Composition for preventing or treating muscle diseases comprising oxiracetam

Abstract

The present invention relates to a new use of oxiracetam, and to a composition for improving, treating or preventing muscle diseases, which contains oxiracetam as an active ingredient. The composition of the present invention can prevent, treat or improve muscle diseases, and has been confirmed to have improving, preventive and therapeutic effects in animal models of muscle atrophy treated with dexamethasone, animal models of age-related muscle atrophy (sarcopenia), animal models of Duchenne muscular dystrophy, and cell models of cachectic muscle disease and inflammatory muscle disease, and can be used as pharmaceutical compositions, food compositions and the like for preventing or treating muscle diseases.

Description

[Technical field]

[0001] The present invention relates to a composition for preventing or treating a muscular disease, comprising oxiracetam as an active ingredient. [Background technology]

[0002] Skeletal muscles are divided into active muscles and postural muscles, and when muscle mass decreases, muscle atrophy occurs, which is a decrease in the volume of muscle fibers.

[0003] Skeletal muscle atrophy or sarcopenia generally occurs naturally with aging, and may be caused by unused muscles or lack of exercise, or may occur secondarily due to other pathological conditions (cancer, renal failure, lung disease, sepsis, starvation, anti-cancer treatment, inflammation, stress hormones, etc.). Such muscle atrophy begins with a weakening of muscle strength for physical activity, creating a vicious cycle that causes problems such as weakness, impaired activity, and long periods of functional recovery. Therefore, it is one of the major problems that must be solved in order to escape from the accelerating aging and increase in diseases worldwide and pursue a healthy and humane life.

[0004] Various researches are being conducted on methods to efficiently control sarcopenia. For example, growth hormone (GH) has been developed to increase muscle mass, but it is very expensive and causes some undesirable side effects such as shortened life expectancy. Mitochondrial stabilizing drugs have also been ineffective against sarcopenia, as the drugs have difficulty penetrating into the mitochondria and affect parts other than the mitochondria, causing off-target effects. In addition, the development of drugs and techniques for sarcopenia that can induce muscle regeneration and differentiation is a major challenge, but these methods are very inappropriate for patients or those who are bedridden. Therefore, further research and drug development on sarcopenia and muscle atrophy, including age-related sarcopenia, is required.

[0005] Muscular dystrophies are hereditary muscle diseases caused by genetic mutations and are distinct from sarcopenia caused by aging and muscle atrophy induced by hypoactivity, denervation, nutritional deficiency, and steroids.

[0006] Among muscular dystrophies, those caused by mutations in the dystrophin gene on the X chromosome include Duchenne muscular dystrophy (DMD) and the milder Becker muscular dystrophy (BMD). The Duchenne muscular dystrophy is the most frequent progressive muscular dystrophies, and is known to occur mainly in boys aged 2 to 5 years.

[0007] Dystrophin is a gigantic gene with a total length of 2.2 Mbp (base pairs) and is present between chromosomes Xp21.2 and Xp21.1, but the portion translated into dystrophin protein is only 11 kbp. Muscle-type dystrophin is present just under the muscle membrane and is the core protein of the dystrophin-associated glycoprotein complex that connects the cytoskeleton and the extracellular matrix, and is involved in the damage of muscle cell membranes due to muscle contraction.

[0008] Duchenne muscular dystrophy progresses very rapidly, with more than 90% of patients losing the ability to walk before the age of 12, and heart failure and abnormal electrocardiograms due to myocardial dysfunction are found after the age of 18. Most patients die before the age of 30 from respiratory failure due to segmental muscular atrophy and deformation of the spine and thoracic cage.

[0009] To date, there are few effective drugs for muscular dystrophy. Although steroid administration for muscular dystrophy has the effect of extending the walking period, it cannot stop or reverse the progression, and side effects from long-term administration must be tolerated. In addition, although gene therapy agents have been developed, there are limitations in that only about 10-13% of patients can undergo exon skipping gene therapy. In addition, there are problems in that weekly subcutaneous or intravenous administration is required and penetration into cardiac muscle cells is not smooth, so treatment of cardiac disease cannot be expected, and there are problems in that only a very small number of patients (about 11-14%) can use nonsense mutation therapy agents. Gene therapy using viruses also has the problem that the size of the dystrophin gene (cDNA length is about 14kb) cannot be transmitted beyond the dose in the vector. To overcome this, micro-dystrophin, which retains only 4 of the 24 rod repeat structures in the middle part of dystrophin, has been developed, but there are problems such as immune reaction side effects caused by AAV vectors and very limited expression of dystrophin.

[0010] Therefore, there is an urgent need to develop a more fundamental and side effect-free therapeutic agent for treating muscle diseases including sarcopenia and muscular dystrophy. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] Korean Patent Publication No. 10-2021-0093954 [Patent Document 2] Korean Patent Publication No. 10-2018-0010961 Summary of the Invention [Problem to be solved by the invention]

[0012] Therefore, the present inventors have searched for a substance that has excellent preventive or therapeutic effects on muscle diseases and can be safely applied. As a result, they have found that Oxiracetam, a nootropic drug of the Racetam family, has activity for improving, preventing or treating muscle diseases, and have completed the present invention.

[0013] SUMMARY OF THE PRESENT EMBODIMENTS Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating muscular diseases, which contains Oxiracetam as an active ingredient.

[0014] Another object of the present invention is to provide a food composition for improving or preventing muscular diseases, which contains Oxiracetam as an active ingredient.

[0015] It is still another object of the present invention to provide a food composition for improving or preventing muscle function, which contains Oxiracetam as an active ingredient.

[0016] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, the claims and the drawings. [Means for solving the problem]

[0017] In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating a muscular disease, which comprises oxiracetam, a pharma- ceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[0018] The present invention also provides a food composition for improving or preventing a muscular disease, which contains oxiracetam, a pharma- ceutical acceptable salt thereof, or a hydrate thereof as an active ingredient.

[0019] The present invention also provides a feed additive for improving or preventing a muscle disease, which comprises oxiracetam, a pharma- ceutical acceptable salt thereof, or a hydrate thereof as an active ingredient.

[0020] The present invention also provides a composition comprising Oxiracetam, a pharma- ceutical acceptable salt or a hydrate thereof as an active ingredient for use in therapy in the manufacture of a medicament for the prevention or treatment of a muscular disease.

[0021] The present invention also provides a method for treating a muscular disease, comprising administering to a patient suffering from the muscular disease a pharmaceutical composition comprising oxiracetam, a pharma- ceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[0022] The configuration of the present invention will be specifically described below.

[0023] The inventors of the present invention evaluated the effects of Oxiracetam in, first, a muscle atrophy animal model induced by dexamethasone treatment, second, an aging animal model, third, a Duchenne muscular dystrophy animal model, fourth, a cachectic muscle atrophy cell model, and fifth, an inflammatory muscle atrophy cell model, and confirmed that administration of Oxiracetam is effective in improving, preventing, or treating muscle diseases.

[0024] The present invention provides a pharmaceutical composition for preventing or treating a muscle disease, which contains oxiracetam, a pharma- ceutical acceptable salt or a hydrate thereof as an active ingredient; a pharmaceutical composition for improving or preventing a muscle disease for animals, which contains oxiracetam, a pharma- ceutical acceptable salt or a hydrate thereof as an active ingredient; a food composition for improving or preventing a muscle disease, which contains oxiracetam, a pharma- ceutical acceptable salt or a hydrate thereof as an active ingredient; or a feed additive for improving or preventing a muscle disease, which contains oxiracetam, a pharma- ceutical acceptable salt or a hydrate thereof as an active ingredient; or a method for treating a muscle disease, which comprises applying oxiracetam, a pharma- ceutical acceptable salt or a hydrate thereof to humans or non-human animals.

[0025] The present invention also relates to a pharmaceutical composition for promoting muscle differentiation, regenerating muscle or strengthening muscle, comprising oxiracetam or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0026] The present invention provides a composition containing oxiracetam, a pharma- ceutically acceptable salt or a hydrate thereof as an active ingredient for use in therapy.

[0027] The present invention also provides a novel use of Oxiracetam or a pharma- ceutical acceptable salt thereof for the manufacture of a medicine for treating a muscle disease or a medicine for animals.

[0028] The oxiracetam of the present invention is a nootropic drug of the Racetam family, Cas No. is 62613-82-5, and the molecular formula is CH 10It is N2O3, has a molecular weight of 158.155 g / mol, and has a structure as shown in the following chemical formula 1, but is not limited thereto. Any isomer, hydrate, or derivative having the same or similar activity as oxiracetam and within the scope that can be understood by a person skilled in the art can be applied.

[0029] The IUPAC name of oxiracetam is (RS)-2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide. Oxiracetam is a white solid. The method of obtaining the oxiracetam is not particularly limited, and the oxiracetam can be chemically synthesized using a known method or a commercially available product can be used.

[0030] [Chemical formula 1] [ka]

[0031] In the present invention, nootropics are a term that refers to drugs, supplements, and other substances that improve cognitive function, executive function, memory, etc. in healthy individuals. Racetams are generally reported to regulate central neurotransmitters including acetylcholine and glutamate, and are considered to improve memory through interaction with glutamate receptors. Oxiracetam, a derivative of piracetam, is known to be a safe substance even when taken in high doses over a long period of time, and can easily pass through the blood-brain barrier with high selective permeability. It is therefore used to treat memory disorders, cognitive disorders, cerebrovascular diseases, and cerebral infarction dementia. However, there has been no research on its use in muscle atrophy or hereditary muscle diseases such as muscular dystrophy, particularly age-related sarcopenia and Duchenne muscular dystrophy (DMD), or cachexia caused by cancer or anticancer drugs.

[0032] The pharmaceutical composition of the present invention contains oxiracetam or a pharma- ceutical acceptable salt thereof as an active ingredient, and promotes muscle differentiation by increasing ATP activity required for myocytes or myoblasts to differentiate into myotubes, has a protective effect against myotubes atrophied by TNF-α, promotes muscle strength improvement in animal models induced with sarcopenia by dexamethasone and aging animal models, inhibits and induces muscle loss in the tibialis anterior muscle, and increases the recovery of lean body mass and gastrocnemius muscle, thereby promoting muscle regeneration or muscle strengthening and inhibiting muscle atrophy or muscle loss. It has been confirmed that administration of oxiracetam is effective in improving, preventing, or treating muscle diseases caused by muscle wasting or degeneration.

[0033] In addition, the pharmaceutical composition of the present invention was orally administered with Oxiracetam in an animal model in which Duchenne muscular dystrophy was induced, and muscle size, strength, and muscle movement were evaluated. As a result, it was confirmed that oral administration of Oxiracetam is effective in improving, preventing, or treating muscular dystrophy.

[0034] In addition, the pharmaceutical composition of the present invention was evaluated by administering oxiracetam to a cell model of cachexia induced by an anticancer drug, and it was confirmed that the pharmaceutical composition of the present invention can inhibit myotube cell atrophy in a concentration-dependent manner. Through this, the pharmaceutical composition of the present invention was confirmed to be effective in inhibiting, improving, preventing or treating general muscle loss in the body induced by secondary muscle diseases such as sarcopenia, muscular dystrophy, and cancer or anticancer drugs.

[0035] From the above results, it can be seen that the active ingredient oxiracetam or its pharma- ceutically acceptable salt or hydrate according to the present invention can be used for the prevention or treatment of muscle diseases.

[0036] In the present invention, the muscular disease is not particularly limited as long as it is a muscular disease caused by muscle wasting or degeneration. Muscle wasting and degeneration occur due to genetic factors, acquired factors, aging, etc., and muscle wasting is characterized by a gradual loss of muscle mass, and weakening and degeneration of muscles, particularly skeletal or voluntary muscles and cardiac muscles.

[0037] In the present invention, the muscle disease caused by muscle wasting or degeneration may be any one or more selected from the muscle diseases consisting of atony, muscular atrophy, muscular dystrophy, muscle degeneration, myasthenia, cachexia, myositis and sarcopenia, preferably any one or more selected from the muscle diseases consisting of sarcopenia, muscular dystrophy, cachexia and / or muscle inflammation, and more preferably any one or more selected from the muscle diseases consisting of sarcopenia, muscular dystrophy and cachexia.

