confirming the increase in muscle strength by indole-3-carbinol intake.
도 4는 인돌-3-카비놀 섭취에 의한 마우스 근육조직의 섬유직경을 대퇴직근(rectus femoris)(A) 및 가자미근(soleus)(B)에서 확인한 결과이다. 정량값은 8마리에 대한 각 근육의 섬유 직경을 평균±표준오차로 나타낸 것이다. P < 0.05는 통계적 유의성을 나타낸다.Figure 4 is the result of confirming the fiber diameter of the mouse muscle tissue by indole-3-carbinol intake in the rectus femoris (A) and soleus (B). Quantitative values represent the fiber diameter of each muscle for 8 rats as mean ± standard error. P <0.05 indicates statistical significance.
본 발명자들은 인돌(indole)계 화합물인 인돌-3-카비놀이 근육단백질의 분해작용을 억제하고, 합성을 촉진시킴으로써 근육 증강 및 근 손실 개선에 효과가 있음을 확인함으로써, 본 발명을 완성하였다. The present inventors have completed the present invention by confirming that indole-3-carbinol, an indole-based compound, inhibits the degradation of muscle proteins and promotes synthesis, and is effective in muscle enhancement and muscle loss improvement.
본 발명에서 "근"은 심줄, 근육, 건을 포괄적으로 지칭하고, "근 기능"은 근육의 수축에 의해 힘을 발휘하는 능력을 의미하며, 근육이 저항을 이겨내기 위하여 최대한으로 수축력을 발휘할 수 있는 능력인 근력, 근육이 주어진 중량에 얼마나 오랫동안 또는 얼마나 여러 번 수축과 이완을 반복할 수 있는지를 나타내는 능력인 근지구력, 단시간 내에 강한 힘을 발휘하는 능력인 순발력을 포함한다. 이러한 근 기능은 간이 주관하며, 근육량에 비례하고, "근 기능 개선"은 근 기능을 더 좋게 향상시키는 것을 의미한다.In the present invention, "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. These muscle functions are subjective to the liver, proportional to muscle mass, and "muscle improvement" means better muscle function.
이하, 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating muscle diseases, comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
구체적으로, 상기 인돌-3-카비놀은 회색빛이 도는 흰색의 고체로서, 산성용액 하에서 극히 불안정하여 위산에 노출될 경우 생물학적 활성에 의해 다른 유도체로 변화되는 인돌(indole)계 화합물이고, 구조식은 C9H9NO, 분자량은 147.17 g/mol이다. 인돌-3-카비놀은 하기 화학식 1로 표시될 수 있으며, IUPAC name은 1H-Indol-3-ylmethanol이다. Specifically, the indole-3-carbinol is a grayish white solid, which is an indole compound which is extremely unstable under acidic solution and is changed to another derivative by biological activity when exposed to gastric acid. C 9 H 9 NO, molecular weight is 147.17 g / mol. Indole-3-carbinol may be represented by Formula 1 below, and the IUPAC name is 1H-Indol-3-ylmethanol.
[화학식 1][Formula 1]
Figure PCTKR2018000304-appb-I000001
Figure PCTKR2018000304-appb-I000001
또한, 상기 인돌-3-카비놀과 동일한 효능을 갖는 범위 내에서 인돌-3-카비놀 수화물, 인돌-3-카비놀 유도체 등을 포함할 수 있고, 이의 용매 화합물이나 입체 이성질체 또한 포함할 수 있다.In addition, indole-3-carbinol hydrate, indole-3-carbinol derivative, and the like may be included within the range having the same efficacy as the indole-3-carbinol, and may also include a solvent compound or stereoisomer thereof. .
상기 인돌-3-카비놀의 수득방법은 특별히 한정되지 않으며, 상기 인돌-3-카비놀을 함유하고 있는 식물로부터 분리하거나, 공지된 제법을 사용하여 화학적으로 합성하거나, 시판되는 것을 사용할 수 있다. 구체적으로, 상기 인돌-3-카비놀 또는 그의 유도체는 십자화과 식물의 추출물 또는 분획물에 포함된 것일 수 있다. 상기 십자화과 식물은 인돌-3-카비놀 유도체를 포함하는 한 특별하게 제한되지 않으며, 브라시카 올레라체아(Brassica oleracea)에 속하는 양배추(cabbage), 브로콜리(broccoli), 콜리플라워(cauliflower), 브뤼셀 스프라우츠(brussels sprouts), 콜라드(collards), 케일(kale) 등, 브라시카 라파(Brassica rapa)에 속하는 순무(turnip), 배추(Chinese cabbage) 등, 브라시카 나푸스(Brassica napus)에 속하는 평지씨(rapeseed) 등, 라파누스 사티부스(Raphanus sativus)에 속하는 일반 무(radish) 등, 아로마시아 루스티카나(Armoracia rusticana)에 속하는 서양고추냉이(horseradish), 마티올라(Matthiola)에 속하는 스토크(stock), 아라비도프시스 탈리아나(Arabidopsis thaliana) 등이 바람직하나, 이에 한정되지 않는다(Hall, J. C., K. J. Sytsma and H. H. Iltis. 2002. Phylogeny of Capparaceae and Brassicaceae based on chloroplast sequence data. American Journal of Botany 89: 1826-1842; Walter S. Judd, Christopher S. Campbell, Elizabeth A. Kellogg, Peter F. Stevens, Michael J. Donoghue: Plant Systematics: A Phylogenetic Approach, Sinauer Associates Inc. 2007; Stevens, P. F. (2001 onwards). Angiosperm Phylogeny Website. Version 7, May 2006; Strasburger, Noll, Schenck, Schimper: Lehrbuch der Botanik fur Hochschulen. 4. Auflage, Gustav Fischer, Jena 1900, p. 459).The method for obtaining the indole-3-carbinol is not particularly limited, and may be isolated from a plant containing the indole-3-carbinol, chemically synthesized using a known manufacturing method, or commercially available. Specifically, the indole-3-carbinol or derivatives thereof may be included in extracts or fractions of cruciferous plants. Wherein the cruciferous plant is not specially limited, including indole-3-carbinol derivatives, oleic Brassica la chair cabbage (cabbage) belonging to the (Brassica oleracea), broccoli (broccoli), cauliflower (cauliflower), Brussels's Brussels sprouts, collards, kale, etc. Brassica Such as turnip Rapa (turnip) belonging to the (Brassica rapa), cabbage (Chinese cabbage), Brassica Such crispus or rapeseed (rapeseed) belongs to the (Brassica napus), Rafa Taunus Such as sati booth General-free (radish) belongs to the (Raphanus sativus), scented shea Ruseutikana (Armoracia rusticana) such as horseradish (horseradish), Marty Stoke (stock), Arabian doped cis Italia or (Arabidopsis thaliana) belonging to the up (Matthiola) belonging to one preferred, but are not limited to (Hall, JC, KJ Sytsma and HH Iltis. 2002. Phylogeny of Capparaceae and Brassicaceae based on chloroplast sequence data.American Journal of Botany 89: 1826-1842; Walter S. Judd, Christopher S. Campbell, Elizabeth A. Kellogg, Peter F. Stevens, Michael J Donoghue: Plant Systematics: A Phylogenetic Approach, Sinauer Associates Inc. 2007; Stevens, PF (2001 onwards) .Angiosperm Phylogeny Website.Version 7, May 2006; Strasburger, Noll, Schenck, Schimper: Lehrbuch der Botanik fur Hochschulen. 4. Auflage, Gustav Fischer, Jena 1900, p. 459).
본 발명에 따른 조성물은 p-4E-BP1 또는 p-p70S6K1 단백질의 발현을 증가시킬 수 있다. The composition according to the invention can increase the expression of p-4E-BP1 or p-p70S6K1 protein.
또한, 본 발명에 따른 조성물은 MuRF1(Muscle Ring-Finger Protein) 또는 MaFbx(Muscle atrophy F-box)의 발현을 감소시킬 수 있다. 구체적으로, 단백질 합성과 관련이 있는 대표적인 분자로는 p70S6K1, 4E-BP1, 그리고 eIF members가 있고, 이 세 가지 분자들은 상위의 mTORC에 의해 활성이 조절된다. mTORc의 활성화는 p70S6K1를 인산화시키고, 활성화된 p70S6K1은 40S 리보솜단백질(ribosomal protein) S6를 인산화시켜서 mRNA 번역(translation)을 증가시키게 된다. 또한 mTORC의 활성화는 eIF4G의 활성을 증가시키는 동시에 4E-BP1을 인산화시키는데, 이 두 분자는 eIF4F 복합체를 형성하는데 관여한다. 즉, eIF4G는 eIF4A 그리고 eIF4E와 결합하여 eIF4F 복합체를 형성하는 한편, 4E-BP1은 인산화되면 eIF4E와의 결합능이 저해되어 유리상태의 eIF4E를 증가시키게 된다. 후자는 다른 translation initiation factor들(eIF4G 및 eIF4A)과 결합하여 eIF4F 복합체를 형성하고, 이렇게 형성된 eIF4F 복합체는 리보솜 구조를 안정화시킴으로써 번역개시(translation initiation)를 촉진하여 궁극적으로 단백질 합성을 증가시키게 된다. MAFbx/Atrogin-1과 MuRF1은 muscle-specific ubiquitin-ligase로, ubiquitin을 표적단백질의 lysine 부위에 부착시켜 단백질 분해를 촉진시키고, 근육의 감소를 유도하는 대표적인 단백질로서, 본 발명의 조성물은 MuRF1(Muscle Ring-Finger Protein) 또는 MaFbx(Muscle atrophy F-box)의 발현을 감소시킴으로써, 근육의 감소를 저해할 수 있다. In addition, the composition according to the present invention can reduce the expression of the MuRF1 (Muscle Ring-Finger Protein) or MaFbx (Muscle atrophy F-box). Specifically, 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. That is, 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). By reducing the expression of Ring-Finger Protein or MaFbx (Muscle atrophy F-box), muscle loss can be inhibited.
