Racetam-based compound for ameliorating or suppressing muscle-loss side effect of Anti-obesity agent, and pharmaceutical composition for preventing or treating obesity comprising racetam-based compound and Anti-obesity agent as active ingredients

Abstract

The present invention relates to a racetam-based compound for ameliorating or suppressing the muscle-loss side effect of an anti-obesity agent, and a pharmaceutical composition for preventing or treating obesity, the pharmaceutical composition comprising the racetam-based compound and an anti-obesity agent as active ingredients. The racetam-based compound, particularly oxiracetam, can ameliorate side effects such as a reduction in muscle mass while maintaining the weight loss effect of a glucagon-like peptide-1 receptor agonist such as semaglutide, and thus can be effectively used to prevent or treat obesity without reducing muscle mass.

Description

A racetam-class compound for improving or suppressing the muscle-loss side effects of an anti-obesity agent, and a pharmaceutical composition for the prevention or treatment of obesity comprising a racetam-class compound and an anti-obesity agent as active ingredients.

[0001] The present invention relates to a racetam-based compound for improving or suppressing the muscle-reducing side effects of an anti-obesity agent, and a pharmaceutical composition for preventing or treating obesity comprising a racetam-based compound and an anti-obesity agent as active ingredients.

[0002] In modern society, the obese population is rapidly increasing due to convenient living environments resulting from rapid automation, excessive nutrient intake caused by the rise in processed foods and eating out, and a decrease in physical activity. The World Health Organization (WHO) defines obesity as a condition in which fat is abnormally or excessively accumulated in the body to the extent that it threatens health; this refers to a state where the number and size of fat cells increase, leading to the excessive accumulation of fat in subcutaneous or body tissues. Factors influencing obesity are reported to include genetic factors as well as environmental factors such as lifestyle, dietary habits, lack of exercise and physical activity, and socioeconomic status.

[0003] According to the World Health Organization, the obese population is increasing rapidly worldwide. As of 2016, over 1.9 billion adults were overweight, and 650 million were obese. According to the Ministry of Health and Welfare, more than one in three adults in Korea is obese as well. At this rate of increase, it is predicted that nearly half of the world's adult population will be overweight or obese by 2030, making obesity a serious global issue. Compared to the general population, obesity increases the risk of developing diseases such as diabetes (2.5 times for obese individuals, 2.8 times for severely obese individuals) and hypertension (2 times for obese individuals, 2.7 times for severely obese individuals). Furthermore, it causes various cancers, including colorectal, ovarian, and prostate cancer, increases the risk of death, and leads to a growing socioeconomic burden. According to the National Health Insurance Service, the socioeconomic loss due to obesity amounted to 9.2 trillion won as of 2015, comprising 5.4 trillion won in medical expenses, 1.6 trillion won in losses due to premature death, 1.4 trillion won in productivity losses, 0.5 trillion won in caregiving costs, and 0.3 trillion won in transportation costs. Socioeconomic losses due to obesity have doubled over the past decade compared to 4.8 trillion won in 2006, and the Health Insurance Service reports that these losses are expected to accelerate further due to factors such as an aging population, indicating that obesity is a serious problem in Korean society. Consequently, the rapid increase in the obese population is a problem that goes beyond individual concerns to exacerbate the social burden, making it urgent to find measures to prevent and address obesity.

[0004] Existing strategies for developing obesity treatments include reducing food intake, inhibiting calorie absorption, promoting thermogenic responses, regulating energy metabolism, and controlling signal transduction through the nervous system. Based on these principles, obesity treatments developed primarily consist of appetite suppressants acting on the central nervous system; among these, the majority were drugs that modulate the action of neurotransmitters (e.g., phentermine, mazindol, lorcaserin, fluoxetine, and sibutramine). However, the aforementioned neurotransmitter modulators exert a wide range of effects on various physiological processes in addition to appetite suppression through numerous subtype receptors. Consequently, these drugs have the disadvantage of lacking selectivity for each subtype, leading to various side effects when administered for a long period.

[0005] Recently, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have garnered significant attention upon their market launch; however, just as existing drugs are associated with various side effects, they are reported to be accompanied by serious side effects, such as lethargy along with a decrease in muscle mass and strength. Therefore, in the globally growing obesity treatment market, the decline in muscle mass and strength that causes lethargy is one of the major problems that must be solved to pursue a healthier and more humane life.