[0038] In the present invention, sarcopenia includes a range of diseases caused by muscle hypofunction, muscle loss, muscle atrophy, muscle wasting, or muscle degeneration, including atrophic diseases of all muscles present in the body, such as the eyes and face. Specifically, the muscle hypofunction, muscle loss, muscle atrophy, muscle wasting, or muscle degeneration occurs due to genetic factors, acquired factors, aging, etc., and is preferably characterized by gradual muscle loss, particularly atrophy, weakening, reduction, and degeneration of skeletal or voluntary muscles. Age-related sarcopenia is different from muscle diseases such as muscular dystrophy, muscular atrophy, and cachexia, and refers to a state in which skeletal muscle mass or muscle density and function gradually decrease due to various causes associated with aging, and in addition to a direct decrease in muscle strength, muscle mass (lean) and physical function decrease simultaneously. Therefore, in order to confirm the improvement, prevention or treatment of age-related muscular weakness, effects must be shown on all of muscle mass, muscle strength and physical function. Since increases in muscle strength and muscle mass do not necessarily coincide, a clear analysis of the above three effects is required, unlike other muscle diseases.

[0039] In the present invention, the muscular dystrophy may be any one or more selected from the group consisting of Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophy, Myotonic dystrophy type 1, and Myotonic dystrophy type 2.

[0040] Muscular dystrophies are distinguished from other muscle diseases because muscle tissue tests show muscle necrosis, muscle fibers are not uniform in size, and the necrotic areas of muscle fibers are replaced by fat and fibrotic tissue. In particular, Duchenne muscular dystrophy is clearly distinguished from other muscle diseases because it is caused by a specific gene mutation. As a treatment for muscular dystrophy, the standard corticosteroid therapy such as prednisone and deflazacort is proposed as a DMD treatment guideline, but it only delays symptoms and is not a complete cure. The corticosteroids used for muscular dystrophy are rarely used as a treatment for other muscle diseases because they cause side effects. Specifically, it is known that corticosteroids induce muscle diseases due to muscle fiber weakness and atrophy, and that steroids may actually induce muscle diseases when administered to cachectic or malnourished patients or patients with other muscle diseases such as polymyositis. Therefore, it can be seen that muscular dystrophies, particularly Duchenne muscular dystrophy, are distinct from other muscle diseases not only in the cause of the disease but also in the treatment method.

[0041] In the present invention, cachexia is characterized by a severe generalized debilitating symptom seen in the terminal stages of cancer, tuberculosis, cardiac abnormalities, renal abnormalities, diabetes, acquired immunodeficiency syndrome (AIDS), and the like.

[0042] In the present invention, cachexia may be cachexia induced by cancer or anticancer drugs. Cachexia is characterized by weight loss, which is seen in age-related muscle wasting and temporary hunger, but muscle loss occurs due to increased catabolic reactions caused by inflammatory reactions and changes in carbohydrate, protein and fat metabolism caused by various cytokines, and muscle and weight loss occurs despite normal food intake. Muscle loss in cachexia is known to occur due to increased protein catabolism and decreased protein production caused by overactivation of various cytokines, which affects insulin and testosterone that regulate muscle metabolism, causing abnormalities in muscle protein synthesis, but there is currently no drug that has shown clear results.

[0043] The cancers include leukemia, lymphoma, myeloma, myelodysplastic syndrome, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer (= colon cancer), rectal cancer, anal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), thymic cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, sarcoma, gastrointestinal stromal tumor (GIST), cancer of unknown primary site, mesothelioma, melanoma, neuroendocrine tumor, skin cancer, and blood cancer. The anticancer drug may be any one or more selected from the group consisting of doxorubicin, irinotecan, paclitaxel, daunorubicin, docetaxel, cisplatin, and 5-fluorouracil.

[0044] Furthermore, oxiracetam, the active ingredient of the present invention, has been confirmed to have a remarkable effect in animal models of Duchenne muscular dystrophy and age-related sarcopenia, and has been confirmed to suppress muscle atrophy caused by anticancer drugs in a cachexia cell model and restore it to normal levels or higher, and has been confirmed to have excellent improving, preventing or treating effects on Duchenne muscular dystrophy, cachexia and age-related sarcopenia, which have different mechanisms. In other words, oxiracetam, the active ingredient of the present invention, is significant in that it can improve, prevent and treat three muscle diseases with one drug, and therefore it may be possible to treat all inflammatory muscle diseases caused by TNF-α.

[0045] In the present invention, "muscle" refers to tendons and muscles in a comprehensive manner, and "muscle function" refers to the ability to exert force by muscle contraction, including muscle strength, which is the ability of a muscle to exert maximum contractile force to overcome resistance, muscle endurance, which is the ability of a muscle to repeat contraction and relaxation for a given weight for how long or how many times, and explosive power, which is the ability to exert strong force within a short period of time. Such muscle function is proportional to muscle mass, and improvement of muscle function means further improvement of muscle function, and more preferably, it may be promotion of muscle differentiation, muscle regeneration, muscle strengthening, or strengthening of athletic ability.

[0046] In the present invention, the promotion of muscle differentiation means inducing or culturing differentiation into myotubes and myofibers, and particularly means inducing differentiation from muscle cells into myotubes and myofibers, which can be measured by an increase in mitochondrial activity in muscle cells and an increase in the diameter of myofibers due to an increase in all myofibers. Specifically, the mitochondrial activity measured with an ATP detection reagent is increased by 10%, 20%, 30%, 40%, 50%, 60%, 70% or more compared to a normal control group, and the diameter of myotubes is increased by 10%, 20%, 30%, 40% or more compared to an atrophy model in which muscle atrophy is caused by TNF-α, or is within the range of 60% to 120%, 70% to 110% of the diameter of myotubes in the normal control group.

[0047] Myoblasts of the present invention are muscle cells in an undifferentiated state, and when mononuclear satellite cells are activated, they proliferate into myoblasts. As myoblast differentiation progresses, they fuse with other cells to form multinucleated, thin and long myotubes, which then produce muscle fibers. Myogenesis refers to any fusion of myoblasts to produce myotubes, and the differentiation-promoting effect of myoblasts can be induced in, but is not limited to, skeletal, cardiac and smooth muscles.

[0048] The muscle regeneration and strengthening were characterized by an increase in Tibialis Anteriors (TA) diameter by 1%, 5%, 10%, 15%, 20% or more compared to animals with dexamethasone-induced muscle loss, an increase in lean mass for the Gastrocnemius Muscle (GS) and Tibialis Anterior (TA) by 2%, 4%, 5%, 7%, 8%, 10% or more compared to animals with dexamethasone-induced muscle loss, and an increase in muscle strength (Grip) by 1%, 5%, 10%, 15%, 20% or more compared to animals with dexamethasone-induced muscle loss. These are increases in strength of 2%, 4%, 5%, 7%, 8%, 10%, 15%, or 20% or more, and increases in velocity of 0.1%, 0.5%, 0.8%, or 1% or more compared to animals in which muscle loss was induced by dexamethasone during exercise testing.

[0049] In the present invention, "prevention" refers to any action that suppresses or delays the onset and symptoms of the muscle disease. In the present invention, "treatment" refers to any action that improves or beneficially changes the symptoms of the muscle disease. "Improvement" refers to any action that improves or beneficially changes any symptom, disease, or pathological state, and examples thereof include improving symptoms such as muscle depletion or muscle loss, decreased muscle function or decreased ability to perform exercise, and decreased ability to recover from physical fatigue, inhibiting pseudohypertrophy of muscles due to muscular dystrophy, increasing muscle mass, inhibiting fat accumulation, improving muscle size, muscle strength, muscle function, and muscle movement, and inhibiting muscle loss and muscle atrophy due to anticancer drugs or cancer.

[0050] Oxiracetam of the present invention can be used in the form of a pharma- ceutically acceptable salt, and the salt is preferably an acid addition salt formed with a pharma- ceutically acceptable free acid, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharma- ceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, butyne-1,4-dioate, hexaphosphate ... The phenylsulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandalate.

[0051] The acid addition salts according to the invention can be prepared by conventional methods, for example by dissolving the oxiracetam in an excess amount of aqueous acid and precipitating the salt with a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. They can also be prepared by heating equal amounts of oxiracetam and an acid or alcohol in water, followed by evaporating the mixture to dryness or suction filtering the precipitated salt.

[0052] Also, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts can be prepared, for example, by dissolving the compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare sodium, potassium or calcium salts as metal salts. Corresponding silver salts can be prepared by reacting alkali metal or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate). The oxiracetam of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates that can be prepared by conventional methods.

[0053] The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving oxiracetam in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of an organic acid or an aqueous solution of an inorganic acid, followed by precipitation or crystallization. Subsequently, the solvent or excess acid is evaporated from the mixture, followed by drying to obtain the addition salt, or the precipitated salt can be filtered off with suction.

[0054] In the present invention, the term "hydrate" refers to the oxiracetam or a salt thereof of the present invention, which contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of oxiracetam of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing the oxiracetam of the present invention, its isomer or a pharma- ceutically acceptable salt thereof from water or a solvent containing water.

[0055] As used herein, the term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents in this regard include solvents that are volatile, non-toxic, and / or suitable for administration to humans.

[0056] In the present invention, the term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or stereochemically different. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having asymmetric carbon centers, geometric isomers (trans, cis), and enantiomers. All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0057] The "pharmaceutical composition", "medicine", "veterinary pharmaceutical composition" or "veterinary medicine" may further contain suitable carriers, excipients and diluents that are commonly used in the manufacture of pharmaceutical compositions, in addition to the active ingredient Oxiracetam or a pharma- ceutical acceptable salt thereof.

[0058] The "carrier" is a compound that facilitates the addition of a compound into cells or tissues. The "diluent" is a compound that is diluted with water to dissolve the compound as well as to stabilize the biologically active form of the compound of interest.

[0059] The carriers, excipients and diluents that can be used include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts, electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silica, magnesium trisilicate, polyethylene glycol, polyarylate, wax, wool fat and mineral oil.

[0060] The pharmaceutical composition, the medicine, the veterinary pharmaceutical composition, or the veterinary medicine can be formulated and used in the form of an oral dosage form such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, external preparation, suppository, or sterile injection solution by a conventional method. In particular, when the pharmaceutical composition is formulated, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, or surfactant. Solid preparations for oral administration include tablets, pills, powder, granule, capsule, etc., and such solid preparations can be prepared by mixing the pharmaceutical composition of the present invention with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Oral liquid preparations include suspensions, liquids for internal use, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, Hank's solution, Ringer's solution, etc. Suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, etc.

[0061] The administration route of the pharmaceutical composition, medicament, veterinary pharmaceutical composition or veterinary medicine includes, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, percutaneous, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal. Oral or parenteral administration is preferred. The term "parenteral" used in the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intradural, intralesional and intracranial injection or infusion techniques, and may also be administered in the form of a suppository for rectal administration.

[0062] The pharmaceutical composition of the present invention can be formulated into a preparation for oral or parenteral administration by the above-mentioned administration route. When formulated, it can be prepared using one or more buffers (e.g., saline or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, extenders, binders, adjuvants (e.g., aluminum hydroxide), suspending agents, thickeners, wetting agents, disintegrating agents or surfactants, diluents or excipients.

[0063] Solid preparations for oral administration include nano dosage forms (forms for increasing bioabsorption rate and capable of rapidly exerting effects), tablets, pills, powders, granules, liquids, gels, syrups, slurries, suspensions, or capsules, and such solid preparations can be prepared by mixing the pharmaceutical composition of the present invention with at least one or more excipients, such as starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol, maltitol, cellulose, methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethyl-cellulose or gelatin, etc. For example, tablets or sugar-coated tablets can be obtained by blending the active ingredient with a solid excipient, pulverizing the mixture, adding appropriate auxiliary agents, and processing it into a granular mixture.

[0064] In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, flavoring agents, or preservatives in addition to water or liquid paraffin, which is a commonly used simple diluent.

[0065] In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, and an anti-coagulant, a lubricant, a wetting agent, a flavoring, an emulsifier, a preservative, and the like may further be included.