본 발명에서 "근육 질환"은 근 기능 저하, 근육 감소, 근육 소모 또는 근육 퇴화로 인한 근육 질환으로 당업계에 보고된 질병인 것이 바람직하며, 구체적으로 상기 근육 질환은 긴장감퇴증(atony), 근위축증(muscular atrophy), 근이영양증(muscular dystrophy), 근무력증, 악액질(cachexia), 경직성 척추 증후군(rigid spinesyndrome), 근위축성 측삭경화증(루게릭병, amyotrophic lateral sclerosis), 샤르코-마리-투스병(Charcot-Marie-Tooth disease) 및 근육 감소증(sarcopenia)으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것일 수 있으나, 이에 한정되지 않는다. 또한, 상기 근육 소모 또는 퇴화는 전적 요인, 후천적 요인, 노화 등을 원인으로 발생하며, 근육 소모는 근육량의 점진적 손실, 근육, 특히 골격근 또는 수의근 및 심장근육의 약화 및 퇴행을 특징으로 한다.In the present invention, "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. In addition, 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.
본 발명에 따른 근육 질환 예방 또는 치료용 약학적 조성물은 인돌-3-카비놀 또는 이의 약학적으로 허용 가능한 염을 포함하는 것이라면 그 함량을 특별히 제한하지는 않으나, 바람직하게 상기 인돌-3-카비놀의 용량은 0.1 μM 내지 1000 μM의 농도로 포함할 수 있으나, 이에 한정되지 않는다. 이때, 인돌-3-카비놀이 상기 농도 범위 미만인 경우, 근육세포에서 단백질 합성 및 분해 활성이 저하되어, 근육 질환 예방 또는 치료 효과를 발휘하기 어려운 문제점이 있고, 인돌-3-카비놀이 상기 농도 범위를 초과하는 경우, 세포독성을 포함한 독성의 우려사항이 있을 수 있다.The pharmaceutical composition for preventing or treating muscle diseases according to the present invention is not particularly limited as long as it contains indole-3-carbinol or a pharmaceutically acceptable salt thereof, preferably the indole-3-carbinol The dose may include, but is not limited to, a concentration of 0.1 μM to 1000 μM. At this time, if the indole-3-carbinol is less than the concentration range, there is a problem that the protein synthesis and degradation activity in muscle cells is lowered, it is difficult to exhibit the effect of preventing or treating muscle disease, indole-3-carbinol in the concentration range If exceeded, there may be toxicity concerns, including cytotoxicity.
본 발명에 따른 근육 질환 예방 또는 치료용 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구제 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화되어 사용할 수 있고, 제형화를 위하여 약학 조성물의 제조에 통상적으로 사용되는 적절한 담체, 부형제 또는 희석제를 포함할 수 있다.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.
상기 담체 또는, 부형제 또는 희석제로는 락토즈, 덱스트로즈, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리게이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 포함한 다양한 화합물 혹은 혼합물을 들 수 있다.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.
제제화할 경우에는 보통 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조할 수 있다.When formulated, it may be prepared using conventional diluents or excipients, such as fillers, weights, binders, wetting agents, disintegrating agents, surfactants.
경구 투여를 위한 고형제제는 상기 인돌-3-카비놀에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 제조할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용할 수 있다.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 indole-3-carbinol. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
경구를 위한 액상 제제로는 현탁액, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용하는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 포함할 수 있다.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. .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등을 사용할 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤젤라틴 등을 사용할 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, suppositories. As the 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. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol gelatin and the like can be used.
본 발명에 따른 근육 질환 예방 또는 치료용 약학 조성물의 바람직한 투여량은 환자의 상태, 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서는 1일 0.0001 내지 2,000 mg/kg으로, 바람직하게는 0.001 내지 2,000 mg/kg으로 투여할 수 있다. 투여는 하루에 한 번 투여할 수도 있고, 수회 나누어서 투여할 수도 있다. 다만, 상기 투여량에 의해서 본 발명의 범위를 한정하는 것은 아니다.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.
본 발명에 따른 근육 질환 예방 또는 치료용 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유 동물에 다양한 경로로 투여할 수 있다. 투여의 모든 방식은 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해서 투여할 수 있다.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.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 약학적 조성물을 제공한다. 상기 인돌-3-카비놀의 구체적인 내용은 전술한 바와 같다. In addition, the present invention provides a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol are as described above.
근육의 성장은 섬유크기(fiber size)의 증가에 의해 및/또는 섬유수의 증가에 의해 일어날 수 있다. 상기 근육의 성장은 A) 습윤중량(wet weight)의 증가, B) 단백질 함량의 증가, C) 근섬유 수의 증가, D) 근섬유 직경의 증가에 의해 측정될 수 있다. 근섬유 성장의 증가는 직경을 단면 타원체의 단축으로 정의할 때 직경의 증가로 정의될 수 있다. 유용한 치료제는 이전에 유사하게 처리된 대조군 동물(즉, 근육 성장 화합물로 처리되지 않은 퇴행된 근육조직을 갖는 동물)에 비해 적어도 10% 정도 근육이 퇴행된 동물에 있어서 습윤증량, 단백질 함량 및/또는 직경을 10% 이상, 더욱 바람직하게 50% 이상, 및 가장 바람직하게 100% 이상 증가시키는 것이다. 근섬유의 수를 증가시킴으로써 성장을 증가시키는 화합물은 그것이 질병에 걸린 조직에서 근섬유의 수를 적어도 1%, 더욱 바람직하게 적어도 20%, 그리고 가장 바람직하게 적어도 50% 증가시킬 때 치료제로 유용하다. 이러한 백분율 값은 화합물이 투여되어 국부적으로 작용하는 경우에 비처리되고 질병에 걸리지 않은 비교 포유동물에 있어서 또는 대측성인 병에 걸리지 않은 근육에 있어서의 기초수준에 대하여 상대적으로 결정된 것이다. 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.
근육 재생은 근육 모세포로부터 새로운 근섬유가 형성되는 과정을 의미한다. 재생을 위한 유용한 치료제는 상술한 바와 같이 적어도 약 1%, 더욱 바람직하게 적어도 20%, 및 가장 바람직하게 적어도 50% 새로운 섬유(new fiber)의 수를 증가시킨다.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.
근세포의 분화는 수축기관(미오피브릴)과 같은 근섬유의 성분들을 특정하는 근육 발생 프로그램(muscle developmental program)의 유도를 의미한다. 분화를 위한 유용한 치료제는 유사하게 처리된 대조군 동물에 있는 동등한 조직에 비하여, 질병에 걸린 조직에 있는 모든 근섬유 성분의 양을 약 10% 이상, 더욱 바람직하게 50% 이상, 및 가장 바람직하게 100% 이상 증가시킨다.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.
구체적으로, 본 발명의 일 구현예에 따르면, 덱사메타손(dexamethasone)에 의해 감소한 마우스 근아세포에 인돌-3-카비놀을 처리한 경우, 상기 마우스 근아세포의 근관세포(myotube)가 유의적으로 증가하였음을 확인할 수 있다. 즉, 본 발명의 인돌-3-카비놀은 마우스 근아세포에서 근관세포의 두께를 증가시킴으로써 근손실을 억제하고, 근육의 성장을 촉진시킬 수 있다. Specifically, according to one embodiment of the present invention, when indole-3-carbinol was treated to mouse myoblasts reduced by dexamethasone, myotubes of the mouse myoblasts were significantly increased. can confirm. That is, the indole-3-carbinol of the present invention can suppress muscle loss and promote muscle growth by increasing the thickness of myotubes in mouse myoblasts.
