WO2020017913A1 - Composition pharmaceutique pour la prévention ou le traitement de la sarcopénie, comprenant une myokine - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de la sarcopénie, comprenant une myokine Download PDF

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Publication number
WO2020017913A1
WO2020017913A1 PCT/KR2019/008915 KR2019008915W WO2020017913A1 WO 2020017913 A1 WO2020017913 A1 WO 2020017913A1 KR 2019008915 W KR2019008915 W KR 2019008915W WO 2020017913 A1 WO2020017913 A1 WO 2020017913A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
preventing
myostatin
myopathy
muscle
Prior art date
Application number
PCT/KR2019/008915
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English (en)
Korean (ko)
Inventor
김현수
Original Assignee
고려대학교 산학협력단
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Publication date
Priority claimed from KR1020190086372A external-priority patent/KR20200010087A/ko
Application filed by 고려대학교 산학협력단 filed Critical 고려대학교 산학협력단
Publication of WO2020017913A1 publication Critical patent/WO2020017913A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT 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
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of myopathy containing mycaine as an active ingredient.
  • Muscular dystrophy refers to the decrease in muscle strength associated with aging with a decrease in muscle mass.
  • Muscle here means skeletal muscle and has nothing to do with smooth muscle.
  • myotropia mainly refers to a loss of skeletal muscle mass distributed in the extremities, and muscle loss due to acute diseases such as cachexia and flu, which are significant muscle loss states in the late stages of malignant tumors. wasting, or primary muscle disease.
  • Myostatin is a polypeptide growth factor belonging to the superfamily of TGF- ⁇ .
  • TGF- ⁇ has a large amount of isoforms, which are known to be involved in proliferation, apoptosis, differentiation, bone formation and maintenance of cells (Massague & Chen, 2000).
  • Myostatin belongs to growth differentiation factor (GDF) No. 8, is involved in the growth and development of tissues, and acts by activating the Smad signaling system.
  • GDF growth differentiation factor
  • the p21 gene has been reported to inhibit the proliferation of cell cycle and progenitor cells, thereby affecting bone formation and regeneration.
  • Myostatin is produced mainly in skeletal muscle cells, causing muscle loss and muscle strength by the method of self-secretion.
  • myostatin inhibits the expression of IGF-1 or Follistatin, which is involved in muscle hypertrophy, and causes protein synthesis and proliferation in myoblasts. It is known to suppress.
  • the present inventors have made diligent efforts to identify substances capable of treating myotropin by inhibiting myostatin expression causing muscle loss and muscle strength.
  • Biglycan, Chitinase-3-like 1 The present invention was completed by discovering that Leukemia inhibitory factor (LIF) and Follistatin-related protein 1 (FSTL-1) components can be used to prevent or treat myostatin by inhibiting the production of myostatin protein and increasing mRNA expression. It was.
  • LIF Leukemia inhibitory factor
  • FSTL-1 Follistatin-related protein 1
  • An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of myopathy containing mycaine as an active ingredient.
  • Another object of the present invention relates to a food composition for preventing or improving myopathy containing mycaine as an active ingredient.
  • a pharmaceutical composition for the prevention or treatment of myopathy containing mycaine as an active ingredient.
  • the mycaine may be one or more selected from the group consisting of Biglycan, Chitinase-3-like 1, LIF (Leukemia inhibitory factor) and FSTL-1 (Follistatin-related protein 1).
  • the pharmaceutical composition may inhibit the expression of myostatin mRNA or protein.
  • the myostatin mRNA or protein expression may be due to bleomycin (bleomycin).
  • the myostatin mRNA or protein expression may be due to UV.
  • the pharmaceutical composition may inhibit the expression of MURF1 (Muscle RING-finger protein-1) mRNA or protein.
  • a food composition for preventing or improving myopathy containing mycaine as an active ingredient.
  • the pharmaceutical composition for preventing or treating myotropin containing myocaine of the present invention as an active ingredient inhibits the production of myostatin protein and mRNA expression which directly affect muscle loss and muscle strength reduction, It may have a prophylactic or therapeutic effect of more fundamental myotropia.
  • Figure 1 confirms the effect of inhibiting myostatin expression increased by UV during Biglycan treatment.
  • Figure 2 confirms the effect of inhibiting the increased myostatin expression by UV during Chitinase-3-like 1 treatment.
  • FIG. 3 confirms the effect of inhibiting myostatin expression increased by UV when treated with Leukemia inhibitory factor (LIF).
  • LIF Leukemia inhibitory factor
  • Figure 4 confirms the effect of inhibiting myostatin expression increased by UV when Follistatin-related protein 1 (Fstl-1) treatment.