[0066] When administered parenterally, the pharmaceutical composition of the present invention can be formulated in the form of injections, transdermal preparations and nasal inhalants together with a suitable parenteral carrier by a method generally known in the art. The injections must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. In the case of injections, examples of suitable carriers include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol), mixtures thereof and / or vegetable oils. More preferably, suitable carriers include Hanks' solution, Ringer's solution, PBS (phosphate buffered saline) containing triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. In order to protect the injections from microbial contamination, various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal and the like may be further included. In most cases, the injections may further contain isotonic agents, such as sugars or sodium chloride.

[0067] The transdermal formulation may be in the form of an ointment, cream, lotion, gel, external liquid, paste, liniment, aerosol, etc. The term "transdermal administration" as used herein means that a pharmaceutical composition is administered topically to the skin, and an effective amount of an active ingredient contained in the pharmaceutical composition is delivered into the skin.

[0068] For inhalation administration, the compound used according to the present invention can be conveniently delivered in aerosol spray form from pressurized packs or nebulizers using suitable propellants, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. For pressurized aerosols, dosage units can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges used in inhalers or insufflators can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch. Dosage forms for parenteral administration are described in the literature (Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour), a formulary commonly known to all pharmaceutical chemists.

[0069] The amount of the pharmaceutical composition, medicament, veterinary pharmaceutical composition or veterinary medicine used may vary depending on the age, sex and weight of the patient or animal being treated, and will depend, among other things, on the condition of the individual being treated, the particular category or type of disease being treated, the route of administration, and the attributes of the therapeutic agent being used.

[0070] The pharmaceutical composition, medicine, veterinary pharmaceutical composition or veterinary medicine is appropriately selected depending on the absorbance and excretion rate of the active ingredient in the body, the age and weight, sex and condition of the patient or the treated animal, the severity of the disease to be treated, etc., and is generally administered at 0.1 to 1,000 mg / kg, preferably 1 to 500 mg / kg, more preferably 5 to 250 mg / kg, and most preferably 10 to 100 mg / kg per day. The unit dosage formulation thus formulated can be administered several times at regular time intervals as necessary. The dosage does not limit the scope of the present invention in any aspect.

[0071] The pharmaceutical composition, medicine, veterinary pharmaceutical composition or veterinary medicine may be administered individually as a preventive or therapeutic agent, or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents.

[0072] The method for treating a muscle disease comprises administering the composition to a human or a non-human animal, particularly a mammal, and specifically may be orally administered, for example by orally administering the composition to an individual having a muscle disease.

[0073] As described above, the subject having a muscle disease may have one or more muscle diseases selected from the group consisting of atony, muscular atrophy, muscular dystrophy, muscle degeneration, myasthenia, cachexia, and sarcopenia, and preferably has one or more muscle diseases selected from the group consisting of sarcopenia, muscular dystrophy, cachexia, or inflammatory muscle diseases. More preferably, the subject individual having a muscle disease may suffer from age-related sarcopenia, in which muscle mass, muscle density and function gradually decrease with aging, and in which muscle mass, muscle strength and physical function have all decreased; or may suffer from muscle function decline, muscle loss, muscle atrophy, muscle wasting or muscle degeneration induced by a specific genetic mutation; or may suffer from cachexia, in which muscle function decline, muscle loss, muscle atrophy or muscle wasting occurs due to cancer or an anticancer drug administered to treat the cancer.

[0074] The dosage, administration method and administration frequency for the treatment can be determined by reference to the dosage, administration method and administration frequency of the pharmaceutical composition, medicament, veterinary pharmaceutical composition or veterinary medicine.

[0075] The present invention relates to a food composition for improving or preventing a muscular disease, which contains oxiracetam, a pharma- ceutical acceptable salt thereof, or a hydrate thereof as an active ingredient.

[0076] The present invention relates to a food composition for improving muscle function, which contains oxiracetam or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0077] In the food composition, the specific details of the Oxiracetam or a pharma- ceutical acceptable salt thereof are as described above.

[0078] The food composition can be used to improve or prevent one or more muscle diseases selected from the group consisting of atony, muscular atrophy, muscular dystrophy, muscle degeneration, myasthenia, cachexia, myositis, and sarcopenia. Specific details of the food composition for the muscle diseases are as described above.

[0079] In the present invention, athletic ability is also called the ability to execute athletics, and refers to physical movements seen in daily life and sports, and generally means the ability to perform the movements when classified into running, jumping, throwing, and swimming. Improvement of athletic ability means improvement or enhancement of the ability to execute athletics, specifically, improvement or enhancement to be able to perform the movements quickly, strongly, accurately, and for a long time, or recovery to original athletic ability or a level superior to original athletic ability when the athletic ability is decreased. The athletic ability can be defined by factors such as muscle strength, agility, and endurance.

[0080] The food composition of the present invention includes all forms of functional foods, nutritional supplements, health function foods, food additives, feeds, etc., and is intended for consumption by humans or animals, including livestock. The food compositions of the above types can be prepared in various forms by conventional methods generally known in the art.

[0081] The "food composition" is a food product that is listed in the Food Standards and Specifications ("Food Regulations") commonly used in the manufacture of food products and contains, in addition to Oxiracetam or a pharma- ceutically acceptable salt thereof as an active ingredient, food ingredients that may be used, and food additives listed in the Food Additives Regulations.

[0082] Although not particularly limited, for example, it includes protein, carbohydrate, fat, nutrient, seasoning and flavoring. The carbohydrate can be monosaccharide, such as glucose, fructose, etc.; disaccharide, such as maltose, sugar, lactose, etc.; oligosaccharide or polysaccharide, such as dextrin, starch syrup, cyclodextrin, etc.; sugar alcohol, such as xylitol, sorbitol, erythritol, etc. The flavoring can be natural flavoring [thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring (saccharin, aspartame, etc.).

[0083] When a food composition is produced using the oxiracetam or a pharma- ceutically acceptable salt thereof as an active ingredient, the amount of oxiracetam or a pharma- ceutically acceptable salt thereof need not be particularly limited as long as it is an amount that is effective against muscle diseases, and may be, for example, 0.1 to 99% by weight, 0.5 to 95% by weight, 1 to 90% by weight, 2 to 80% by weight, 3 to 70% by weight, 4 to 60% by weight, or 5 to 50% by weight.

[0084] The active ingredient in the food composition, oxiracetam or its pharma- ceutically acceptable salt, may be appropriately selected by a person skilled in the art, depending on the condition, weight, presence or absence, severity and duration of illness of the person who takes it. For example, the daily dosage may be 1 to 5,000 mg, preferably 5 to 2,000 mg, more preferably 10 to 1,000 mg, even more preferably 20 to 800 mg, and most preferably 25 to 500 mg, and the number of times of administration is not particularly limited, but may be adjusted by a person skilled in the art within the range of 3 times a day to once a week. In the case of long-term intake for the purpose of health and hygiene or health regulation, the amount may be less than the above range.

[0085] The food composition need not be particularly limited, and may be, for example, a powder, granule, tablet, capsule, pill, extract, jelly, tea bag, or beverage form.

[0086] In addition, in order to impart functionality for preventing or improving muscle diseases and improving muscle function to general foods, Oxiracetam or a pharma- ceutically acceptable salt thereof can be added, and the foods to which it can be added are not particularly limited, but can be, for example, confectionery, bread or rice cakes, processed cocoa products or chocolates, processed meat or egg products, processed fish products, tofu or jelly, noodles, tea, coffee, beverages, special-use foods, soy sauces, seasonings, dressings, kimchi, jeokgal, pickled foods, stewed foods, alcoholic beverages, dried foods, and other foods exemplified in the food standards and ingredient specifications under Article 7 of the Food Sanitation Act ("Food Regulations"). In addition, it can be added to dairy products, processed meat products, packaged meat, and processed egg products exemplified in the processing standards and ingredient specifications for livestock products under Article 4 of the Livestock Products Sanitation Control Act ("Livestock Products Regulations").

[0087] In addition, the food composition containing Oxiracetam or a pharma- ceutical acceptable salt thereof as an active ingredient may be used alone as a "health food with functional properties that helps prevent or improve muscle diseases" or may be used as a "health food with functional properties that helps muscle function."

[0088] The term "health functional foods" refers to foods that are manufactured (including processed) according to legal standards using raw materials or ingredients that have beneficial functionalities for the human body (Article 3, Paragraph 1 of the Health Functional Foods Act). The terminology and scope of "health functional foods" may differ from country to country, but they can be classified as "dietary supplements" in the United States, "food supplements" in Europe, "health functional foods" or "Food for Special Health Use (FoSHU)" in Japan, and "health foods" in China.

[0089] The food composition or health functional food may further contain a food additive, and its suitability as a food additive shall be determined in accordance with the specifications and standards for the item in question, such as the general provisions and general test methods of the "Food Additives Regulations," unless otherwise specified.

[0090] In addition, the health functional food may be used in combination with Oxiracetam or a pharma- ceutically acceptable salt thereof, in addition to a functional ingredient that is notified or individually certified as a functional ingredient used in a "health functional food that helps prevent or improve muscle diseases" or a "health functional food that helps muscle function", and that is related to improving exercise performance or muscle strength, such as fruit extract powder, fermented cordyceps sinensis extract, creatine, or Schisandra chinensis extract.

[0091] The composition of the present invention can be added to a feed additive or a feed composition containing the same for the purpose of preventing or improving muscle diseases.

[0092] The present invention relates to a feed composition for improving muscle function, which contains oxiracetam or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0093] In the present invention, the term "feed additive" includes substances added to feed for various purposes such as supplementing nutrients and preventing weight loss, increasing the digestibility of fiber in the feed, improving milk quality, preventing reproductive disorders and improving conception rates, preventing high temperature stress in summer, etc. The feed additive of the present invention corresponds to an auxiliary feed under the Feed Management Act, and may further include mineral preparations such as sodium bicarbonate, bentonite, magnesium oxide, and complex minerals, mineral preparations such as trace minerals such as zinc, copper, cobalt, and selenium, vitamin preparations such as keratin, vitamins A, D, and E, nicotinic acid, and vitamin B complex, protected amino acid preparations such as methionine and lysine, protected fatty acid preparations such as fatty acid calcium salts, live bacteria preparations (lactic acid bacteria preparations), live bacteria such as yeast cultures and mold fermentation products, yeast preparations, etc.

[0094] In the present invention, the term "feed" refers to any natural or artificial feed, meal, etc., or a component of said meal, which is intended to be eaten, ingested, and digested by any animal, including pets, or is suitable for this purpose. Feed containing the composition for preventing or improving muscle diseases according to the present invention as an active ingredient can be produced in various forms of feed generally known in the art, and preferably may include, but is not limited to, concentrated feed, roughage, and / or special feed.

[0095] Concentrated feed includes, but is not limited to, seeds and nuts including grains such as wheat, oats, and corn; rice bran, bran, and wheat bran as by-products obtained by refining grains; oil cakes, which are by-products obtained by extracting oil from soybeans, rapeseed, sesame, linseed, coconut, and the like; residual starches, which are the main components of starch residues remaining after starch is removed from sweet potatoes, potatoes, and the like; animal feeds such as fish meal, fish waste, fish solubles, which are concentrated fresh liquids obtained from fish, meat meal, blood meal, feather meal, skim milk powder, dried whey, which is the residual liquid when producing cheese from milk and casein from skim milk, yeast, chlorella, and seaweed.

[0096] Roughage includes, but is not limited to, fresh grass feed such as wild grass, pasture grass, and green cuttings, root vegetables such as feed turnip, feed beet, and turnip-like Luterberger, fresh grass, green cutting crops, grains, etc., which are filled into silos and stored by lactic acid fermentation, hay made by cutting and drying wild grass and pasture grass, straw of breeding crops, and leaves of legumes.Special feed includes, but is not limited to, mineral feed such as oyster shells and rock salt, urea feed such as urea and its derivative diureidoisobutane, feed additives that are substances added in small amounts to compound feed to supplement ingredients that tend to be lacking when only natural feed ingredients are mixed or to improve the shelf life of the feed, and nutritional supplements.

[0097] The feed additive for preventing or improving muscle diseases according to the present invention can be prepared by adding oxiracetam in an appropriate effective concentration range using various feed preparation methods generally known in the art.