또한, 덱사메타손에 의해 감소한 마우스 근아세포에 인돌-3-카비놀을 처리한 경우, 단백질 합성에 관련이 있는 p-4E-BP1 및 p-p70S6K 단백질의 발현을 유의적으로 증가시킬 뿐만 아니라, 근육 감소를 유도하는 단백질인 MuRF1 및 Mafbx/atrogin1의 발현을 유의적으로 감소시킴을 확인할 수 있다. 즉, 본 발명의 인돌-3-카비놀은 마우스 근아세포에서 4E-BP1 및 p70S6K 단백질의 인산화를 증가시키고, MuRF1 및 Mafbx/atrogin1 유전자 발현을 억제함으로써 근육의 양을 증가시킬 수 있다. In addition, treatment with indole-3-carbinol in mouse myoblasts reduced by dexamethasone significantly increased the expression of p-4E-BP1 and p-p70S6K proteins involved in protein synthesis, as well as muscle reduction. It can be seen that significantly reduces the expression of MuRF1 and Mafbx / atrogin1 proteins that induce. In other words, indole-3-carbinol of the present invention can increase the amount of muscle by increasing the phosphorylation of 4E-BP1 and p70S6K protein in mouse myoblasts and inhibiting the expression of MuRF1 and Mafbx / atrogin1 genes.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 근 기능 개선용 건강기능성 식품 조성물을 제공한다. 상기 인돌-3-카비놀 및 근육 질환의 구체적인 내용은 전술한 바와 같다. The present invention also provides a health functional food composition for preventing muscle diseases or improving muscle function, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Details of the indole-3-carbinol and muscle diseases are as described above.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 건강기능성 식품 조성물을 제공한다. 상기 인돌-3-카비놀의 구체적인 내용은 전술한 바와 같다.The present invention also provides a health functional food composition for promoting muscle differentiation, muscle regeneration, or muscle strengthening, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol are as described above.
본 발명에 따른 근 기능 개선용 건강기능식품에 있어서, 상기 인돌-3-카비놀을 건강기능식품의 첨가물로 사용하는 경우 이를 그대로 첨가하거나 다른 식품 또는 식품성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효 성분의 혼합양은 예방, 건강 또는 치료 등의 각 사용 목적에 따라 적합하게 결정할 수 있다.In the health functional food for improving muscle function according to the present invention, when the indole-3-carbinol is used as an additive for the health functional food, it may be added as it is or used together with other foods or food ingredients, Can be used accordingly. The mixed amount of the active ingredient can be appropriately determined depending on the purpose of use, such as prevention, health or treatment.
건강기능식품의 제형은 산제, 과립제, 환, 정제, 캡슐제의 형태뿐만 아니라 일반 식품 또는 음료의 형태 어느 것이나 가능하다.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.
상기 식품의 종류에는 특별히 제한은 없고, 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸콜렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 식품을 모두 포함할 수 있다.There is no restriction | limiting in particular in the kind of said food, 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.
일반적으로, 식품 또는 음료의 제조시에 상기 인돌-3-카비놀은 원료 100 중량부에 대하여 15 중량부 이하, 바람직하게는 10 중량부 이하의 양으로 첨가할 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 또한 본 발명은 천연물로부터의 분획물을 이용하는 점에서 안전성 면에서 문제가 없으므로 상기 범위 이상의 양으로도 사용할 수 있다.In general, the indole-3-carbinol 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. However, in the case of long-term intake for health and hygiene or for health control, 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.
본 발명에 따른 건강기능식품 중 음료는 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명에 따른 음료 100 mL당 약 0.01 ~ 0.04 g, 바람직하게는 약 0.02 ~ 0.03 g일 수 있다.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. As the 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.
상기 외에 본 발명에 따른 근 기능 개선용 건강기능식품은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제를 함유할 수 있다. 그 밖에 본 발명의 수면 개선용 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 제한되지 않으나 본 발명의 건강기능식품 100 중량부 대비 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the health functional foods for improving muscle function according to the present invention, various nutritional supplements, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH regulators, stabilizers And preservatives, glycerin, alcohols, carbonated beverages used in carbonated drinks. In addition, the 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.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 개선용 가축 사료용 조성물을 제공한다. 상기 인돌-3-카비놀의 구체적인 내용은 전술한 바와 같다.In addition, the present invention provides a composition for animal feed for preventing or improving muscle diseases, which comprises indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol are as described above.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 가축 사료용 조성물을 제공한다. 상기 인돌-3-카비놀의 구체적인 내용은 전술한 바와 같다. The present invention also provides a composition for animal feed for promoting muscle differentiation, muscle regeneration or muscle enhancement, including indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol are as described above.
상기 가축은 소, 돼지, 닭, 오리, 염소, 양 및 말로 이루어진 군 중에서 선택된 1종의 가축인 것이 바람직하나, 이에 한정되지 않는다. 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.
상기 사료용 조성물은 사료 첨가제를 포함할 수 있다. 본 발명의 사료첨가제는 사료관리법상의 보조사료에 해당한다.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.
본 발명에서 용어, "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미할 수 있다.As used herein, the term "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.
상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2 종 이상을 혼합하여 사용될 수 있다.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.
또한 상기 사료첨가제는 추가적으로 단위 동물에 허용되는 담체를 함유할 수 있다. 본 발명에 있어서는 상기 사료첨가제를 그대로 또는 공지의 담체, 안정제 등을 가할 수 있으며, 필요에 따라 비타민, 아미노산류, 미네랄 등의 각종 양분, 항산화제 및 기타의 첨가제 등을 가할 수도 있으며, 그 형상으로서는 분체, 과립, 펠릿, 현탁액 등의 적당한 상태일 수 있다. 본 발명의 사료첨가제를 공급하는 경우는 단위 동물에 대하여 단독으로 또는 사료에 혼합하여 공급할 수 있다.In addition, the feed additive may additionally contain a carrier that is acceptable to the unit animal. In the present invention, 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. In the case of supplying the feed additive of the present invention, the unit animal may be supplied alone or mixed with the feed.
또한, 본 발명은 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근 기능 개선용 화장료 조성물을 제공한다. 상기 인돌-3-카비놀의 구체적인 내용은 전술한 바와 같다. In another aspect, the present invention provides a cosmetic composition for improving muscle function comprising indole-3-carbinol (Indole-3-carbinol) or a pharmaceutically acceptable salt thereof as an active ingredient. Specific details of the indole-3-carbinol are as described above.
본 발명의 화장료 조성물은 인돌-3-카비놀을 유효성분으로 함유하며 피부학적으로 허용 가능한 부형제와 함께 기초 화장품 조성물(화장수, 크림, 에센스, 클렌징 폼 및 클렌징 워터와 같은 세안제, 팩, 보디오일), 색조 화장품 조성물(화운데이션, 립스틱, 마스카라, 메이크업 베이스), 두발 제품 조성물(샴푸, 린스, 헤어컨디셔너, 헤어젤) 및 비누 등의 형태로 제조될 수 있다.The cosmetic composition of the present invention contains an indole-3-carbinol as an active ingredient and a dermatologically acceptable excipient, together with a basic cosmetic composition (face wash, pack, body oil such as cosmetic water, cream, essence, cleansing foam and cleansing water) , Color cosmetic composition (foundation, lipstick, mascara, makeup base), hair product composition (shampoo, rinse, hair conditioner, hair gel) and soap and the like.
상기 부형제로는 이에 한정되지는 않으나 예를 들어, 피부연화제, 피부 침투 증강제, 착색제, 방향제, 유화제, 농화제 및 용매를 포함할 수 있다. 또한, 향료, 색소, 살균제, 산화방지제, 방부제 및 보습제 등을 추가로 포함할 수 있으며, 물성개선을 목적으로 점증제, 무기염류, 합성 고분자 물질 등을 포함할 수 있다. 예를 들면, 본 발명의 화장료 조성물로 세안제 및 비누를 제조하는 경우에는 통상의 세안제 및 비누 베이스에 상기 인돌-3-카비놀을 첨가하여 용이하게 제조할 수 있다. 크림을 제조하는 경우에는 일반적인 수중유적형(O/W)의 크림베이스에 인돌-3-카비놀 또는 이의 염을 첨가하여 제조할 수 있다. 여기에 향료, 킬레이트제, 색소, 산화방지제, 방부제 등과 물성개선을 목적으로 한 단백질, 미네랄, 비타민 등 합성 또는 천연소재를 추가로 첨가할 수 있다. 본 발명의 화장료 조성물에 함유되는 인돌-3-카비놀의 함량은 이에 한정되지 않지만 전체 조성물 총중량에 대하여 0.001 내지 10 중량%인 것이 바람직하고, 0.01 내지 5중량%인 것이 더욱 바람직하다. 상기 함량이 0.001중량% 미만에서는 목적하는 항노화 또는 주름개선 효과를 기대할 수 없고, 10중량% 초과에서는 안전성 또는 제형상의 제조에 어려움이 있을 수 있다.The excipients include, but are not limited to, emollients, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners and solvents. In addition, 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. For example, when the face wash and the soap are manufactured with the cosmetic composition of the present invention, the indole-3-carbinol may be easily added to the face wash and the soap base. When the cream is prepared, it may be prepared by adding indole-3-carbinol 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. The content of indole-3-carbinol contained in the cosmetic composition of the present invention is not limited thereto, but is preferably 0.001 to 10% by weight, 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.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 염을 유효성분으로 포함하는 약학적 조성물을 개체에 투여 또는 복용시키는 단계를 포함하는 근육 질환 예방 또는 치료 방법, 근육 분화 촉진, 근육 재생 또는 근육 강화 방법을 제공한다.In addition, 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 indole-3-carbinol or a salt thereof as an active ingredient, muscle differentiation Provide methods of palpation, muscle regeneration, or muscle strengthening.