[0006] Accordingly, the inventors completed the present invention by conducting research to improve side effects, such as muscle and strength reduction, of next-generation anti-obesity agents like GLP-1 receptor agonists.

[0007] One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of obesity, wherein the composition comprises, as a first pharmacological component, a racetam-class compound or a pharmaceutically acceptable salt thereof; and as a second pharmacological component, an anti-obesity agent or a pharmaceutically acceptable salt thereof.

[0008] Another objective of the present invention is to provide a method for preventing or treating obesity comprising the step of administering the composition to a subject.

[0009] Another object of the present invention is to provide a kit for the prevention or treatment of obesity, wherein the composition comprises, as a first pharmacological component, a racetam-class compound or a pharmaceutically acceptable salt thereof; and as a second pharmacological component, an anti-obesity agent or a pharmaceutically acceptable salt thereof.

[0010]

[0011] One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of obesity, wherein the composition comprises, as a first pharmacological component, a racetam-class compound or a pharmaceutically acceptable salt thereof; and as a second pharmacological component, an anti-obesity agent or a pharmaceutically acceptable salt thereof.

[0012] Another objective of the present invention is to provide a method for preventing or treating obesity, comprising the step of administering the composition to a subject.

[0013] Another object of the present invention is to provide a kit for the prevention or treatment of obesity, wherein the composition comprises, as a first pharmacological component, a racetam-class compound or a pharmaceutically acceptable salt thereof; and as a second pharmacological component, an anti-obesity agent or a pharmaceutically acceptable salt thereof.

[0014]

[0015] According to the racetam-class compound for improving or suppressing the muscle loss side effects of the anti-obesity agent of the present invention, and the pharmaceutical composition for preventing or treating obesity comprising the racetam-class compound and the anti-obesity agent as active ingredients, the racetam-class compound, in particular oxiracetam, can improve side effects such as muscle mass loss while maintaining the weight loss effect of the anti-obesity agent, particularly glucagon-like peptide-1 receptor agonist such as semaglutide, and thus can be effectively utilized to prevent or treat obesity without muscle mass loss.

[0016]

[0017] Figure 1 shows photographs of mice in each group after the end of the experiment for the normal diet group, high-fat diet group (Vehicle), oxiracetam monotherapy group (Oxiracetam, Oxi), semaglutide monotherapy group (SEMA), and oxiracetam and semaglutide combination therapy group (Oxiracetam + SEMA), as well as graphs showing changes in food intake and body weight during the experiment.

[0018] Figure 2 is a representative image showing the total fat analyzed through dual-energy X-ray absorptiometry (DEXA) analysis of mice in each group before and after the experiment, and graphs showing the changes in total lean mass and inguinal white adipose tissue (iWAT), respectively.

[0019] Figure 3 shows representative images of skeletal muscle analysis through dexamethyrography of mice in each group before and after the experiment, and graphs showing changes in lean mass for the tibialis anterior (TA) and gastrocnemius muscle (GM), respectively.

[0020] Figure 4 is a graph showing the change in lean muscle mass of the anterior tibia and calf of mice for each group before and after the experiment.

[0021] Figure 5 is a graph showing the grip strength of mice in each group measured by week of the experiment.

[0022] Figure 6 is an image and graph showing the change in protein levels of the p-Akt / Akt protein synthesis pathway in the calf muscles of mice after the end of the experiment in the normal diet group (Nor), high-fat diet group (Veh), oxiracetam monotherapy group (Oxi), semaglutide monotherapy group (SEMA), and oxiracetam and semaglutide combination therapy group (Oxi + SEMA).

[0023] Figure 7 is an image and graph showing the change in protein of the protein degradation pathway LC3A / B in the calf muscles of mice after the end of the experiment for the normal diet group (Nor), high-fat diet group (Veh), oxiracetam monotherapy group (Oxi), semaglutide monotherapy group (SEMA), and oxiracetam and semaglutide combination therapy group (Oxi + SEMA), expressed as the ratio of LC3A / B-II to LC3A / B-I (LC3A / B II / I ratio).

[0024] Figure 8 is an image and graph showing the change in protein levels of succinate dehydrogenase (SDHA), a major factor in mitochondrial metabolism, in the adipose tissue (epididymal white adipose tissue, EWAT) of mice after the end of the experiment in the normal diet group (Nor), high-fat diet group (Veh), oxiracetam monotherapy group (Oxi), semaglutide monotherapy group (SEMA), and oxiracetam and semaglutide combination therapy group (Oxi + SEMA).