[0098] The feed additive according to the present invention can be applied to any individual for which the prevention or improvement of muscle diseases is desired, including, for example, non-human animals such as cows, horses, pigs, goats, sheep, dogs, cats, rabbits, etc., birds, and fish. Effect of the Invention

[0099] The oxiracetam of the present invention can prevent, treat or improve muscle diseases. In particular, the oxiracetam has been confirmed to have ameliorative, preventive and therapeutic effects in dexamethasone-treated animal models of muscle atrophy, aging animal models, Duchenne muscular dystrophy animal models and cachectic cell models. The oxiracetam of the present invention can be used in pharmaceutical compositions and food compositions for preventing or treating muscle diseases.

[0100] Specifically, the oxiracetam of the present invention significantly increases muscle strength, muscle diameter, and muscle mass in animal models of muscle atrophy, aging, and genetic muscular dystrophy, and exhibits effects of muscle differentiation, muscle regeneration, and muscle mass increase, and can be used in pharmaceutical or food compositions for improving muscle function. [Brief description of the drawings]

[0101] [Figure 1] 1 is a graph showing the muscle strength (Grip strength) measured in a non-treatment group (normal) and a dexamethasone treatment group (Dexamethasone). [Diagram 2] These are representative images analyzed by dual energy X-ray absorptiometry (DEXA) on the 21st day in the untreated group (normal) and the dexamethasone-treated group (Dexamethasone). [Diagram 3] 1 is a graph showing the diameter (T1) of the tibialis anterior muscle measured on day 21 in the untreated group (normal) and the dexamethasone-treated group (Dexamethasone). [Figure 4]1 is a graph showing the lean body mass measured on day 21 in a non-treatment group (normal) and a dexamethasone treatment group (Dexamethasone). [Diagram 5] 1 is a graph showing the diameter (T1) of the tibialis anterior muscle in a dexamethasone-treated (Dexamethasone, vehicle) and oxiracetam-administered group (Oxiracetam) in a dexamethasone-treated muscle disease model animal. [Figure 6] 1 is a graph showing the results of measuring lean muscle mass (LEAN MASS) of the gastrocnemius muscle (GS) in a dexamethasone-treated group (Dexamethasone, vehicle) and an oxiracetam-administered group (Oxiracetam) in dexamethasone-treated muscle disease model animals. [Figure 7] 1 is a graph showing the lean muscle mass (LEAN MASS) of the tibialis anterior (TA) muscle in a dexamethasone-treated (Dexamethasone, vehicle) and oxiracetam-administered group (Oxiracetam) in dexamethasone-treated muscle disease model animals. [Figure 8] 1 is a graph showing the muscle strength (Grip Strength) measured in a dexamethasone-treated (Dexamethasone, vehicle) group and an oxiracetam-administered group (Oxiracetam) in a dexamethasone-treated muscle disease model animal. [Figure 9] 1 is a graph showing the results of an exercise stress test on muscle function in a dexamethasone-treated muscle disease model animal group (Dexamethasone, vehicle) and an oxiracetam-administered group (Oxiracetam). [Figure 10] This is a graph showing the change in muscle strength (Grip Strength) in aged mice in a control group (Vehicle) and in oxiracetam-administered groups (Oxiracetam 30, Oxiracetam 100, Oxiracetam 300). The control group (Vehicle) was not administered any drug and was treated with saline. [Figure 11]These are representative images of aged mice analyzed by dual energy X-ray absorptiometry (DEXA) on day 83 in the control group (Vehicle) and the oxiracetam-administered groups (Oxiracetam 30, Oxiracetam 100, Oxiracetam 300). [Figure 12] This is a graph showing the lean mass of the tibialis anterior (TA) muscle in aged mice, measured every 7 days in a control group (Vehicle) and oxiracetam-administered groups (Oxi 30, Oxi 100, Oxi 300). [Figure 13] This is a graph showing the lean mass of the gastrocnemius muscle (GS) of aged mice, measured every 7 days, in a control group (Vehicle) and in oxiracetam-administered groups (Oxi 30, Oxi 100, Oxi 300). [Figure 14] 14A and 14B are graphs showing the results of an exercise stress test on muscle function in aged mice in a control group (Vehicle) and oxiracetam-administered groups (Oxi 30, Oxi 100, Oxi 300), where FIG. 14A shows the running distance (m) and FIG. 14B shows the running time (sec). [Figure 15] This is a graph showing the changes in muscle strength (Grip Strength) measured in a control group (Vehicle) and oxiracetam-administered groups (Oxi 42, Oxi 83, Oxi 167, Oxi 333) in aged mice. [Figure 16] This is a graph showing representative images analyzed by dual energy X-ray absorptiometry (DEXA) on day 91 in aged mice in a control group (Vehicle) and oxiracetam-administered groups (Oxi 42, Oxi 83, Oxi 167, Oxi 333) and the lean mass of the gastrocnemius muscle (GS) measured every 7 days. [Figure 17]This is a graph showing the lean mass of the tibialis anterior (TA) muscle measured every 7 days in aged mice in a control group (Vehicle) and oxiracetam-treated groups (Oxi 42, Oxi 83, Oxi 167, Oxi 333). [Figure 18] This is a graph showing the changes in muscle strength (Grip Strength) measured in a control group (Vehicle), a dexamethasone-treated group (Dexamethasone, vehicle), and drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, prami 30, briva 30, roli 30). [Figure 19] This is a graph showing the change in muscle strength (Grip Strength) measured in a control group (Vehicle), a dexamethasone-treated group (Dexamethasone, vehicle), and drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, leveti 30, nefi 30, colu 30). [Figure 20] This is a graph showing the change in grip strength from day 0 to day 21 in the control group (Vehicle), dexamethasone treatment group (Dexamethasone, vehicle), and drug administration groups (Oxi 30, Rolzi 30, Faso 30, Prami 30). [Figure 21] This is a graph showing the lean mass of the tibialis anterior (TA) muscle measured every 7 days in the control group (Vehicle), dexamethasone-treated group (Dexamethasone, vehicle), and drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, leveti 30, nefi 30, colu 30). [Figure 22]This is a graph showing the lean mass of the tibialis anterior (TA) muscle measured every 7 days in the control group (Vehicle), dexamethasone-treated group (Dexamethasone, vehicle), and drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, prami 30, briva 30, and roli 30). [Figure 23] This is a graph showing the lean mass of the tibialis anterior (TA) muscle measured every 7 days in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (oxi 30, rolzi 30, faso 30, prami 30). [Figure 24] This is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days in the control group (Vehicle), dexamethasone treatment group (Dexamethasone, vehicle), and drug administration groups (oxi 30, pi 100, phenylpi 30, ani 30, leveti 30, nefi 30, colu 30). [Diagram 25] This is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days in the control group (Vehicle), dexamethasone treatment group (Dexamethasone, vehicle), and drug administration groups (oxi 30, rolzi 30, faso 30, prami 30). [Figure 26] This is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days in the control group (Vehicle), dexamethasone treatment group (Dexamethasone, vehicle), and drug administration groups (oxi 30, pi 100, phenylpi 30, ani 30, prami 30, briva 30, and roli 30). [Figure 27]This is a graph showing the change in grip strength from day 0 to day 21 in the control group (Vehicle), dexamethasone treatment group (Dexamethasone, vehicle), and drug administration groups (Oxiracetam 30, Mirtazapine 10, Olanzapine 10). [Figure 28] This is a graph showing the lean mass of the tibialis anterior (TA) muscle measured every 7 days in the control group (Vehicle), dexamethasone-treated group (Dexamethasone, vehicle), and drug-administered groups (Oxiracetam 30, Mirtazapine 10, Olanzapine 10). [Figure 29] This is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days in the control group (Vehicle), the dexamethasone treatment group (Dexamethasone, vehicle), and the drug administration groups (Oxiracetam 30, Mirtazapine 10, Olanzapine 10). [Diagram 30] These are photographs of the distribution of body fat in a control group (Vehicle) and a drug-administered group (Oxiracetam) taken using dual energy X-ray absorptiometry (DEXA). [Diagram 31] 1 is a graph showing the results of measuring total lean body mass in a control group (Vehicle) and a drug administration group (Oxiracetam). [Diagram 32] 1 is a graph showing the results of measuring body fat mass (fat, %) in a control group (Vehicle) and a drug administration group (Oxiracetam). [Diagram 33] These are photographs of the control group (Vehicle) and the drug-administered group (Oxiracetam) measured using the DEXA method (dual energy X-ray absorptiometry, DEXA). [Diagram 34]1 is a graph showing the lean body mass of the Tibialis Anterior (TA) muscle in a control group (Vehicle) and a drug-administered group (Oxiracetam). [Diagram 35] 1 is a graph showing the results of measuring lean body mass in the gastrocnemius muscle (GS) of a control group (Vehicle) and a drug administration group (Oxiracetam). [Diagram 36] This is a graph showing the results of measuring changes in muscle strength (Grip Strength) in a control group (Vehicle) and a drug administration group (Oxiracetam). [Figure 37] 1 is a graph showing the results of measuring changes in body weight in a control group (Vehicle) and a drug-administered group (Oxiracetam). [Figure 38] 1 is a graph showing the results of confirming the degree of change in ATP content in myotube cells between an oxiracetam-treated group (Oxiracetam 10 μM) and a non-treated group (solvent-treated, control). [Figure 39] The photographs were taken with an optical microscope of TNF-α-treated (TNF-α 10 ng / ml) myotube cells (Myotube) treated with oxiracetam (10 μM) and untreated (0 μM, TNF-α 10 ng / ml). The control group was treated with the solvent (no TNF-α or oxiracetam treatment). [Diagram 40] This is a graph showing the diameter of myotube cells (Myotube) measured in TNF-α-treated (TNF-α 10 ng / ml) myotube cells (Myotube) in an oxiracetam-treated group (Oxiracetam 10 μM) and a non-treated group (Oxiracetam 0 μM, TNF-α 10 ng / ml). The control group is a non-treated group (TNF-α or Oxiracetam-untreated group). [Diagram 41]The photographs are taken with an optical microscope of an anticancer drug treatment group (Doxorubicin), an oxiracetam treatment group (Oxiracetam 0.01 μM, 0.1 μM, 1 μM, 10 μM, 30 μM) and a control group (control). [Diagram 42] 1 is a graph showing the measurement results of the diameter of myotubes in an anticancer drug treatment group (Doxorubicin), an oxiracetam treatment group (Oxiracetam 0.01 μM, 0.1 μM, 1 μM, 10 μM, 30 μM), and a control group (control). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0102] Hereinafter, preferred examples will be presented to aid in understanding the present invention. However, the following examples are merely illustrative of the present invention, and it will be apparent to those skilled in the art that various changes and modifications are possible within the scope and technical spirit of the present invention. Naturally, such changes and modifications also fall within the scope of the appended claims.

[0103] <Example> Oxiracetam having the structure of Chemical Formula 1 (product number: O0398, CAS RN: 62613-82-5, purity: 96%) was purchased and used.

[0104] [Chemical formula 1] [ka]

[0105] <Test Example> Test Example 1. Drug efficacy analysis in an animal model of sarcopenia 1-1. Preparation of experimental animals and samples In the present invention, Oxiracetam was purchased from Tokyo Chemical Industry Co., Ltd. (Japan) (product number: O0398, CAS RN: 62613-82-5, purity: 96%) and used in the experimental group.

[0106] The experimental animals were 7-week-old male ICR mice purchased and used. The experimental animals were provided with regular feed (EEGJ30060: Cargill Agri Purina, Seongnam, Korea) and sufficient water until the day of the experiment, and were adapted to an environment of 23±2°C, 55±10% humidity, and 12-12 hours (light-dark cycle) for one week before use.

[0107] After the adaptation period for the experimental animals, mice were randomly assigned to the following groups to create muscle atrophy models: untreated group (normal, n=10), dexamethasone-treated group (Dexamethasone, n=10), and oxiracetam-treated group (Oxiracetam, n=10), with 10 mice per group. All groups except the untreated group were intraperitoneally injected with 10 mg / kg of dexamethasone for 14 days from the 7th to the 21st. The oxiracetam-treated group was orally administered oxiracetam at a dose of 30 mg / kg / day once a day for 21 days using a probe, starting 7 days before intraperitoneal administration of dexamethasone. During the same period, the untreated group was not administered any drugs, and saline was orally administered at 100 μl once.