또한, 본 발명은 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 염을 유효성분으로 포함하는 조성물의 근육 질환 예방 또는 치료 용도, 근육 분화 촉진, 근육 재생 또는 근육 강화 용도를 제공한다.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 indole-3-carbinol or a salt thereof as an active ingredient.
상기한 바와 같이, 본 발명의 인돌-3-카비놀 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물은 근아세포에서 4E-BP1 및 p70S6K1 단백질 인산화를 증가시키고, MuRF1 및 MaFbx/atrogin1 유전자 발현을 억제함으로써 근기능 저하, 근육 소모 또는 근육 퇴화로 인한 근육 질환에 있어서 근육 분화, 근육 재생, 근육량 증가를 통해 근력 강화 효과를 나타낼 수 있으며, 근육 감소를 억제할 수 있는 바, 근육 질환 예방 또는 치료용, 근육 분화 촉진, 근육 재생 및 근육량 증가용 또는 근 기능 개선에 이용될 수 있다. As described above, the composition comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient increases 4E-BP1 and p70S6K1 protein phosphorylation in myoblasts, and generates MuRF1 and MaFbx / atrogin1 genes. By suppressing the expression, muscle differentiation, muscle regeneration, and muscle mass increase in muscle diseases caused by muscle function deterioration, muscle wasting or muscle degeneration can be exhibited to strengthen muscle strength, and muscle reduction can be suppressed. Dragons, promote muscle differentiation, muscle regeneration and increase muscle mass or improve muscle function.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.
[[ 실시예Example ]]
준비예Preparation . 세포배양. Cell culture
마우스 근아세포(mouse myoblast cell line, C2C12 cell)를 ATCC사(Manassas, VA, USA)로부터 구매하였고, 구입한 세포를 10% fetal bovine serum media (Gibco-BRL)를 이용하여 37℃, 5% CO2 인큐베이터에서 배양하였다. 상기 배양된 세포가 80% confluent해지면 2% horse serum media (Gibco-BRL)를 이용하여 근관세포(myotube)로 분화시켰다.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).
실시예Example 1. One.
분화 4일 째 되는 날부터 이틀 간 덱사메타손(dexamethasone, dexa; Sigma) 50 μM 및 인돌-3-카비놀 (indole-3-carbinol; CAS Number 700-60-1, Sigma) 100 μM을 함께 처리하였다. From day 4 of differentiation, 50 μM of dexamethasone (dexa; Sigma) and 100 μM of indole-3-carbinol (CAS Number 700-60-1, Sigma) were treated together.
비교예Comparative example 1. One.
상기 실시예 1과 동일한 방법으로 덱사메타손(dexamethasone, dexa; Sigma) 50 μM을 처리하였다. Dexamethasone (dexamethasone, dexa; Sigma) 50 μM was treated in the same manner as in Example 1.
실험예Experimental Example 1. 마우스  1. Mouse 근아세포를Myoblasts 이용한 인돌-3-카비놀의  Of indole-3-carbinol 근손실Muscle loss 억제 효능 Inhibitory effect
(1) (One) GiemsaGiemsa -Wright staining-Wright staining
상기 실시예 1에 따른 myotube를 PBS(Phosphate buffered saline)로 2회 세척한 후 100% 메탄올로 10분 동안 고정하였다. 고정이 완료되면 상온에서 10분간 자연 건조시킨 후 myotube를 특이적으로 염색시키는 Giemsa-wright staining solution(아산제약, 서울)을 떨어뜨려 30분간 염색하였다.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.
(2) (2) 근관세포Myotube 두께 측정 Thickness measurement
상기에서 염색된 myotube를 형광현미경(IX 71, Olympus)을 이용하여 X20 배율로 촬영 후 image J software(USA)를 이용하여 분석하였다. 각 well에서 여섯 부분을 무작위로 선택하여 현미경 촬영하였으며, 각 well로부터 최소 100개의 근아세포 두께를 분석하였다(3회 반복/Group).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).
그 결과, 도 1A에 나타난 바와 같이, 비교예 1의 경우, 정상세포(Basal)에 비해 myotube의 두께가 현저히 감소하였으며, 인돌-3-카비놀을 처리한 실시예 1의 경우, 덱사메타손에 의해 감소한 myotube 두께가 다시 증가되는 것을 시각적으로 확인할 수 있었다. 또한, 도 1B에 나타난 바와 같이, 이를 image J software를 이용하여 수치화한 결과에서도 인돌-3-카비놀을 처리한 경우, 덱사메타손에 의해 감소한 myotube 두께를 56% 유의적으로 증가시킴을 확인할 수 있었다. 이로부터, 인돌-3-카비놀은 마우스 근아세포에서 myotube의 두께를 증가시켜 근손실을 억제하고, 근성장을 촉진시키는 것을 알 수 있었다.As a result, as shown in FIG. 1A, in Comparative Example 1, the thickness of the myotube was significantly reduced compared to that of normal cells, and in Example 1 treated with indole-3-carbinol, it was decreased by dexamethasone. Visually, the myotube thickness was increased again. In addition, as shown in Figure 1B, it was confirmed that even when treated with indole-3-carbinol quantified using the image J software, the myotube thickness reduced by dexamethasone increased 56% significantly. From this, it can be seen that indole-3-carbinol increases the thickness of myotube in mouse myoblasts, thereby inhibiting muscle loss and promoting muscle growth.
실험예Experimental Example 2. 작용기작 규명 2. Identify the mechanism of action
(1) (One) TrizolTrizol 방법을 이용한 RNA 분리 및 RT- RNA isolation and RT- PCRPCR (reverse transcription-polymerase chain reaction) (reverse transcription-polymerase chain reaction)
마우스 근아세포 1 X 107 cells 당 Trizol 용액 334 ㎕을 첨가하여 갈아준 후, 4℃, 12,000 X g에서 10분간 원심분리 하였다. 상층액을 새 튜브로 옮긴 후 chloroform 67 ㎕을 첨가하고, vortex하였다. 다시 상층액을 새 튜브로 옮기고 상층액과 isopropanol의 비율이 1:1이 되도록 isopropanol을 첨가하였다. 10회 세게 흔든 다음 실온에서 15분 동안 방치하고, 12,000 X g, 4℃에서 10분간 원심분리 시킨 후 상층액을 제거하고, 남은 침전물에 70% ethanol 1 ml을 가한 후 7,500 X g, 4℃에서 5분 동안 원심분리 하였다. 에탄올을 제거한 후 RNA 침전물이 담긴 튜브를 실온에서 15분 동안 건조시키고, nuclease free water를 사용하여 RNA pellet을 용해시켰다. UV/VIS spectrophotometer(Beckman coulter, DU730)를 이용하여 260 nm 및 280 nm 파장에서 추출된 RNA 시료의 농도를 측정하고, agarose gel electrophoresis를 실시하여 RNA 시료의 integrity를 확인하였다.334 μl of Trizol solution 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 μl 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. Shake vigorously 10 times and leave at room temperature for 15 minutes, centrifuge for 10 minutes at 12,000 X g, 4 ℃, remove the supernatant, add 1 ml of 70% ethanol to the remaining precipitate, and then at 7,500 X g, 4 ℃ Centrifuge for 5 minutes. After removing ethanol, the tube containing the RNA precipitate was dried at room temperature for 15 minutes, and the RNA pellet was dissolved using nuclease free water. Using a UV / VIS spectrophotometer (Beckman coulter, DU730) was measured the concentration of RNA samples extracted at 260 nm and 280 nm wavelength, and the integrity of the RNA samples were confirmed by agarose gel electrophoresis.
마우스 근아세포에서 추출된 RNA 시료를 대상으로 oligo dT primer와 superscript reverse transcriptase (GIBCO BRL, Gaithersburg, MD, USA)을 이용하여 reverse transcription을 수행함으로써 cDNA를 합성하였다. Reverse transcription을 통해 얻은 cDNA를 template로 하고 증폭하고자 하는 유전자 cDNA의 5'과 3' flanking sequence를 primer로 사용하여 PCR을 수행하였으며, 이때 사용된 primer sequence는 하기 표 1에 제시된 바와 같다. 증폭된 PCR 산물 1 ㎕를 1% agarose gel에 전기 영동하여 DNA band를 확인하였다. 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 μl of the amplified PCR product was electrophoresed on a 1% agarose gel to confirm the DNA band.