  • Figure 5 confirms the effect of inhibiting MURF1 protein expression increased by UV when Biglycan, Chitinase-3-like 1, Leukemia inhibitory factor (LIF), Follistatin-related protein 1 (Fstl-1) treatment.
  • a pharmaceutical composition for preventing or treating myopathy which contains mycaine as an active ingredient.
  • myokine is a compound word of the muscle cell 'myocyte' and the bioactive substance 'cytokine', which is produced and expressed in muscle fibers. It refers to a substance that secretes proteins and hormones by directly acting in muscle cells and affects them, or the surrounding tissues of muscle cells or other tissues through blood flow.
  • prevention means any action that inhibits or delays the development of myopathy by administration of the composition.
  • treatment means any action that improves or beneficially changes the symptoms of myotropia by administration of the composition.
  • the myocaine may be at least one selected from the group consisting of Biglycan, Chitinase-3-like 1, Leukemia inhibitory factor (LIF), and Follistatin-related protein 1 (FSTL-1).
  • the pharmaceutical composition of the present invention can inhibit the expression of myostatin mRNA or protein and the expression of MURF1 (Muscle RING-finger protein-1) protein, in particular, the expression of myostatin by bleomycin treatment or UV stimulation.
  • the increase can be reduced (see FIGS. 1-5).
  • the bleomycin is an anti-tumor antibiotic and is used as an effective anticancer agent for squamous cell carcinoma or malignant lymphoma, or is known as an aging-inducing factor.
  • the pharmaceutical composition of the present invention may be prepared by a method known in the pharmaceutical field for use as a medicament, and may be mixed with pharmaceutically acceptable carriers, excipients, diluents, stabilizers, preservatives, etc. to powders, granules, tablets, It may be prepared and used in the form of a capsule or injection.
  • the composition may be prepared in a sustained release formulation including a base used for sustained release purposes in addition to the active ingredient so that the release of the active ingredient occurs slowly.
  • Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration.
  • Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. In addition, it may include various drug delivery materials used for oral administration to the peptide formulation.
  • carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose, glycols, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspension agent, and the like, in addition to the above components.
  • the diluent may be a non-aqueous solvent such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil and peanut oil, or brine (preferably 0.8% saline), water containing a buffer medium (preferably 0.05M phosphate buffer)
  • aqueous solvent such as these, etc. are mentioned, but it is not limited to this.
  • excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, anhydrous skim milk, glycerol, propylene, glycol, water , Ethanol and the like, but is not limited thereto.
  • the stabilizer may include carbohydrates such as sorbitol, mannitol, starch, sucrose, dextran, glutamate, and glucose, and proteins such as animal, vegetable or microbial proteins such as milk powder, serum albumin and casein, but are not limited thereto. no.
  • the preservative may include thimerosal, merthiolate, gentamicin, neomycin, nistatin, amphotericin B, tetracycline, penicillin, streptomycin, polymyxin B, and the like, but is not limited thereto.
  • compositions of the invention can be administered to any mammal, including humans, by any means, for example orally or parenterally.
  • Parenteral administration methods include intravenous, intramuscular, intraarterial, intramedullary, intradural intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or intrarectal administration no.
  • composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.
  • the total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose, and may be administered by a divided therapeutic regimen administered in multiple doses for a long time.
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease. This may be determined in consideration of various factors such as the formulation method, the number of administration routes, as well as the age, weight, health condition, symptoms of the disease, administration time and method of the patient. In view of this, one of ordinary skill in the art will be able to determine appropriate effective dosages of the compositions of the present invention.
  • the pharmaceutical composition according to the present invention is not particularly limited in terms of dosage form, route of administration and method of administration as long as the effect of the present invention is shown.
  • a food composition for preventing or improving myopathy containing mycaine as an active ingredient.
  • the term “improvement” means any action that at least reduces the parameters associated with the condition being treated, for example, the extent of symptoms.
  • the composition of the present invention when used as a food additive, the composition may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the compositions of the invention are added in an amount of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
  • the active ingredient may be used in an amount above the above range.
  • the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, drinks, tea, drink, Alcoholic beverages and vitamin complexes, and the like and include all of the health foods in the conventional sense.
  • C2C12 muscle progenitor cells (ATCC, US) were cultured in DMEM containing 10% FBS. Cells were seeded with 3x10 5 cells in a 60-pie dish. The next day after seeding, Biglycan, Chitinase-3-like 1, LIF (Leukemia inhibitory factor) and FSTL-1 (Follistatin-related protein 1) were treated for 1 hour. After 1 hour, the growth media (10% FBS DMEM) was removed and washed with PBS. After removing PBS, the UV cross-linker (UVP CL-1000) was irradiated with UV of 3J / m2 with the plate cap removed (0 day). Incubation in a CO 2 incubator for 24 hours, the growth media was removed in the same manner PBS wash and then irradiated with UV of 3J / m2 (1 day).