[0108] [Table 1]

[0109] 1-2. Lean changes The lean mass of the gastrocnemius and tibialis anterior muscles of each group was measured every 7 days. Specifically, the animal models of each group were anesthetized with 3% isoflurane, fixed on a bed, and then photographed. During the photographing, the respiratory rate and body temperature of the animal models were measured with an animal monitoring system (SA instrument, USA).

[0110] The animal model was imaged by dual energy X-ray absorptiometry (DEXA) using an iNSiGHT VET DXA (Osteosys, KR) device to image the whole body, and the lean body mass of the gastrocnemius muscle (GS) and tibialis anterior (TA) was measured and calculated using the region of interest (ROI) of the two-dimensional images of the gastrocnemius muscle (GS) and tibialis anterior (TA) as a program.

[0111] 1-3. Muscle strength measurement Grip strength test was performed to measure muscle strength. The tail of the animal model of each group was grabbed so that the rod of the device could be grasped with two front paws, and the rear end was pulled horizontally in this state. The maximum force exerted when the front paws of the animal model of each group could no longer grasp the rod of the device was regarded as grip strength (g). Measurements were performed once every two days, 11 times for each mouse.

[0112] 1-4. Diameter of the Tibialis anterior (T1) Two-dimensional images were taken for each group using dual-energy X-ray absorptiometry, and the diameter of T1 (tibialis anterior) was measured and compared.

[0113] 1-5. Exercise stress test (Treadmill test) Before the measurement, each group of experimental animals was adapted to the treadmill twice (first time: 10° incline, 5m / min for 10 minutes, 10m / min for 10 minutes, second time: 10° incline, 5m / min for 5 minutes, 10m / min for 15 minutes). On the day of the experiment, the animals were initially made to run at a speed of 10m / min with a 10° incline for 20 minutes, and then the speed was increased by 2m / min every 2 minutes, and the end point was when the animals remained without running for 10 seconds, and the running time and distance were measured.

[0114] 1-6.Statistical analysis Statistical analysis was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each repeated experiment are shown as mean ± standard errors of mean and analyzed using analysis of variance (Tukey's test). Statistical significance was recognized when the P-value was 0.05 or less.

[0115] Figure 1 is a graph showing the measurement of muscle strength (grip strength) in the untreated group (normal) and the dexamethasone-treated group (Dexamethasone), Figure 2 is a representative image of the untreated group (normal) and the dexamethasone-treated group (Dexamethasone) analyzed by dual energy X-ray absorptiometry (DEXA) on day 21. Figure 3 is a graph showing the measurement of the diameter (T1) of the tibialis anterior muscle, and Figure 4 is a graph showing the measurement of lean mass (lean) on day 21 in the untreated group (normal) and the dexamethasone-treated group (Dexamethasone).

[0116] As shown in Figures 1 to 4, the dexamethasone treatment group showed a decrease in muscle strength, a significant decrease in the diameter of the tibialis anterior muscle (T1), and a large decrease in lean muscle mass after 14 days of dexamethasone administration. This indicates that a muscle loss model was created that induces muscle atrophy similar to age-related muscle atrophy through dexamethasone administration.

[0117] Figure 5 is a graph showing the diameter (T1) of the tibialis anterior muscle of the dexamethasone-treated group (Dexamethasone, vehicle) and the oxiracetam-treated group (Oxiracetam), Figure 6 is a graph showing the lean mass of the gastrocnemius muscle (GS) of the dexamethasone-treated group (Dexamethasone, vehicle) and the oxiracetam-treated group (Oxiracetam), Figure 7 is a graph showing the lean mass of the tibialis anterior muscle (TA) of the dexamethasone-treated group (Dexamethasone, vehicle) and the oxiracetam-treated group (Oxiracetam). Figure 8 shows the results of the grip strength test of the dexamethasone-treated group (Dexamethasone, vehicle) and the oxiracetam-treated group (Oxiracetam). In this case, the Oxiracetam administration group (Oxiracetam) was indicated in the figure as "Dex+Oxiracetam (30 mg / kg)."

[0118] Figures 5 and 8 show the results of an attempt to confirm the preventive or therapeutic effect of oral administration of Oxiracetam on skeletal muscle atrophy or muscle weakness. Specifically, the diameter of the Tibialis Anteriors (TA), lean mass of the Tibialis Anterior (TA), lean mass of the Gastrocnemius Muscle (GS), and muscle strength test (Grip Strength) were confirmed for the Dexamethasone treatment group (Dexamethasone, vehicle) and Oxiracetam treatment group (Oxiracetam).

[0119] As shown in Figures 5 and 7, the diameter of the Tibialis Anteriors (TA) in the Oxiracetam-administered group (Oxiracetam) was significantly increased compared to the Dexamethasone-administered group (Dexamethasone, vehicle).

[0120] As shown in Figures 6 and 7, in the case of lean muscle mass of the Tibialis Anteriors (TA) and the Gastrocnemius Muscle (GS), the Oxiracetam group showed a significantly more suppressed decrease than the Dexamethasone group (Dexamethasone, vehicle). In other words, the Dexamethasone group (Dexamethasone, vehicle) showed a large overall decrease in lean muscle mass from the time of Dexamethasone treatment, but the Oxiracetam group (Oxiracetam) showed no significant decrease even after Dexamethasone treatment.

[0121] As shown in FIG. 8, it can be seen that the oxiracetam administration group (Oxiracetam) showed a significant increase in muscle strength compared to the dexamethasone treatment group (Dexamethasone, vehicle).

[0122] Taken together, the Oxiracetam group significantly suppressed skeletal muscle atrophy and loss compared to the Dexamethasone group (vehicle), which shows the same tendency as in aged mice.

[0123] FIG. 9 is a graph showing the results of an exercise stress test for the dexamethasone-treated group (Dexamethasone, vehicle) and the oxiracetam-treated group (Oxiracetam). This shows that the oxiracetam-treated group (Oxiracetam) had significantly greater improvements in exercise ability (muscle strength and endurance) than the dexamethasone-treated group (Dexamethasone, vehicle).

[0124] Test Example 2. Efficacy analysis of Oxiracetam in aging animal models 2-1. Preparation of experimental animals and samples In the present invention, Oxiracetam was purchased from Tokyo Chemical Industry Co., Ltd. (Japan) (product number: O0398, CAS RN: 62613-82-5, purity: 96%) and used in the experimental group.

[0125] As a model of age-related sarcopenia, 22-month-old male C57BL / 6J mice were used. The animals were provided with regular feed (EEGJ30060: Cargill Agri Purina, Seongnam, Korea) and sufficient water until the day of the experiment, and were allowed to adapt to an environment of 23±2°C, 55±10% humidity, and 12-12 hours (light-dark cycle) for one week before use.

[0126] Ten rats per group were randomly assigned to a control group (vehicle, n=10) and 30, 100, or 300mg / kg / day oxiracetam groups (Oxiracetam, n=10 for each concentration). The oxiracetam groups were orally administered oxiracetam at doses of 30, 100, or 300mg / kg / day using a probe once a day for 90 days. During the same period, the control group received no drugs and was orally administered 100μl of saline once a day.

[0127] [Table 2]

[0128] 2-2. Muscle strength measurement Grip strength test was performed to measure muscle strength. The tail of the animal model of each group was grabbed so that the rod of the device could be grasped with both front paws, and the tail was pulled horizontally in this state. The maximum force presented when the front paws of the animal model of each group could no longer grasp the rod of the device was considered as grip strength (N). Measurements were performed once every three days, and the average value was shown after five repeated measurements each time. Grip strength adaptation training was performed more than three times before drug administration.

[0129] 2-3. Lean changes The lean mass of the gastrocnemius muscle (GS) and tibialis anterior (TA) of each group was measured every 7 days. Specifically, the animal models of each group were anesthetized with 3% isoflurane and fixed on a bed before being photographed. During the photographing, the respiratory rate and body temperature of the animal models were measured with an animal monitoring system (SA instrument, USA).

[0130] The animal model was imaged by dual energy X-ray absorptiometry (DEXA) using an iNSiGHT VET DXA (Osteosys, KR) device to image the whole body, and the lean body mass of the gastrocnemius muscle (GS) and tibialis anterior (TA) was measured and calculated using the region of interest (ROI) of the two-dimensional images of the gastrocnemius muscle (GS) and tibialis anterior (TA) as a program.

[0131] 2-4. Exercise stress test (Treadmill test) An exercise load test was conducted 90 days after the start of the experiment. Each group of experimental animals was adapted to a treadmill twice before the measurement (first time: 10° incline, 5m / min, 10min, 10m / min, second time: 10° incline, 5m / min, 5min, 10m / min, 15min). On the day of the experiment, the animals were made to run for 20 minutes at an incline of 10°, starting from a speed of 10m / min. The speed was increased by 2m / min every 2 minutes, and the end point was when the animals remained without running for 10 seconds. The running time (sec) and distance (m) were measured and shown.

[0132] 2-5.Statistical analysis Statistical analysis was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each repeated experiment are shown as mean ± standard errors of mean and analyzed using analysis of variance (Tukey's test). Statistical significance was recognized when the P-value was 0.05 or less.

[0133] Figure 10 is a graph showing the change in grip strength in aged mice administered oxiracetam (Oxi 30, Oxi 100, Oxi 300), with the control group (vehicle) being treated with saline without any drug. In the case of the control group, an aged animal model (22 months old), it can be seen that muscle strength significantly decreases over time. In contrast, in the groups treated with oxiracetam (Oxi 30, Oxi 100, Oxi 300), it can be seen that the decrease in muscle strength is significantly suppressed and in fact increases.

[0134] FIG. 11 is a representative image of dual energy X-ray absorptiometry (DEXA) analysis on the 83rd day for the control group (Vehicle) and the oxiracetam-administered groups (Oxi 30, Oxi 100, Oxi 300). FIG. 12 is a graph showing lean mass of the tibialis anterior (TA) muscle in the control group (Vehicle) and the oxiracetam-administered groups (Oxi 30, Oxi 100, Oxi 300) measured every 7 days. FIG. 13 is a graph showing lean mass of the gastrocnemius muscle (GS) in the control group (Vehicle) and the oxiracetam-administered groups (Oxi 30, Oxi 100, Oxi 300) measured every 7 days.

[0135] As shown in Figures 12 and 13, the groups treated with oxiracetam (Oxi 30, Oxi 100, Oxi 300) showed an increase in lean mass in the Tibialis Anteriors (TA) and Gastrocnemius Muscle (GS) rather than a decrease compared to the control group, an aged (22-month-old) animal model, and showed a stable increase in lean mass from the 7th week. In particular, the Oxi 300 group showed a significant increase in lean mass in the Gastrocnemius Muscle (GS) from the 7th week.

[0136] FIG. 14 is a graph showing the results of an exercise stress test, which is a muscle function measurement item, in the control group (Vehicle) and the oxiracetam administration groups (Oxi 30, Oxi 100, Oxi 300). FIG. 14a shows the running distance (m), and FIG. 14b shows the running time (sec).

[0137] As shown in Figure 14, the groups treated with oxiracetam (Oxi 30, Oxi 100, Oxi 300) did not show a decrease in physical executive ability (motor ability) compared to the control group, an aged animal model (22 months old), and in fact showed an increase, with the Oxi 300 group showing a significantly greater increase.

[0138] Therefore, it can be seen that oxiracetam according to the present invention has the effect of not only inhibiting and preventing aging-induced muscle loss, which is a symptom of sarcopenia, but also increasing / restoring it.

[0139] Test Example 3. Efficacy analysis of Oxiracetam at different concentrations in an aging animal model 3-1. Preparation of experimental animals and samples In the present invention, Oxiracetam was purchased from Tokyo Chemical Industry Co., Ltd. (Japan) (product number: O0398, CAS RN: 62613-82-5, purity: 96%) and used in the experimental group.