Gene descriptionGene description PrimersPrimers Sequences (5'→3')Sequences (5 '→ 3') AnnealingAnnealing temperaturetemperature (℃)(℃) PCRPCR product product (bp)(bp)
MaFbx(synonym: atrogin-1)MaFbx (synonym: atrogin-1) FF GTCCAGAGAGTCGGCAAGTCGTCCAGAGAGTCGGCAAGTC 6363 141141
RR GTCGGTGATCGTGAGACCTTGTCGGTGATCGTGAGACCTT
MuRF1(synonym: TRAM63)MuRF1 (synonym: TRAM63) FF CTGAGCTGAGTAACTGCATCCTGAGCTGAGTAACTGCATC 6060 147147
RR AGAGGGTGTCAAACTTCTGAAGAGGGTGTCAAACTTCTGA
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH)Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) FF GTGATGGCATGGACTGTGGTGTGATGGCATGGACTGTGGT 5555 163163
RR GGAGCCAAAAGGGTCATCATGGAGCCAAAAGGGTCATCAT
(2) Western blotting(2) Western blotting
세포에서 western blotting을 수행하기 위해 media를 제거한 각 well에 500 μL의 100 mM Tris-HCl, pH 7.4, 5 mM EDTA, 50 mM sodium pyrophosphate, 50 mM NaF, 100 mM orthovanadate, 1% Triton X-100, 1 mM phenylmethanesulfonyl fluoride, 2 μg/mL aprotinin, 1 μg/mL pepstatin A, and 1 μg/mL leupeptin을 포함하는 lysis buffer를 넣고 harvest한 후 1,300 X g, 4℃에서 20분간 원심분리한 후 가운데 층을 취하고 Bradford 법에 따라 단백질을 정량 하였다(Bio-Rad). 단백질 40 ㎍을 SDS polyacrylamide gel에 전기영동시킨 후 nitrocellulose membranes(Amersham, Buckinghamshire, UK)으로 이동시켰다. Membrane을 tris-buffered saline과 tween 20 용액(TBS-T)을 이용하여 10분 동안 3회 반복하여 세척한 후 10% skim milk를 이용하여 60분간 차단하였다. Membrane을 1:1,000의 비율로 희석한 1차 항체에 넣어 4℃에서 부드럽게 흔들어 12시간 동안 배양한 후 TBS-T를 이용하여 세척하였고, membrane을 다시 1:2,000의 비율로 희석한 2차 항체와 함께 60분 동안 배양하고 세척하였다. 이 때, 1차 항체는 p70S6K1, phopho-p70S6K1(p-p70S6K1), 4E-BP1, phospho-4E-BP1(p-4E-BP1) 그리고 GAPDH (Cell Signaling Technology, Beverly, MA, USA)를 사용하였다. 최종적으로 단백질을 X-ray 필름에 ECL Western blot detection kit (RPN2106, Amersham, Arlington Heights, IL, USA)를 사용하여 시각화하였다. X-ray 필름에 시각화된 밴드를 스캔 후 Quantity One analysis software (Bio-Rad)를 이용하여 정량화하였다.500 μL of 100 mM Tris-HCl, pH 7.4, 5 mM EDTA, 50 mM sodium pyrophosphate, 50 mM NaF, 100 mM orthovanadate, 1% Triton X-100, in each well from which media was removed to perform western blotting in cells Add and harvest lysis buffer containing 1 mM phenylmethanesulfonyl fluoride, 2 μg / mL aprotinin, 1 μg / mL pepstatin A, and 1 μg / mL leupeptin, harvest, centrifuge at 1,300 X g, 4 ° C for 20 minutes, and Protein was quantified according to Bradford method (Bio-Rad). 40 μg of protein was electrophoresed on SDS polyacrylamide gel and then transferred to nitrocellulose membranes (Amersham, Buckinghamshire, UK). Membrane was washed three times for 10 minutes using tris-buffered saline and tween 20 solution (TBS-T) and then blocked for 60 minutes using 10% skim milk. Membrane was added to the primary antibody diluted at a ratio of 1: 1,000, shaked gently at 4 ° C, incubated for 12 hours, washed with TBS-T, and the membrane was again diluted with a secondary antibody at a ratio of 1: 2,000. Incubate for 60 minutes and wash together. In this case, p70S6K1, phopho-p70S6K1 (p-p70S6K1), 4E-BP1, phospho-4E-BP1 (p-4E-BP1) and GAPDH (Cell Signaling Technology, Beverly, MA, USA) were used as primary antibodies. . Finally, 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).
도 2는 인돌-3-카비놀을 처리한 마우스 근아세포에서 단백질 분해 및 합성 관련 분자들의 발현 변화를 나타낸 그래프이다. 도 2에 나타난 바와 같이, 비교예 1의 경우, 정상세포(Basal)에 비해 단백질 합성과 관련이 있는 p-4E-BP1 및 p-p70S6K1 단백질 양이 유의적으로 감소하였고(도 2A), 단백질 분해 유전자인 MaFbx/atrogin1과 MuRF1 발현은 유의적으로 증가함을 확인할 수 있다(도 2B). 인돌-3-카비놀을 처리한 실시예 1의 경우, dexamethasone에 의해 감소한 p-4E-BP1 및 p-p70S6K 단백질 양을 다시 유의적으로 증가시키고(도 2A), MuRF1 및 MaFbx/atrogin1의 발현은 유의하게 감소시킴을 확인할 수 있다(도 2B). 즉, 인돌-3-카비놀은 마우스 근아세포에서 4E-BP1 및 p70S6K1 단백질 인산화를 증가시키고, MuRF1 및 MaFbx/atrogin1 유전자 발현을 억제함으로써 궁극적으로 근육의 양을 증가시키는데 관여하였을 것으로 사료된다.Figure 2 is a graph showing the change in expression of protein degradation and synthesis in mouse myoblasts treated with indole-3-carbinol. As shown in FIG. 2, 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). For Example 1 treated with indole-3-carbinol, 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 Significant decrease can be seen (FIG. 2B). That is, indole-3-carbinol 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.
실험예Experimental Example 3. 마우스를 이용한 인돌-3-카비놀의 근력강화 효능 3. Strengthening effect of indole-3-carbinol using mouse
3-1. 실험방법3-1. Experiment method
1) 실험식이 제조 및 실험동물의 사육1) Preparation of experimental diet and breeding of experimental animals
5주령의 수컷 C57BL/6N 마우스 24마리(mating, 한국)를 상업적인 정상식이(rodant chow)로 1주일 간 실험실 환경에 적응시킨 후, 난괴법에 따라 세 개의 군(Chow군, HFD군, Indole-3-carbinol군)으로 군당 8 마리씩 임의 배치하여 10주간 사육하였다. 본 실험에서 사용한 비만유도식이는 고지방대조식이(high fat diet, HFD: 40% fat calorie, 17 g lard + 3% corn oil/ 100 g diet)이며, 인돌-3-카비놀이 보충된 식이(Indole-3-carbinol-supplemented high fat diet, Indole-3-carbinol)는 HFD와 조성이 동일하되 인돌-3-카비놀이 0.2% 수준으로 포함되었다(표 2). 정상식이군(Chow)은 상업적인 rodent chow를 섭취시켰다. 인돌-3-카비놀은 씨그마-알드리치 사에서 구입하였다.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 in three groups (Chow, HFD, and Indole-) according to the ovary method. 8 animals per group were randomly placed in 3-carbinol group for 10 weeks. The obesity induction diet used in this experiment was a high fat diet (HFD: 40% fat calorie, 17 g lard + 3% corn oil / 100 g diet) and an indole-3-carbinol supplement (Indole) -3-carbinol-supplemented high fat diet (Indole-3-carbinol) had the same composition as HFD but contained 0.2% of indole-3-carbinol (Table 2). Chow fed a commercial rodent chow. Indole-3-carbinol was purchased from Sigma-Aldrich.