[0025] One aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of obesity, wherein the composition comprises, as a first pharmacological component, a racetam-class compound or a pharmaceutically acceptable salt thereof; and as a second pharmacological component, an anti-obesity agent or a pharmaceutically acceptable salt thereof.

[0026] In the present invention, it was confirmed that when a racetam-class compound such as oxiracetam is administered in combination with an anti-obesity agent, particularly a GLP-1 receptor agonist, side effects such as muscle loss, muscle strength reduction, and lethargy, which may occur when an anti-obesity agent is administered alone, can be effectively suppressed.

[0027] According to one embodiment of the present invention, the racetam-based compound can improve or suppress the muscle-reducing side effects of the anti-obesity agent.

[0028] According to one embodiment of the present invention, the anti-obesity agent may be accompanied by one or more side effects selected from the group consisting of muscle atrophy, sarcopenia, muscular dystrophy, and cachexia.

[0029] According to one embodiment of the present invention, the racetam series compound may be any one compound selected from the group consisting of Oxiracetam, Piracetam, Phenylpiracetam, Aniracetam, Levetiracetam, Nefiracetam, Coluracetam, Rolziracetam, Fasoracetam, Pramiracetam, and Brivaracetam.

[0030] In addition, the racetam-based compound according to the present invention may preferably be oxiracetam.

[0031] Oxiracetam is a nootropic of the racetam class, and its IUPAC name is (RS)-2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide. The CAS No. of oxiracetam is 62613-82-5, and its molecular formula is C6H 10 N2O3, with a molecular weight of 158.155 g / mol, and a structure as shown in Chemical Formula 1 below. Oxiracetam is a white solid. The method of obtaining the above oxiracetam is not particularly limited, and the above oxiracetam may be chemically synthesized using known methods or commercially available without limitation.

[0032]

[0033] According to one embodiment of the present invention, the pharmaceutically acceptable salt may be any one salt selected from the group consisting of hydrochloride, sulfate, nitrate, phosphate, hydrobromide, and hydroiodide.

[0034] The racetam-based compounds of the present invention may be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids are useful as such salts. Specifically, the acid addition salts may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, or phosphoric acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples of such pharmaceutically non-toxic salts include, for instance, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, buty-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, and methoxybenzoates. It may be phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate.

[0035] The acid addition salt of a racetam-based compound according to the present invention may be prepared by a method commonly used in the art, for example, by dissolving the racetam-based compound in an excess amount of an aqueous acid solution and precipitating the salt with a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. Alternatively, it may be prepared by, for example, heating an equal amount of a racetam-based compound and an acid or alcohol in water, and then drying the mixture by evaporating it or by suction filtration of the precipitated salt.

[0036] In addition, the pharmaceutically acceptable salt of the racetam-based compound according to the present invention may be a metal salt prepared using a base. Specifically, an alkali metal or alkaline earth metal salt may be prepared, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, the metal salt is preferably a sodium, potassium, or calcium salt. Additionally, the corresponding silver salt may be prepared by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt, for example, silver nitrate. Furthermore, the racetam-based compound of the present invention may include all salts, hydrates, and solvates that can be prepared by methods generally used in the art, in addition to the pharmaceutically acceptable salt.

[0037] The addition salt of a racetam-based compound according to the present invention can be prepared, for example, by dissolving a racetam-based compound in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic acid or an aqueous solution of an inorganic acid, and then precipitating or crystallizing. Subsequently, the solvent or excess acid can be evaporated from the mixture and dried to obtain the addition salt, or the precipitated salt can be prepared by suction filtration.

[0038] The term 'hydrate' as used in the present invention means containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces. Hydrates of the racetam-based compounds of the present invention may contain stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces. Such hydrates may contain at least one equivalent, preferably one to five equivalents, of water. Such hydrates may be prepared by crystallizing the racetam-based compounds of the present invention, their isomers, or pharmaceutically acceptable salts thereof from water or a water-containing solvent.

[0039] As used in the present invention, the term 'solvate' means comprising stoichiometric or non-stoichiometric amounts of solvent bonded by non-covalent intermolecular forces. Preferred solvents may be, for example, volatile, non-toxic, and / or solvents suitable for administration to humans.