[0140] As a model of age-related sarcopenia, 24-month-old male C57BL / 6J mice were used. The animals were provided with regular feed (EEGJ30060: Cargill Agri Purina, Seongnam, Korea) and sufficient water until the day of the experiment, and were allowed to adapt to an environment of 23±2°C, 55±10% humidity, and 12-12 hours (light-dark cycle) for one week before use.

[0141] Ten rats per group were randomly assigned to a control group (vehicle, n=10) and groups administered oxiracetam at 42, 83, 167, or 333mg / kg / day (Oxiracetam, n=10 for each concentration). The Oxiracetam groups were orally administered oxiracetam at doses of 42, 83, 167, or 333mg / kg / day using a probe once a day for 93 days. During the same period, the control group received no drugs and was orally administered 100μl of saline once a day.

[0142] [Table 3]

[0143] 3-2. Muscle strength measurement A grip strength test was conducted to measure muscle strength (Grip strength). The tail of the animal model of each group was grabbed so that the rod of the device could be grasped with both front paws, and the tail was pulled horizontally in this state. The maximum force exerted when the front paws of the animal model of each group could no longer grasp the rod of the device was considered as grip strength (N). Measurements were performed once every three days, and the average value was shown after five repeated measurements each time. Grip strength adaptation training was performed more than three times before drug administration.

[0144] 3-3. Lean changes The lean mass of the gastrocnemius and tibialis anterior muscles of each group was measured every 7 days. Specifically, the animal models of each group were anesthetized with 3% isoflurane and fixed on a bed for imaging before imaging. During imaging, the respiratory rate and body temperature of the animal models were measured with an animal monitoring system (SA instrument, USA).

[0145] The animal model was imaged by dual energy X-ray absorptiometry (DEXA) using an iNSiGHT VET DXA (Osteosys, KR) device to image the whole body, and the lean body mass of the gastrocnemius muscle (GS) and tibialis anterior (TA) was measured and calculated using the region of interest (ROI) of the two-dimensional images of the gastrocnemius muscle (GS) and tibialis anterior (TA) as a program.

[0146] 3-4.Statistical analysis Statistical analysis was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each repeated experiment are shown as mean ± standard errors of mean and analyzed using analysis of variance (Tukey's test). Statistical significance was recognized when the P-value was 0.05 or less.

[0147] Figure 15 is a graph showing the change in muscle strength (Grip Strength) in the control group (Vehicle) and the oxiracetam-administered groups (Oxi 42, Oxi 83, Oxi 167, Oxi 333). In the case of the control group, which is an aged (24-month-old) animal model, it can be seen that muscle strength significantly decreased over time. In contrast, in the oxiracetam-treated groups (Oxi 42, Oxi 83, Oxi 167, Oxi 333), it can be seen that the decrease in muscle strength was significantly suppressed and in fact increased. It was confirmed that the effect of oxiracetam increased in a concentration-dependent manner.

[0148] FIG. 16 shows representative images analyzed by dual energy X-ray absorptiometry (DEXA) on day 91 in the control group (Vehicle) and the oxiracetam-administered groups (Oxi 42, Oxi 83, Oxi 167, Oxi 333) and a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days. FIG. 17 shows the lean mass of the tibialis anterior (TA) measured every 7 days in the control group (Vehicle) and the oxiracetam-administered groups (Oxi 42, Oxi 83, Oxi 167, Oxi 333).

[0149] As shown in Figures 16 and 17, the control group, which is an aged animal model (24 months old), showed a significant decrease in fat-free mass in the Gastrocnemius Muscle (GS) and Tibialis Anteriors (TA) over time. On the other hand, the groups treated with oxiracetam (Oxi 42, Oxi 83, Oxi 167, Oxi 333) showed a significant increase in fat-free mass in the Gastrocnemius Muscle (GS) and Tibialis Anteriors (TA) compared to the control group, which is an aged animal model (24 months old), with the Oxi 333 group showing the largest increase.

[0150] Therefore, it can be seen that oxiracetam according to the present invention has the effect of not only inhibiting and preventing aging-induced muscle loss, which is a symptom of sarcopenia, but also increasing / restoring it.

[0151] Test Example 4. Comparison of efficacy with racetam drugs 4-1. Preparation of experimental animals and samples In the present invention, oxiracetam was purchased from Tokyo Kasei Kogyo Co., Ltd. (Japan, product number: O0398, CAS RN: 62613-82-5, purity: 96%) for the experimental group. Other racetam drugs, aniracetam and nefiracetam, were purchased from BiDe (China, product numbers: BD114391, BD140804, purity: 96%). Piracetam, phenylpiracetam, coluracetam and pramiracetam were purchased from Tokyo Kasei Kogyo Co., Ltd. (Japan, product numbers: P2880, P2604, C3689, P2061, purity: 96%). Levetiracetam was purchased from LuoEn (China, product number: R025860, purity: 96%). Brivaracetam was purchased from R&D The following compounds were purchased from System (USA, product number: 7271, purity: 96%), lorziracetam and fasoracetam were purchased from Targetmol (USA, product numbers: T16783 and T19624, purity: 96%), and rolipram was purchased from Aladdin (China, product number: R129674, purity: 96%).

[0152] The experimental animals were 7-week-old male ICR mice purchased and used. The experimental animals were provided with regular feed (EEGJ30060: Cargill Agri Purina, Seongnam, Korea) and sufficient water until the day of the experiment, and were allowed to adapt to an environment of 23±2°C, 55±10% humidity, and 12-12 hours (light-dark cycle) for one week before use. After the adaptation period, mice were randomly assigned to a control group (Vehicle, n=7), a dexamethasone-treated group (Dexamethasone, n=7), and a drug-treated group (n=7) with 10 mice per group to create a muscle atrophy model. All groups except the control group were intraperitoneally injected with dexamethasone at 10mg / kg for 14 days from the 7th to the 21st. The drug-treated groups were orally administered drugs at a dose of 30 or 100mg / kg / day once a day for 21 days starting 7 days before intraperitoneal administration of dexamethasone. During the same period, the control group was not administered any drugs, but was orally administered 100μl of saline per time. The dexamethasone-treated group (Dexamethasone, vehicle) was added with 100μl of 0.5% CMC (0.5% carboxymethylcellulose) solution instead of drugs. This is to set the effect of the vehicle as a blank.

[0153] [Table 4]

[0154] 4-2. Muscle strength measurement A grip strength test was conducted to measure muscle strength. The tail of the animal model of each group was grabbed so that the rod of the device could be grasped with both front paws, and the tail was pulled horizontally in this state. The maximum force presented when the front paws of the animal model of each group could no longer grasp the rod of the device was considered as grip strength (N). Grip strength adaptation training was performed more than three times before drug administration. After measuring before drug administration (day 0) and on the 20th day of drug administration, the change in muscle strength (%) after drug administration (day 20) compared to before drug administration (day 0) was calculated and shown.

[0155] 4-3. Lean changes The lean mass of the gastrocnemius and tibialis anterior muscles of each group was measured every 7 days. Specifically, the animal models of each group were anesthetized with 3% isoflurane and fixed on a bed for imaging before imaging. During imaging, the respiratory rate and body temperature of the animal models were measured with an animal monitoring system (SA instrument, USA).

[0156] The animal model was imaged by dual energy X-ray absorptiometry (DEXA) using an iNSiGHT VET DXA (Osteosys, KR) device to image the whole body, and the lean body mass of the gastrocnemius muscle (GS) and tibialis anterior (TA) was measured and calculated using the region of interest (ROI) of the two-dimensional images of the gastrocnemius muscle (GS) and tibialis anterior (TA) as a program.

[0157] 4-4.Statistical analysis Statistical analysis was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each repeated experiment are shown as mean ± standard errors of mean and analyzed using analysis of variance (Tukey's test). Statistical significance was recognized when the P-value was 0.05 or less.

[0158] FIG. 18 is a graph showing the results of measuring changes in muscle strength (Grip Strength) in the control group (Vehicle), dexamethasone-treated groups (Dexamethasone, vehicle), and drug-administered groups (Oxi 30, Pi 100, Phenylpi 30, Ani 30, Prami 30, Briva 30, and Roli 30). FIG. 19 is a graph showing the results of measuring changes in muscle strength (Grip Strength) in the control group (Vehicle), dexamethasone-treated groups (Dexamethasone, vehicle), and drug-administered groups (Oxi 30, Pi 100, Phenylpi 30, Ani 30, Leveti 30, Nefi 30, and Colu 30). FIG. 20 is a graph showing the results of measuring changes in muscle strength (Grip Strength) in the control group (Vehicle), dexamethasone-treated groups (Dexamethasone, vehicle), and drug-administered groups (Oxi 30, Rolzi 30, Faso 30, and Prami 30) is a graph showing the results of measuring changes in muscle strength (Grip Strength).

[0159] As shown in Figures 18, 19 and 20, it was confirmed that the control group did not show any increase in muscle strength. However, it was confirmed that the dexamethasone treatment group showed a significant decrease in muscle strength over time. From this, it can be seen that the racetam drugs, which have the same mechanism as oxiracetam, were administered to the comparison group, and that, except for oxiracetam, they did not show any significant muscle strength recovery effect.

[0160] It was confirmed that the oxiracetam group (Oxi 30) not only prevented muscle weakness in an animal model in which muscle atrophy was induced by dexamethasone through administration of 30 mg / kg / day, but also recovered muscle strength to a level higher than that of the control group (vehicle). Therefore, it was confirmed that the ameliorative, preventive, and therapeutic effects of oxiracetam of the present invention on muscle weakness cannot be obtained even though it is a racetam drug having the same mechanism as oxiracetam.

[0161] FIG. 21 is a graph showing the lean mass of the tibialis anterior (TA) muscle in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, leveti 30, nefi 30, colu 30) measured every 7 days. FIG. 22 is a graph showing the lean mass of the tibialis anterior (TA) muscle in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, prami 30, briva 30, and rolli 30). FIG. 23 is a graph showing lean mass (LEM) of the tibialis anterior (TA) muscle in a control group (Vehicle), a dexamethasone-treated group (Dexamethasone, vehicle), and drug-administered groups (oxi 30, rolzi 30, faso 30, prami 30) measured every 7 days, with the exception that FIG. 26 shows the calculated change in lean mass (%) in the drug-administered groups compared to the control group (Vehicle).

[0162] As shown in Figures 21, 22 and 23, the control group showed little change in fat loss in the Tibialis Anteriors (TA), while the dexamethasone-treated group showed a significant decrease in fat loss in the Tibialis Anteriors (TA) over time. As a result, when the comparison group was treated with a racetam drug having the same mechanism as oxiracetam, all racetam drugs except oxiracetam did not restore fat loss in the Tibialis Anteriors (TA), but rather decreased it, as in the dexamethasone-treated group.

[0163] Meanwhile, the oxiracetam group (Oxi 30) not only prevented the loss of fat mass in the tibialis anterior (TA) muscle of the animal model in which muscle atrophy was induced by dexamethasone through administration of 30 mg / kg / day, but also restored fat mass in the TA muscle to the control group (vehicle) level. Therefore, it was confirmed that the ameliorative, preventive and therapeutic effects of oxiracetam of the present invention on muscle wasting cannot be obtained even though it is a racetam drug having the same mechanism as oxiracetam.

[0164] FIG. 24 is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, leveti 30, nefi 30, colu 30). FIG. 25 is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (oxi 30, rolzi 30, faso 30, prami 30). FIG. 25 is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days in the control group (Vehicle), dexamethasone-treated group (Dexamethasone, vehicle), and drug-administered groups (oxi 30, pi 100, phenylpi 30, ani 30, prami 30, briva 30, and roli 30).

[0165] As shown in Figures 24, 25 and 26, the control group showed little change in fat loss, while the dexamethasone-treated group showed a significant and remarkable decrease in fat loss in the gastrocnemius muscle (GS) over time. As a result of treating the comparison group with a racetam drug having the same mechanism as oxiracetam, all racetam drugs except oxiracetam showed a significant decrease in fat loss in the gastrocnemius muscle (GS) without recovery, as in the dexamethasone-treated group (Dexamethasone, vehicle).