성분ingredient 고지방 High fat 대조식이Control diet (( HFDHFD )) (g/kg diet)(g / kg diet) 인돌-3-카비놀(Indole-3-carbinol)Indole-3-carbinol 보충식이Supplementary diet (g/kg diet)(g / kg diet)
카제인 Casein 200200 200200
DL-메티오닌DL-Methionine 33 33
옥수수 전분Corn starch 111111 109109
수크로오스Sucrose 370370 370370
셀룰로오스 cellulose 5050 5050
옥수수유Corn oil 3030 3030
라아드Laad 170170 170170
비타민 복합물Vitamin complex 1212 1212
미네랄 복합물Mineral complex 4242 4242
콜린 비타르트레이트Choline Bitartrate 22 22
콜레스테롤 cholesterol 1010 1010
tert-부티하이드로퀴논tert-butyhydroquinone 0.040.04 0.040.04
실험물질(인돌-3-카비놀)Test substance (Indole-3-carbinol) -- 22
총합(g)Total (g) 1,0001,000 1,0001,000
2) 2) 사지근력Limb strength 측정시험(four limb hanging test) Four limb hanging test
마우스의 사지근력을 측정하기 위하여, 사육 10주차에 마우스의 네 발을 이용하여 거꾸로 매달리는 시간을 측정하였다. 철망 뚜껑(지름 < 0.5 cm)이 장착된 케이지(20 x 30 x 50 cm, (주)정도비앤피, 한국)에 마우스가 거꾸로 매달리는 시간(초)을 총 3회 측정하였고, 매 회 측정 사이에 30분 이상의 휴식시간을 주었다. 실험결과는 매달리는 시간(초)과 그 시간을 체중(kg)으로 곱한 값으로 구하였다. In order to measure the limb muscle strength of the mouse, the time to hang upside down using the four feet of the mouse at the 10th week of breeding. The total number of seconds the mouse hangs upside down was measured three times in a cage equipped with a wire mesh cap (diameter <0.5 cm) (20 x 30 x 50 cm, Jeong-Bi P & P, Korea). He gave me more than 30 minutes of rest. The experimental results were obtained by multiplying the hanging time (seconds) by the weight (kg).
3) 악력 측정시험(grip test)3) grip test
마우스의 악력을 측정하기 위하여, 사육 10주차에 마우스의 네 발을 이용하여 악력을 측정하였다. 철망(20 x 10 cm)이 장착된 악력 측정기((주)대종기기산업, 한국)를 이용하여 마우스가 철망을 잡는 힘(N)을 총 5회 측정하였고, 매 회 측정 사이에 1분 이상의 휴식시간을 주었다. 실험결과는 측정된 힘(N)과 체중(kg)으로 나눈 값으로 구하였다. In order to measure the grip force of the mouse, 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).
4) 근육조직의 면역조직화학적 염색4) Immunohistochemical staining of muscle tissue
마우스의 근육 조직을 적출하고 10% 포르말린에 고정한 다음, 한국 CFC (경기도, 한국)에 의뢰하여 Hematoxylin and eosin(H&E) 염색을 한 뒤 광학현미경 (IX71, Olympus, JPN)을 이용하여 관찰하고, digital camera (DP71, Olympus, JPN)를 이용하여 사진을 촬영하였다.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).
5) 통계분석5) Statistical Analysis
모든 자료의 통계분석은 statistical package for the social sciences(SPSS version 21.0, IBM, Armonk, NY, USA) PC package를 사용하여 실시하였고, 분석수치는 mean±SEM으로 나타내었으며, 군간 유의적인 차이는 ANOVA를 실시하여 검증하였다. Statistical analysis of all data was carried out using the statistical package for the social sciences (SPSS version 21.0, IBM, Armonk, NY, USA) PC package, and the analysis value was expressed as mean ± SEM, and the significant difference between groups was ANOVA. And verified.
3-2. 실험결과3-2. Experiment result
1) 인돌-3-카비놀 섭취에 의한 마우스의 1) Induction of Mice by Indole-3-carbinol Intake 근력 증가Strength gain 확인 Confirm
실험 결과, 인돌-3-카비놀을 섭취한 마우스의 체중은 고지방식이를 섭취한 마우스의 체중보다 36% 유의적으로 감소하였다(도 3A). 또한 인돌-3-카비놀은 고지방식이를 섭취하는 마우스의 매달리는 시간(holding impulse)(도 3B) 및 악력(grip strength)(도 3C)을 각 169% 및 38% 유의적으로 증가시켰다. 이로부터 인돌-3-카비놀은 고지방식이로 유도된 근손실 동물모델에서 매우 탁월한 근력증강 효과를 나타냄을 알 수 있었다.As a result, the weight of the mice ingested indole-3-carbinol was significantly reduced by 36% than the weight of the mice fed the high fat diet (Fig. 3A). Indole-3-carbinol also significantly increased the holding impulse (FIG. 3B) and grip strength (FIG. 3C) of mice fed high fat diets by 169% and 38%, respectively. From these results, indole-3-carbinol was found to have a very good strength enhancing effect in high fat diet induced muscle loss animal model.
2) 인돌-3-카비놀 섭취에 의한 마우스 근육 조직의 2) Mouse Muscle Tissue by Indole-3-carbinol Intake 섬유직경Fiber diameter 변화 change
또한 마우스 근육 조직을 관찰한 결과, 인돌-3-카비놀은 고지방식이를 섭취하는 마우스의 대퇴직근(rectus femoris)(6%, 도 4A) 및 가자미근(soleus)(6%, 도 4B)의 섬유직경을 유의적으로 증가시켰다. 따라서 인돌-3-카비놀은 고지방식이로 유도된 근손실 동물모델에서 매우 탁월한 골격근육 증가효과를 나타냄을 알 수 있었다.In addition, the observation of mouse muscle tissue showed that indole-3-carbinol was found in the rectus femoris (6%, FIG. 4A) and soleus (6%, FIG. 4B) of high-fat diet mice. The fiber diameter was significantly increased. Therefore, it was found that indole-3-carbinol showed a very good skeletal muscle increase effect in the high fat diet induced muscle loss animal model.
하기에 본 발명의 추출물을 함유하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, a preparation example of a composition containing an extract of the present invention will be described, but the present invention is not intended to be limited thereto but only to be described in detail.
제제예Formulation example 1.  One. 산제의Powder 제조 Produce
인돌-3-카비놀 20 ㎎Indole-3-carbinol 20 mg
유당수화물 100 ㎎ Lactose Carb 100 mg
탈크 10 ㎎ Talc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in an airtight cloth to prepare a powder.
제제예Formulation example 2. 정제의 제조 2. Preparation of Tablets
인돌-3-카비놀 10 ㎎Indole-3-carbinol 10 mg
옥수수전분 100 ㎎ Corn starch 100 mg
유당수화물 100 ㎎ Lactose Carb 100 mg
스테아르산마그네슘 2 ㎎Magnesium stearate 2mg
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
제제예Formulation example 3. 캅셀제의 제조 3. Manufacture of capsule
인돌-3-카비놀 10 ㎎Indole-3-carbinol 10 mg
미결정셀룰로오스 3 ㎎ 3 mg of microcrystalline cellulose
유당수화물 14.8 ㎎Lactose carb 14.8 mg
스테아르산마그네슘 0.2 ㎎Magnesium Stearate 0.2 mg
상기의 성분을 혼합한 후, 통상의 캅셀제의 제조방법에 다라서 젤라틴캡슐에 충전하여 캅셀제를 제조하였다.After mixing the above components, it was filled in gelatin capsules according to the conventional method for producing a capsule to prepare a capsule.
제제예Formulation example 4. 주사제의 제조 4. Preparation of Injectables
인돌-3-카비놀 10 ㎎Indole-3-carbinol 10 mg
만니톨 180 ㎎ Mannitol 180 mg
주사용 멸균 증류수 2974 ㎎Sterile distilled water for injection 2974 mg
인산일수소나트퓸 26 ㎎Monohydrogen phosphate 26 mg
상기의 성분을 혼합한 후, 통상의 주사제의 제조방법에 따라 1앰플당(2mL) 상기의 성분 함량으로 제조하였다.After mixing the above components, it was prepared in the above ingredient content per ampoules (2 mL) according to the conventional method for preparing injections.
제제예Formulation example 5.  5. 액제의Liquid 제조 Produce
인돌-3-카비놀 10 ㎎Indole-3-carbinol 10 mg
이성화당 10 ㎎ Isomerized sugar 10 mg
만니톨 5 ㎎Mannitol 5 mg
정제수 적량Purified water
레몬향 적량Lemon flavor
상기의 성분을 통상의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 정제수를 가하여 전체 100mL로 조절한 후 멸균시켜 갈색병에 충진하여 액제를 제조한다. 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.
제제예Formulation example 6. 건강기능식품의 제조 6. Preparation of dietary supplements
인돌-3-카비놀 10 ㎎Indole-3-carbinol 10 mg
비타민 혼합물 적량Vitamin mixture proper amount
비타민 A 아세테이드 70 ㎍70 μg of Vitamin A Acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B2 0.15 mg
비타민 B6 0.5 ㎎Vitamin B6 0.5 mg
비타민 B12 0.2 ㎍0.2 μg of vitamin B12
비타민 C 10 ㎎ Vitamin C 10 mg
비오틴 10 ㎍10 μg biotin
니코틴산아미드 1.7 ㎎Nicotinic Acid 1.7 mg
엽산 50 ㎍ Folate 50 ㎍
판토텐산 칼슘 0.5 ㎎Calcium Pantothenate 0.5mg
무기질 혼합물 적량Mineral mixture
황산제1철 1.75 ㎎Ferrous Sulfate 1.75 mg
산화아연 0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium monophosphate 15 mg
제2인산칼슘 55 ㎎Dibasic calcium phosphate 55 mg
구연산칼륨 30 ㎎Potassium citrate 30 mg
탄산칼슘 100 ㎎ Calcium Carbonate 100 mg
염화마그네슘 24.8 ㎎Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the 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.