  • UV cross-linker UV cross-linker
  • Figs. 1 to 5 the expression of myostatin and MURF1 increased by UV irradiation was shown to be Biglycan, Chitinase-3-like 1, LIF (Leukemia inhibitory factor) and FSTL-1 (Follistatin-related protein 1). It was confirmed that the decrease with the treatment).
  • C2C12 muscle progenitor cells (ATCC, US) were cultured in DMEM containing 10% FBS. At this time, the cells were seeded with 3x10 5 cells in a 60-pie dish, and then left for 1 hour by bleomycin treatment after seeding.
  • the mixture was treated with Biglycan, Chitinase-3-like 1, Leukemia inhibitory factor (LIF), and Follistatin-related protein 1 (FSTL-1), respectively, and left for 1 hour, followed by removal of growth media (10% FBS DMEM). Washed with PBS. After washing, Western blot method was used to measure the expression changes of myostatin and MURF1, the muscle protein regulatory target proteins in cell lysates. Expression of myostatin was analyzed using Anti-GDF8 (Genetex, GTX32624), and beta-actin antibody (Enogene E12-041-4) as a protein loading control.
  • Anti-GDF8 Genetex, GTX32624
  • beta-actin antibody Endogene E12-041-4
  • Figs. 1 to 4 the expression of myostatin increased by bleomycin treatment was increased to Biglycan, Chitinase-3-like 1, LIF (Leukemia inhibitory factor) and FSTL-1 (Follistatin-related protein 1). It was confirmed that the decrease as the treatment.
  • mycaine corresponding to Biglycan, Chitinase-3-like 1, Leukemia inhibitory factor (LIF) and Follistatin-related protein 1 is myoin which is an indicator protein related to muscle mass control. It can be seen that by inhibiting the expression of otastatin and MURF1 it can be usefully used for the prevention or treatment of myopathy.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Physical Education & Sports Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Un mode de réalisation de la présente invention concerne une composition pharmaceutique pour la prévention ou le traitement de la sarcopénie, comprenant une myokine comme principe actif, et une composition alimentaire pour la prévention ou l'atténuation de la sarcopénie, comprenant une myokine comme principe actif.
PCT/KR2019/008915 2018-07-19 2019-07-19 Composition pharmaceutique pour la prévention ou le traitement de la sarcopénie, comprenant une myokine WO2020017913A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2018-0084052 2018-07-19
KR20180084052 2018-07-19
KR1020190086372A KR20200010087A (ko) 2018-07-19 2019-07-17 마이오카인을 함유하는 근감소증의 예방 또는 치료용 약학적 조성물
KR10-2019-0086372 2019-07-17

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WO2020017913A1 true WO2020017913A1 (fr) 2020-01-23

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017187033A1 (fr) * 2016-04-27 2017-11-02 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Procédé d'évaluation de la capacité d'une composition à prévenir la fatigue et les dommages musculaires; complément alimentaire et medicament
KR101803224B1 (ko) * 2017-01-19 2017-11-29 영남대학교 산학협력단 매트릭스 gla 단백질을 유효성분으로 함유하는 미오스타틴 활성 저해용 조성물
WO2018015945A2 (fr) * 2016-07-18 2018-01-25 Brainstorm Cell Therapeutics Ltd Procédés de traitement de la sclérose latérale amyotrophique (sla)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017187033A1 (fr) * 2016-04-27 2017-11-02 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Procédé d'évaluation de la capacité d'une composition à prévenir la fatigue et les dommages musculaires; complément alimentaire et medicament
WO2018015945A2 (fr) * 2016-07-18 2018-01-25 Brainstorm Cell Therapeutics Ltd Procédés de traitement de la sclérose latérale amyotrophique (sla)
KR101803224B1 (ko) * 2017-01-19 2017-11-29 영남대학교 산학협력단 매트릭스 gla 단백질을 유효성분으로 함유하는 미오스타틴 활성 저해용 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEE, HYE JEONG: "Characterization of Myokine as a Research Target in Metabolic Disease", THESIS FOR THE DEGREE OF DOCTOR, December 2017 (2017-12-01), pages 1 - 158, Retrieved from the Internet <URL:http://www.riss.kr/link?id=T14705732> *
REZA, M, M. ET AL.: "Irisin treatment improves healing of dystrophic skeletal muscle", ONCOTARGET, vol. 8, no. 58, 2017, pages 98553 - 98566, XP055680919, Retrieved from the Internet <URL:https://doi.org/10.18632/oncotarget.21636> *

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