[0166] Meanwhile, it was confirmed that the oxiracetam administration group (Oxi 30) not only prevented the loss of fat mass in the gastrocnemius muscle of the animal model in which muscle atrophy was induced by dexamethasone through administration of 30 mg / kg / day, but also restored fat mass in the gastrocnemius muscle to the control group (vehicle) level. Therefore, it was confirmed that the ameliorative, preventive and therapeutic effects of oxiracetam of the present invention on muscle wasting cannot be obtained, even though it is a racetam drug having the same mechanism as oxiracetam.

[0167] Through the above experiments, it has been confirmed that oxiracetam, which is the active ingredient of the present invention, has a significantly remarkable muscle strength and lean mass recovery effect compared to other racetam drugs (piracetam, oxiracetam, phenylpiracetam, aniracetam, levetiracetam, nefiracetam, coluracetam, rolziracetam, fasoracetam, pramiracetam, brivaracetam, rolipram). In particular, it has been confirmed that oxiracetam, which is a derivative of piracetam, has a significantly more significant muscle strength and muscle mass recovery effect than piracetam.

[0168] Test Example 5. Comparison of efficacy with dementia medication 5-1. Preparation of experimental animals and samples In the present invention, Oxiracetam was purchased from Tokyo Chemical Industry Co., Ltd. (Japan) (product number: O0398, CAS RN: 62613-82-5, purity: 96%) and used as an experimental group. Mirtazapine and Olanzapine were purchased from Tokyo Chemical Industry Co., Ltd. (Japan, product number: M2151, O0393, purity: 96%) and used.

[0169] The experimental animals were 7-week-old male ICR mice purchased and used. The experimental animals were provided with regular feed (EEGJ30060: Cargill Agri Purina, Seongnam, Korea) and sufficient water until the day of the experiment, and were allowed to adapt to an environment of 23±2°C, 55±10% humidity, and 12-12 hours (light-dark cycle) for one week before use.

[0170] After the adaptation period of the experimental animals, mice were randomly assigned to a control group (Vehicle, n=7), a dexamethasone treatment group (Dexamethasone, n=7), and a drug administration group (n=7) with 10 mice per group to create a muscle atrophy model. All groups except the control group were intraperitoneally injected with dexamethasone at 10mg / kg for 14 days from the 7th to the 21st. The drug administration groups were orally administered drugs at a dose of 30 or 10mg / kg / day once a day for 21 days starting 7 days before intraperitoneal administration of dexamethasone. During the same period, the control group was not administered any drugs, and saline was orally administered at 100μl per time. The dexamethasone treatment group (Dexamethasone vehicle, CMC) was added with 100μl of 0.5% CMC (0.5% carboxymethylcellulose) solution instead of drugs. This is to set the effect of the vehicle as a blank.

[0171] [Table 5]

[0172] 5-2. Muscle strength measurement Grip strength tests were performed to measure muscle strength. The tails of the animal models in each group were grabbed so that the rods of the device could be grasped with both front paws, and the tails were pulled horizontally in this state. The maximum force exerted when the front paws of the animal models in each group could no longer grasp the rods of the device was regarded as grip strength (N). Grip strength adaptation training was performed three or more times before drug administration. Measurements were performed before drug administration (day 0) and on the 20th day of drug administration, and the change in muscle strength (%) after drug administration (day 20) compared to before drug administration (day 0) was calculated and shown.

[0173] 5-3. Lean changes The lean mass of the gastrocnemius and tibialis anterior muscles of each group was measured every 7 days. Specifically, the animal models of each group were anesthetized with 3% isoflurane and fixed on a bed for imaging before imaging. During imaging, the respiratory rate and body temperature of the animal models were measured with an animal monitoring system (SA instrument, USA).

[0174] The animal model was imaged by dual energy X-ray absorptiometry (DEXA) using an iNSiGHT VET DXA (Osteosys, KR) device to image the whole body, and the lean body mass of the gastrocnemius muscle (GS) and tibialis anterior (TA) was measured and calculated using the region of interest (ROI) of the two-dimensional images of the gastrocnemius muscle (GS) and tibialis anterior (TA) as a program.

[0175] 5-4.Statistical analysis Statistical analysis was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each repeated experiment are shown as mean ± standard errors of mean and analyzed using analysis of variance (Tukey's test). Statistical significance was recognized when the P-value was 0.05 or less.

[0176] FIG. 27 is a graph showing changes in muscle strength (Grip Strength) measured in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (Oxiracetam 30, Mirtazapine 10, Olanzapine 10). FIG. 28 is a graph showing lean mass of the tibialis anterior (TA) muscle measured every 7 days in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (Oxiracetam 30, Mirtazapine 10, Olanzapine 10). FIG. 29 is a graph showing lean mass of the tibialis anterior (TA) muscle measured every 7 days in the control group (Vehicle), the dexamethasone-treated group (Dexamethasone, vehicle), and the drug-administered groups (Oxiracetam 30, Mirtazapine 10, Olanzapine 10). 10) is a graph showing the lean mass of the gastrocnemius muscle (GS) measured every 7 days. In this graph, the dexamethasone treatment group is represented by DEX vehicle (CMC).

[0177] As shown in Figures 27 to 29, the control group showed little change in muscle strength and lean body mass in the Tibialis Anteriors (TA) and Gastrocnemius Muscle (GS), while the dexamethasone treatment group showed a significant decrease in muscle strength and lean body mass over time. As a result of administering dementia drugs such as mirtazapine and olanzapine to the comparison group, muscle strength decreased in both cases, similar to the dexamethasone treatment group (Dexamethasone, vehicle), and lean body mass in the Tibialis Anteriors (TA) and Gastrocnemius Muscle (GS) did not recover but rather decreased.

[0178] Meanwhile, the oxiracetam group (Oxiracetam 30) not only prevents the loss of muscle strength and fat-free mass in the gastrocnemius and tibialis anterior muscles in the animal model in which muscle atrophy is induced by dexamethasone through administration of 30mg / kg / day, but also recovers muscle strength and fat-free mass significantly more than the control group (vehicle). Therefore, it can be confirmed that the ameliorative, preventive and therapeutic effects of oxiracetam of the present invention on muscle atrophy cannot be obtained even though it is a dementia drug with the same mechanism as oxiracetam.

[0179] Test Example 6. Efficacy analysis of Oxiracetam in an animal model of Duchenne syndrome 6-1.Animal keeping 23-week-old male mice (C57BL / 10 ScSn-Dmdmdx / J) were purchased from THE JACKSON LABORATORY (USA) as experimental animals, and the experiment was carried out. The temperature of the breeding room for all animals was maintained at 23±2°C and relative humidity of 55±10%. Before the start of the experiment, a total of 20 mice were randomly divided into groups of 10 mice. After adapting for one week, 30 mg / kg of Oxiracetam (Oxiracetam) of Example 1 was orally administered every day for 35 days (drug administration group, Oxiracetam). In this case, the control group (Vehicle) was orally administered saline instead of the sample.

[0180] 6-2. Statistics For statistical analysis of the experiments, a paired t-test was used to confirm significant differences in the mean values ​​between groups. Significant differences were indicated with * if the p-value was lower than 0.05, ** if the p-value was lower than 0.01, *** if the p-value was lower than 0.001, and NS if there was no significant difference. Error bars indicate SEM.

[0181] 6-3. Confirmation of Oxiracetam's effect on improving fat loss and reducing fat From the first day of oral administration (day 0), the lean body mass, fat mass (fat,%), and fat mass of the gastrocnemius muscle (GS) and tibialis anterior (TA) were analyzed every 7 days using dual energy X-ray absorptiometry (DEXA). Specifically, the animal models of each group were anesthetized with 3% isoflurane and fixed on a bed before imaging. During imaging, the respiratory rate and body temperature of the animal models were measured using an animal monitoring system (SA instrument, USA).

[0182] The animal model was photographed using dual energy X-ray absorptiometry (DEXA) using an iNSiGHT VET DXA (Osteosys, KR) device, and the total lean body mass and body fat mass (fat,%) were analyzed. In addition, the two-dimensional images of the gastrocnemius muscle (GS) and the tibialis anterior (TA) were designated as ROIs (region of interest) by a program from the photographed images, and the lean body mass of the gastrocnemius muscle (GS) and the tibialis anterior (TA) was measured and calculated. Since DEXA images can measure and analyze the lean body mass, fat, and bone density of mice, not only detailed lean body mass but also total lean body mass and body fat mass (fat,%) can be measured and calculated.

[0183] 6-4. Confirmation of the muscle function improving effect of Oxiracetam Grip strength was measured every two days from the first day of oral administration (day 0). Grip strength was measured using a BIOSEB mouse grip strength measuring device. The mouse was placed on a wire mesh attached to an instrument panel that can monitor the strength of the force, and the mouse's grip on the wire mesh was measured while grabbing the tail and pulling downward. The average value was recorded after five consecutive repeats.

[0184] 6-5. Confirmation of the weight maintenance effect of Oxiracetam Body weight was measured every day from the first day of oral administration (day 0). Figure 30 is a photograph taken by dual energy X-ray absorptiometry (DEXA) of the drug-administered group (Oxiracetam) and the control group (Vehicle), Figure 31 is a graph showing the lean body mass of the experimental group (Oxiracetam) and the control group (Vehicle), and Figure 32 is a graph showing the body fat mass (fat, %) of the drug-administered group (Oxiracetam) and the control group (Vehicle).

[0185] As shown in Figures 30 to 32, administration of oxiracetam to Duchenne muscular dystrophy animal models resulted in an increase in total lean body mass and a decrease in body fat. In particular, the drug administration group showed a significant increase in lean body mass on the 35th day compared to the control group, and the drug administration group showed a significant decrease in body fat compared to the control group.

[0186] In addition, in the control group, as Duchenne muscular dystrophy progresses, excessive growth of connective tissue and fat accumulation occurs along with fiber atrophy, resulting in pseudohypertrophy, a characteristic sign of Duchenne muscular dystrophy.On the other hand, in the drug-treated group administered oxiracetam, muscle loss and fat accumulation are suppressed, and pseudohypertrophy, a characteristic sign of Duchenne muscular dystrophy, is reduced.

[0187] Therefore, it is clear that oxiracetam has the effect of reducing pseudohypertrophy of lean body mass in Duchenne muscular dystrophy caused by genetic factors.

[0188] FIG. 33 is an image of the drug administration group (Oxiracetam) and the control group (Vehicle) measured by DEXA (dual energy X-ray absorptiometry), and FIG. 34 is a graph showing the lean body mass of the Tibialis Anteriors (TA) of the drug administration group (Oxiracetam) and the control group (Vehicle).

[0189] As shown in Figures 33 and 34, the control group showed a rapid decrease in lean mass of the tibialis anterior muscle, which is a characteristic symptom of Duchenne muscular dystrophy. On the other hand, the drug administration group to which oxiracetam was administered showed a significant increase in lean mass of the tibialis anterior muscle compared to the control group.

[0190] FIG. 35 is a graph showing the lean body mass of the gastrocnemius muscle (GS) of a drug-administered group (Oxiracetam) and a control group (Vehicle). According to this graph, it can be seen that in the control group, the lean body mass of the gastrocnemius muscle (GS), which is a characteristic symptom of Duchenne muscular dystrophy, gradually decreased.

[0191] Meanwhile, the drug-treated group had a significant increase in lean body mass in the gastrocnemius muscle (GS) compared to the control group, indicating that oxiracetam significantly inhibits the loss of lean body mass in the gastrocnemius muscle (GS) caused by Duchenne muscular dystrophy.

[0192] FIG. 36 is a graph showing the results of measuring changes in muscle strength (Grip Strength) in a drug-administered group (Oxiracetam) and a control group (Vehicle).

[0193] As shown in Figure 36, the control group showed muscle strength and muscle function weakening, which are characteristic symptoms of Duchenne muscular dystrophy. On the other hand, the drug administration group showed a significant increase in grip strength, a measure of muscle function, compared to the control group. In other words, it can be seen that oxiracetam has a therapeutic effect on Duchenne muscular dystrophy.

[0194] Figure 37 is a graph showing the change in body weight between the drug-administered group (Oxiracetam) and the control group (Vehicle), and it was confirmed that there was no significant effect on body weight when Oxiracetam was administered to a model with Duchenne muscular dystrophy. In other words, Oxiracetam does not show side effects on the body of animals with Duchenne muscular dystrophy.