제제예Formulation example 7. 건강음료의 제조 7. Manufacture of health drinks
인돌-3-카비놀 10 mgIndole-3-carbinol 10 mg
비타민 C 15 g15 g of vitamin C
비타민 E(분말) 100 g100 g of vitamin E (powder)
젖산철 19.75 gIron lactate 19.75 g
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinamide 3.5 g
비타민 A 0.2 g0.2 g of vitamin A
비타민 B1 0.25 g0.25 g of vitamin B1
비타민 B2 0.3 g0.3 g of vitamin B2
정제수 정량Purified Water Quantification
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1 시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다.After mixing the above components according to the conventional healthy beverage production method, and stirred and heated at 85 ℃ for about 1 hour, 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.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the 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.
하기에 본 발명의 추출물을 함유하는 화장료 조성물의 제조예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, an example of preparation of a cosmetic composition containing an extract of the present invention will be described, but the present invention is not intended to be limited thereto, but is intended to be described in detail.
제조예Production Example 1. 영양화장수( 1. Nutritional Cosmetics ( 밀크로션Milk Croissant ))
인돌-3-카비놀 2.0 중량%Indole-3-carbinol 2.0 wt%
스쿠알란 5.0 중량%Squalane 5.0 wt%
밀납 4.0 중량%Beeswax 4.0 wt%
폴리솔베이트60 1.5 중량%Polysorbate60 1.5 wt%
솔비탄세스퀴올레이트 1.5 중량%Sorbanthesquioleate 1.5 wt%
유동파라핀 0.5 중량%0.5% by weight of liquid paraffin
카프릴릭/카프릭트리글리세라이드 5.0 중량%Caprylic / Capric Triglycerides 5.0 wt%
글리세린 3.0 중량%Glycerin 3.0 wt%
부틸렌글리콜 3.0 중량%Butylene Glycol 3.0 wt%
프로필렌글리콜 3.0 중량%Propylene Glycol 3.0 wt%
카르복시비닐폴리머 0.1 중량%Carboxy vinyl polymer 0.1 wt%
트리에탄올아민 0.2 중량%0.2% by weight of triethanolamine
방부제, 색소, 향료 적량Preservatives, colorings, flavors
정제수 to 100 중량%Purified water to 100% by weight
상기의 배합비는 비교적 영양화장수에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상적인 화장품 분야에서의 제조방법에 따라 제조할 수 있다. Although the above-mentioned 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.
제조예Production Example 2. 유연화장수(스킨로션) 2. Softening Cosmetics (Skin Lotion)
인돌-3-카비놀 2.0 중량 %Indole-3-carbinol 2.0% by weight
글리세린 3.0 중량 %Glycerin 3.0 wt%
부틸렌글리콜 2.0 중량 %Butylene glycol 2.0% by weight
프로필렌글리콜 2.0 중량 %Propylene Glycol 2.0 wt%
카르복시비닐폴리머 0.1 중량 %Carboxy vinyl polymer 0.1 wt%
PEG 12 노닐페닐에테르 0.2 중량 %PEG 12 nonylphenylether 0.2% by weight
폴리솔베이트80 0.4 중량 %Polysorbate 80 0.4% by weight
에탄올 10.0 중량 %Ethanol 10.0 wt%
트리에탄올아민 0.1 중량 %Triethanolamine 0.1% by weight
방부제, 색소, 향료 적량Preservatives, colorings, flavors
정제수 to 100 중량 %Purified water to 100% by weight
상기의 배합비는 비교적 유연화장수에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상적인 화장품 분야에서의 제조방법에 따라 제조할 수 있다. 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.
제조예Production Example 3. 영양크림 3. Nutrition Cream
인돌-3-카비놀 2.0 중량 % Indole-3-carbinol 2.0% by weight
폴리솔베이트60 1.5 중량 %Polysorbate 60 1.5% by weight
솔비탄세스퀴올레이트 0.5 중량 %Solbitan Sesquioleate 0.5% by weight
PEG60 경화피마자유 2.0 중량 %PEG60 Cured Castor Oil 2.0% by weight
유동파라핀 10 중량 %10% by weight of liquid paraffin
스쿠알란 5.0 중량 %Squalane 5.0 wt%
카프릴릭/카프릭트리글리세라이드 5.0 중량 %Caprylic / Capric Triglycerides 5.0 wt%
글리세린 5.0 중량 %Glycerin 5.0 wt%
부틸렌글리콜 3.0 중량 %Butylene glycol 3.0% by weight
프로필렌글리콜 3.0 중량 %Propylene Glycol 3.0 Weight%
트리에탄올아민 0.2 중량 %Triethanolamine 0.2% by weight
방부제 적량Preservative
색소 적량Pigment amount
향료 적량Spices
정제수 to 100 중량 %Purified water to 100% by weight
상기의 배합비는 비교적 영양크림에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상적인 화장품 분야에서의 제조방법에 따라 제조할 수 있다. Although the above-mentioned 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.
제조예Production Example 4. 마사지크림 4. Massage Cream
인돌-3-카비놀 1.0 중량 %1.0% by weight indole-3-carbinol
밀납 10.0 중량 %Beeswax 10.0 weight%
폴리솔베이트60 1.5 중량 %Polysorbate 60 1.5% by weight
PEG 60 경화피마자유 2.0 중량 %PEG 60 Cured Castor Oil 2.0% by weight
솔비탄세스퀴올레이트 0.8 중량 %Sorbanthesquioleate 0.8 wt%
유동파라핀 40.0 중량 %40.0% by weight of liquid paraffin
스쿠알란 5.0 중량 %Squalane 5.0 wt%
카프릴릭/카프릭트리글리세라이드 4.0 중량 %Caprylic / Capric Triglyceride 4.0 wt%
글리세린 5.0 중량 %Glycerin 5.0 wt%
부틸렌글리콜 3.0 중량 %Butylene glycol 3.0% by weight
프로필렌글리콜 3.0 중량 %Propylene Glycol 3.0 Weight%
트리에탄올아민 0.2 중량 %Triethanolamine 0.2% by weight
방부제, 색소, 향료 적량Preservatives, colorings, flavors
정제수 to 100 중량 %Purified water to 100% by weight
상기의 배합비는 비교적 마사지크림에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상적인 화장품 분야에서의 제조방법에 따라 제조할 수 있다. Although the above-mentioned 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.
제조예Production Example 5. 팩 5. Pack
인돌-3-카비놀 1.0 중량 %1.0% by weight indole-3-carbinol
폴리비닐알콜 13.0 중량 %Polyvinyl alcohol 13.0 wt%
소듐카르복시메틸셀룰로오스 0.2 중량 %Sodium Carboxymethylcellulose 0.2% by weight
글리세린 5.0 중량 %Glycerin 5.0 wt%
알란토인 0.1 중량 %Allantoin 0.1 wt%
에탄올 6.0 중량 %Ethanol 6.0 wt%
PEG 12 노닐페닐에테르 0.3 중량 %PEG 12 nonylphenyl ether 0.3% by weight
폴리솔베이트60 0.3 중량 %Polysorbate60 0.3 wt%
방부제, 색소, 향료 적량Preservatives, colorings, flavors
정제수 to 100 중량 %Purified water to 100% by weight
상기의 배합비는 비교적 팩에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상적인 화장품 분야에서의 제조방법에 따라 제조할 수 있다. Although the above-mentioned 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.
제조예Production Example 6. 젤 6. Gel
인돌-3-카비놀 0.5 중량 %0.5% by weight indole-3-carbinol
에틸렌디아민초산나트륨 0.05 중량 %0.05% by weight of ethylenediamine sodium acetate
글리세린 5.0 중량 %Glycerin 5.0 wt%
카르복시비닐폴리머 0.3 중량 %Carboxy vinyl polymer 0.3 wt%
에탄올 5.0 중량 %Ethanol 5.0 wt%
PEG 60 경화피마자유 0.5 중량 %PEG 60 Cured Castor Oil 0.5% by weight
트리에탄올아민 0.3 중량 %0.3% by weight of triethanolamine
방부제, 색소, 향료 적량Preservatives, colorings, flavors
정제수 to 100 중량 %Purified water to 100% by weight
상기의 배합비는 비교적 젤에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상적인 화장품 분야에서의 제조방법에 따라 제조할 수 있다. Although the above-mentioned 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.
상기 배합비는 비교적 화장료 조성물에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그외의 색채 화장품을 포함하는 다양한 용도의 화장품에 적용될 수 있는 것이고, 그 효능에 따라 인체에 얇게 도포하여 바를 수 있는 약제 즉, 연고로 제조에 이용될 수 있으며 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.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.
하기에 본 발명의 추출물을 함유하는 가축 사료 조성물의 제조예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, an example of preparing a livestock feed composition containing an extract of the present invention will be described, but the present invention is not intended to be limited thereto but merely to be described in detail.
제조예Production Example 7. 사료첨가제의 제조 7. Preparation of feed additives
조성물 0.1~10%Composition 0.1-10%
제3 인산칼슘 1~20%Tricalcium phosphate 1-20%
비타민 E 0.01~0.1%Vitamin E 0.01 ~ 0.1%
효소 분말 1~10% Enzyme Powder 1 ~ 10%
유산균 0.1~10%Lactobacillus 0.1-10%
포도당 20~90%Glucose 20-90%
제조예Production Example 8. 사료의 제조 8. Preparation of feed
상기 제조예 1의 사료첨가제를 유효성분으로 하여 하기와 같은 조성으로 사료를 제조하였다.Using the feed additive of Preparation Example 1 as an active ingredient, a feed was prepared as follows.
제조예 1의 사료 첨가제 0.1~10%Feed additive 0.1 ~ 10% of Preparation Example 1
밀기울 40~49.9%Bran 40-49.9%
마일로 21.20%Milo 21.20%
대두박 20.00%Soybean meal 20.00%
어분 3.00%Fish Meal 3.00%
당밀 4.00%Molasses 4.00%
미네랄 1.53%Mineral 1.53%
비타민 0.27%0.27% vitamin
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims (17)

  1. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 치료용 약학적 조성물.Indole-3-carbinol (Indole-3-carbinol) or a pharmaceutical composition for preventing or treating muscle diseases comprising a pharmaceutically acceptable salt thereof as an active ingredient.
  2. 제1항에 있어서,The method of claim 1,
    상기 조성물은 p-4E-BP1 또는 p-p70S6K1 단백질의 발현을 증가시키는 것을 특징으로 하는 근육질환 예방 또는 치료용 약학적 조성물.The composition is a pharmaceutical composition for preventing or treating muscle diseases, characterized in that to increase the expression of p-4E-BP1 or p-p70S6K1 protein.
  3. 제1항에 있어서,The method of claim 1,
    상기 조성물은 MuRF1(Muscle Ring-Finger Protein) 또는 MaFbx(Muscle atrophy F-box)의 발현을 감소시키는 것을 특징으로 하는 근육 질환 예방 또는 치료용 약학적 조성물.The composition is a pharmaceutical composition for preventing or treating muscle diseases, characterized in that the expression of MuRF1 (Muscle Ring-Finger Protein) or MaFbx (Muscle atrophy F-box) is reduced.
  4. 제1항에 있어서,The method of claim 1,
    상기 근육 질환은 근 기능 저하, 근육 감소, 근육 소모 또는 근육 퇴화로 인한 근육 질환인 것을 특징으로 하는 근육 질환 예방 또는 치료용 약학적 조성물.The muscle disease is a muscle disease prevention or treatment pharmaceutical composition, characterized in that the muscle disease due to muscle function decline, muscle reduction, muscle wasting or muscle degeneration.
  5. 제1항 내지 제4항 중 어느 한 항에 있어서,The method according to any one of claims 1 to 4,
    상기 근육 질환은 긴장감퇴증(atony), 근위축증(muscular atrophy), 근이영양증(muscular dystrophy), 근무력증, 악액질(cachexia), 경직성 척추 증후군(rigid spinesyndrome), 근위축성 측삭경화증(루게릭병, amyotrophic lateral sclerosis), 샤르코-마리-투스병(Charcot-Marie-Tooth disease) 및 근육 감소증(sarcopenia)으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는 근육 질환 예방 또는 치료용 약학적 조성물.The muscle diseases include atony, muscular atrophy, muscular dystrophy, myasthenia, cachexia, rigid spinesyndrome, amyotrophic lateral sclerosis A pharmaceutical composition for preventing or treating muscle diseases, characterized in that any one or more selected from the group consisting of Charcot-Marie-Tooth disease and sarcopenia.
  6. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 약학적 조성물.Indole-3-carbinol (Indole-3-carbinol) or a pharmaceutical composition for promoting muscle differentiation, muscle regeneration or muscle enhancement comprising a pharmaceutically acceptable salt thereof as an active ingredient.
  7. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 근 기능 개선용 건강기능성 식품 조성물.Indole-3-carbinol (Indole-3-carbinol) or a health functional food composition for preventing muscle diseases or improving muscle function comprising a pharmaceutically acceptable salt thereof as an active ingredient.
  8. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 건강기능성 식품 조성물.Health functional food composition for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising indole-3-carbinol or a pharmaceutically acceptable salt thereof as an active ingredient.
  9. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 질환 예방 또는 개선용 가축 사료용 조성물.Indole-3-carbinol (Indole-3-carbinol) or a pharmaceutical composition for animal feed for preventing or improving muscle diseases comprising a pharmaceutically acceptable salt thereof as an active ingredient.
  10. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화용 가축 사료용 조성물.Indole-3-carbinol (Indole-3-carbinol) or a pharmaceutical composition for animal feed for promoting muscle differentiation, muscle regeneration or muscle strengthening comprising a pharmaceutically acceptable salt thereof as an active ingredient.
  11. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 근 기능 개선용 화장료 조성물.Indole-3-carbinol (Indole-3-carbinol) or a pharmaceutical composition for improving muscle function comprising a pharmaceutically acceptable salt thereof as an active ingredient.
  12. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 염을 유효성분으로 포함하는 약학적 조성물을 개체에 투여 또는 복용시키는 단계를 포함하는 근육 질환 예방 또는 치료 방법.A method of preventing or treating muscle diseases, comprising administering to or administering to a subject a pharmaceutical composition comprising indole-3-carbinol or a salt thereof as an active ingredient.
  13. 제12항에 있어서,The method of claim 12,
    상기 근육 질환은 긴장감퇴증(atony), 근위축증(muscular atrophy), 근이영양증(muscular dystrophy), 근무력증, 악액질(cachexia), 경직성 척추 증후군(rigid spinesyndrome), 근위축성 측삭경화증(루게릭병, amyotrophic lateral sclerosis), 샤르코-마리-투스병(Charcot-Marie-Tooth disease) 및 근육 감소증(sarcopenia)으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는 근육 질환 예방 또는 치료 방법.The muscle diseases include atony, muscular atrophy, muscular dystrophy, myasthenia, cachexia, rigid spinesyndrome, amyotrophic lateral sclerosis Method for preventing or treating muscle diseases, characterized in that any one or more selected from the group consisting of Charcot-Marie-Tooth disease and sarcopenia.
  14. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 염을 유효성분으로 포함하는 조성물을 개체에 투여 또는 복용시키는 단계를 포함하는 근육 분화 촉진, 근육 재생 또는 근육 강화 방법.A method for promoting muscle differentiation, muscle regeneration, or muscle strengthening, comprising administering to or administering to a subject a composition comprising indole-3-carbinol or a salt thereof as an active ingredient.
  15. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 염을 유효성분으로 포함하는 조성물의 근육 질환 예방 또는 치료 용도.Use for preventing or treating muscle diseases of a composition comprising indole-3-carbinol or a salt thereof as an active ingredient.
  16. 제15항에 있어서,The method of claim 15,
    상기 근육 질환은 긴장감퇴증(atony), 근위축증(muscular atrophy), 근이영양증(muscular dystrophy), 근무력증, 악액질(cachexia), 경직성 척추 증후군(rigid spinesyndrome), 근위축성 측삭경화증(루게릭병, amyotrophic lateral sclerosis), 샤르코-마리-투스병(Charcot-Marie-Tooth disease) 및 근육 감소증(sarcopenia)으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는 근육 질환 예방 또는 치료 용도.The muscle diseases include atony, muscular atrophy, muscular dystrophy, myasthenia, cachexia, rigid spinesyndrome, amyotrophic lateral sclerosis Use for preventing or treating muscle diseases, characterized in that any one or more selected from the group consisting of Charcot-Marie-Tooth disease and sarcopenia.
  17. 인돌-3-카비놀(Indole-3-carbinol) 또는 이의 염을 유효성분으로 포함하는 조성물의 근육 분화 촉진, 근육 재생 또는 근육 강화 용도.Use for promoting muscle differentiation, muscle regeneration or muscle strengthening of a composition comprising indole-3-carbinol or a salt thereof as an active ingredient.
PCT/KR2018/000304 2017-01-06 2018-01-05 Composition for preventing or treating muscular diseases, comprising indole-3-carbinol or pharmaceutically acceptable salt thereof as active ingredient WO2018128481A1 (en)

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Citations (4)

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WO2009103754A2 (en) * 2008-02-19 2009-08-27 Dsm Ip Assets B.V. Novel use of 3,3'-diindolylmethane
US20140056862A1 (en) * 2011-04-18 2014-02-27 Nestec S.A. Nutritional compositions having alpha-hica and alpha-ketoglutarate
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