[0195] Test Example 7. Cell experiments for muscular atrophy The mouse-derived C2C12 cell line was provided by American Type Culture Collection (ATCC, CRL-1772; Manassas, VA, USA) and was cultured at 37°C under 5% CO2. During the cell proliferation phase before differentiation, high-concentration glucose Dulbecco's modified Eagle's medium (DMEM) containing 1% penicillin / streptomycin and 10% fetal bovine serum (FBS) was used, and during differentiation induction, FBS was changed to 2% horse serum (HS). C2C12 myoblasts were cultured at 2 × 10 in 96-well and 6-well culture plates, respectively. 5 / well and 5×10 3The cells were seeded at 1 / well and cultured at 37℃ in a CO2 incubator. When the confluency reached approximately 90%, the medium was changed to DMEM containing 2% horse serum (HS) to induce myoblast differentiation. After 5 days, the C2C12 myotubes, which had completed differentiation, were treated with 10ng / ml of TNF-α, an inflammatory factor, for 48 hours to induce myotube atrophy, forming a TNF-α-treated group (TNF-α), a muscle atrophy cell model.

[0196] During the treatment with TNF-α, 10 μM oxiracetam was administered to prepare an oxiracetam-treated group (10 μM oxiracetam), and cells not treated during the same period were used as a control group.

[0197] Two days after the treatment with TNF-α and Oxiracetam, the TNF-α treatment group (TNF-α), Oxiracetam treatment group (Oxiracetam 10μM) and control group were each treated with ATP detection reagent at room temperature, and the fluorescence was measured using the Mitochondrial ToxGloTM Assay kit (Promega). In addition, the TNF-α treatment group (TNF-α), Oxiracetam treatment group (Oxiracetam 10μM) and control group were photographed under an optical microscope, and the diameter of each myotube was measured and compared.

[0198] Statistical analysis was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each repeated experiment are shown as mean ± standard errors of mean and analyzed using analysis of variance (Tukey's test). Statistical significance was recognized when the P-value was 0.05 or less.

[0199] FIG. 38 is a graph showing the results of confirming the degree of change in ATP content in the oxiracetam treatment group (10 μM) and the control group (control) in myotube cells. According to this, it was confirmed that the ATP production activity of the oxiracetam treatment group (10 μM) was significantly increased by 50 to 80% or more compared to the control group (control). In other words, it can be seen that oxiracetam significantly enhances mitochondrial function activity. Mitochondria are essential organelles that generate ATP, which is cellular energy, and it was confirmed that the amount of ATP in muscle cells increased, and it can be seen that the oxiracetam of the present invention has a protective effect against mitochondrial dysfunction and ATP deficiency caused by skeletal muscle cell atrophy induced by TNF-α.

[0200] Figure 39 is a photograph taken with an optical microscope of TNF-α-treated (TNF-α) myotube cells in an oxiracetam-treated group (Oxiracetam 10 μM) and an untreated group (Oxiracetam 0 μM), and Figure 40 is a graph showing the diameter of TNF-α-treated (TNF-α) myotube cells in an oxiracetam-treated group (Oxiracetam 10 μM) and an untreated group (Oxiracetam 0 μM, TNF-α).

[0201] As shown in Figures 39 and 40, the myotube diameter was significantly increased in the oxiracetam treatment group (10 μM oxiracetam) compared to the TNF-α treatment group (TNF-α). The myotube diameter in the oxiracetam treatment group (10 μM oxiracetam) was restored to the same extent as the control group, but in the TNF-α treatment group (TNF-α), it was significantly reduced to half the level of the control group.

[0202] In summary, we have confirmed that TNF-α causes myotube atrophy, and that treatment with oxiracetam enhances mitochondrial activity, increasing ATP production, thereby inhibiting myotube atrophy and restoring it to control levels.

[0203] Test Example 8. Analysis of the efficacy of Oxiracetam for cachexia The mouse-derived C2C12 cell line was provided by American Type Culture Collection (ATCC, CRL-1772; Manassas, VA, USA) and was cultured at 37°C under 5% CO2. During the cell proliferation phase before differentiation, high-concentration glucose Dulbecco's modified Eagle's medium (DMEM) containing 1% penicillin / streptomycin and 10% fetal bovine serum (FBS) was used, and during differentiation induction, FBS was changed to 2% horse serum (HS). C2C12 myoblasts were cultured at 2 × 10 in 96-well and 6-well culture plates, respectively. 5 / well and 5×10 3 The cells were seeded per well and cultured at 37℃ in a CO2 incubator. When the confluency reached approximately 90%, the medium was changed to DMEM containing 2% horse serum (HS) to induce myoblast differentiation. After 5 days, the C2C12 myotubes, which had completed differentiation, were treated with 500nM of an anti-cancer drug (Doxorubicin) for 48 hours to induce myotube atrophy, forming a cachexia cell model.

[0204] During the treatment with anticancer drugs, Oxiracetam was administered at different concentrations (0, 0.01μM, 0.1μM, 1μM, 10μM, 30μM) to prepare Oxiracetam-treated groups, and cells that were not treated for the same period were prepared as a control group.

[0205] Two days after treatment with the anticancer drugs and Oxiracetam, the anticancer drug treatment group (Doxorubicin), Oxiracetam treatment groups (Oxiracetam 0.01μM, 0.1μM, 1μM, 10μM, 30μM) and the control group were photographed under an optical microscope at room temperature and the diameter (Diameter,%) of each myotube was measured and compared.

[0206] Statistical analysis was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each repeated experiment are shown as mean ± standard errors of mean and analyzed using analysis of variance (Tukey's test). Statistical significance was recognized when the P-value was 0.05 or less.

[0207] Figure 41 is a set of photographs taken with an optical microscope of the anti-cancer drug-treated group (Doxorubicin), the oxiracetam-treated group (Oxiracetam 0 μM, 0.01 μM, 0.1 μM, 1 μM, 10 μM, 30 μM) and the control group, and Figure 42 is a graph showing the measured diameter of myotubes in the anti-cancer drug-treated group (Doxorubicin), the oxiracetam-treated group (Oxiracetam 0 μM, 0.01 μM, 0.1 μM, 1 μM, 10 μM, 30 μM) and the control group.

[0208] As shown in Figures 41 and 42, the anticancer drug-induced cachexia cell model (Doxorubicin) showed a significant decrease and atrophy in myotube diameter compared to the control group. On the other hand, the oxiracetam treatment groups (Oxiracetam 0.01μM, 0.1μM, 1μM, 10μM, 30μM) showed a significant recovery in myotube diameter, which increased significantly to the control (normal) group level.

[0209] In summary, it was confirmed that anticancer drugs induce cachexia, which causes myotube atrophy, and that treatment with oxiracetam inhibits myotube atrophy and restores it to the control level. Therefore, it is found that oxiracetam according to the present invention has an effect of improving, preventing or treating not only sarcopenia and muscular dystrophy, but also cachexia.

[0210] Hereinafter, examples of the preparation of medicines and foods containing oxiracetam as an active ingredient according to the present invention will be described, but the present invention is not intended to be limited thereto, but merely to be specifically described. Using oxiracetam, which has excellent effects of improving, treating or preventing muscular weakness, muscular dystrophy or cachexia, the medicines and food compositions of Preparation Examples 1 and 2 were prepared by a conventional method according to the following compositional ingredients and composition ratios.

[0211] [Production Example 1] Pharmaceuticals <1-1> Powder 50 mg of oxiracetam of the present invention and 2 g of crystalline cellulose were mixed, and then filled into an airtight bag by a conventional powder manufacturing method to produce a powder.

[0212] <1-2> Tablets 50 mg of the oxiracetam of the present invention, 400 mg of crystalline cellulose, and 5 mg of magnesium stearate were mixed together and compressed into tablets by a conventional tablet manufacturing method.

[0213] <1-3> Capsules 30 mg of the oxiracetam of the present invention, 100 mg of whey protein, 400 mg of crystalline cellulose, and 6 mg of magnesium stearate were mixed and then filled into a gelatin capsule by a conventional capsule manufacturing method to produce a capsule.

[0214] [Production example 2] Food <2-1> Manufacturing of health foods The composition of the present invention can be produced by mixing 1000mg of oxiracetam, 70ug of vitamin A acetate, 1.0mg of vitamin E, 0.13mg of vitamin B1, 0.15mg of vitamin B2, 0.5mg of vitamin B6, 0.2ug of vitamin B12, 10mg of vitamin C, 10ug of biotin, 1.7mg of nicotinamide, 50ug of folic acid, 0.5mg of calcium pantothenate, 1.75mg of ferrous sulfate, 0.82mg of zinc oxide, 25.3mg of magnesium carbonate, 15mg of potassium monophosphate, 55mg of calcium diphosphate, 90mg of potassium citrate, 100mg of calcium carbonate, and 24.8mg of magnesium chloride, and the mixing ratio can be changed as desired. The above ingredients are mixed by a conventional method for producing health foods, and then granules are produced, which can be used to produce health food compositions by a conventional method.

[0215] <2-2> Manufacturing of health drinks 1000mg of Oxiracetam of the present invention, 1000mg of citric acid, 100g of oligosaccharides, 2g of plum extract, and 1g of taurine are added to purified water to make a total of 900mL, and the above ingredients are mixed according to a normal method for producing health drinks, and then the mixture is stirred and heated at 85°C for about 1 hour. The resulting solution is then filtered and placed in a sterilized 2L container, which is then sealed, sterilized, and stored in a refrigerator, after which it can be used to produce a health drink composition.

[0216] <2-3> Chewing gum A chewing gum was produced by a conventional method by blending 20% ​​by weight of gum base, 76.9% by weight of sugar, 1% by weight of flavor, 2% by weight of water, and 0.1% by weight of the oxiracetam of the present invention.

[0217] <2-4> Candy 60% by weight of sugar, 39.8% by weight of starch syrup, 0.1% by weight of flavoring, and 0.1% by weight of the oxiracetam of the present invention were mixed together and a candy was produced in a conventional manner.

[0218] <2-5>Biscuits 25.59% by weight of first-grade weak flour, 22.22% by weight of first-grade medium-strength flour, 4.80% by weight of refined sugar, 0.73% by weight of salt, 0.78% by weight of glucose, 11.78% by weight of palm shortening, 1.54% by weight of ammonium, 0.17% by weight of sodium bicarbonate, 0.16% by weight of sodium sulfite, 1.45% by weight of rice flour, 0.0001% by weight of vitamin B, 0.04% by weight of milk aroma, 20.6998% by weight of water, 1.16% by weight of whole milk powder, 0.29% by weight of milk substitute, 0.03% by weight of calcium phosphate monobasic, 0.29% by weight of salt, and 7.27% by weight of spray oil were mixed with 0.8301% by weight of the oxiracetam of the present invention, and biscuits were produced by a conventional method.

Claims

1. A pharmaceutical composition for preventing or treating a muscular disease, comprising oxiracetam, a pharma- ceutical acceptable salt thereof, or a hydrate thereof as an active ingredient, The muscular disease is atony, muscular atrophy, muscular dystrophy, muscle degeneration, myasthenia, muscle inflammation, cachexia, and age-related sarcopenia.

2. 2. The pharmaceutical composition for preventing or treating muscular diseases according to claim 1, wherein oxiracetam is represented by the following formula 1: [Chemical formula 1] 【Chemistry 1】

3. The pharmaceutical composition for preventing or treating a muscular disease according to claim 1, wherein the muscular dystrophy is Duchenne muscular dystrophy.

4. The pharmaceutical composition for preventing or treating a muscle disease according to claim 1, characterized in that the composition is administered by one or more methods selected from the group consisting of oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, percutaneous, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual and rectal administration.

5. A food composition for improving or preventing a muscular disease, comprising oxiracetam, a pharma- ceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, The food composition, wherein the muscle disease is any one or more selected from the group consisting of atony, muscular atrophy, muscular dystrophy, muscle degeneration, myasthenia, muscle inflammation, cachexia, and age-related sarcopenia.

6. A food composition for improving muscle function comprising oxiracetam, a pharma- ceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, The food composition, wherein the improvement in muscle function is promotion of muscle differentiation, muscle regeneration, muscle strengthening, or enhancement of athletic ability.

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