[0040] The term 'isomer' used in the present invention refers to a compound or its salt that has the same chemical formula or molecular formula but is structurally or stereochemically different. Such isomers may include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers).

[0041] The pharmaceutical composition according to the present invention may further include, in addition to a racetam-type compound or a pharmaceutically acceptable salt thereof as a first pharmacological component and an anti-obesity agent or a pharmaceutically acceptable salt thereof as a second pharmacological component, a suitable carrier, excipient, and / or diluent commonly used in the manufacture of pharmaceutical compositions, etc.

[0042] A pharmaceutically acceptable carrier that may be included in the pharmaceutical composition according to the present invention is a compound that facilitates the addition of the compound into a cell or tissue. In addition, the diluent is a compound that not only stabilizes the biologically active form of the target compound but is also diluted in water, thereby dissolving the compound.

[0043] The above-mentioned carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, ion exchange resin, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., various phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides 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, and magnesium. Trisilicates, polyethylene glycol, polyarylates, waxes, wool paper, and mineral oil may be included, but are not limited thereto.

[0044] The pharmaceutical composition according to the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, or sterile injectable solutions, according to methods commonly used in the art. Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, humectants, disintegrants, and surfactants. Solid formulations for oral administration may include tablets, pills, powders, granules, capsules, etc., and such solid formulations may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., in addition to the pharmaceutical composition according to the present invention.

[0045] In addition, lubricants such as magnesium stearate and talc may be used in addition to simple excipients. Liquid formulations for oral administration may include suspensions, oral liquids, emulsions, and syrups, and may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents like water and liquid paraffin.

[0046] Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, Hank's solution, Ringer's solution, etc. Witepsol, Macrogol, Tween 61, cacao gelatin, laurin gelatin, glycerogelatin, etc. may be used as bases for suppositories.

[0047] The administration of the pharmaceutical composition according to the present invention may be oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal administration, and preferably may be oral or parenteral administration.

[0048] The term 'parenteral' as used in the present invention may be an injection or infusion subcutaneously, intradermally, intramuscularly, intra-articularly, intrasynovially, intrasternally, intradurally, intralesionally, and intracranially, and includes the form of a suppository for rectal administration.

[0049] The pharmaceutical composition according to the present invention may be formulated into an oral or parenteral administration formulation according to the administration route described above. When formulated, it may be prepared using one or more buffers (e.g., saline solution or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, extenders, binders, adjuvants (e.g., aluminum hydroxide), suspenders, thickeners, wetting agents, disintegrants or surfactants, diluents or excipients.

[0050] Solid dosage forms for oral administration may include nano-formulations (preparations designed to increase bioavailability and can produce rapid effects), tablets, pills, powders, granules, liquids, gels, syrups, slurries, suspensions, or capsules, and these solid dosage forms may be prepared by mixing at least one excipient, for example, starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol, maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, or gelatin, with the pharmaceutical composition of the present invention. For example, the active ingredient can be combined with a solid excipient, then ground, a suitable auxiliary agent added, and processed into a granular mixture to obtain a tablet or a sugar tablet. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

[0051] Liquid formulations for oral administration may include suspensions, liquid formulations, emulsions, or syrups, and may contain various excipients, such as humectants, sweeteners, flavorings, or preservatives, in addition to water or liquid paraffin, which are commonly used simple diluents. Additionally, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as disintegrants, and anticoagulants, lubricants, humectants, flavorings, emulsifiers, and preservatives may be additionally included.

[0052] When the pharmaceutical composition of the present invention is administered parenterally, it may be formulated in the form of an injectable, transdermal, or nasal inhalant according to methods known in the art, together with a suitable parenteral carrier. When formulated as an injectable, it must be sterile and protected from contamination by microorganisms such as bacteria and fungi. For an injectable, suitable carriers may be, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), mixtures thereof, and / or solvents or dispersion media containing vegetable oils. More preferably, suitable carriers may include Hanks' solution, Ringer's solution, PBS (phosphate buffered saline) containing triethanolamine or sterile water for injection, isotonic solutions such as 10% ethanol, 40% propylene glycol, and 5% dextrose. To protect the above-mentioned injectable from microbial contamination, various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. may be additionally included. In addition, the above-mentioned injectable may, in most cases, additionally include isotonic agents such as sugars or sodium chloride.

[0053] Transdermal administration agents may include forms such as ointments, creams, lotions, gels, external solutions, pastes, liniments, and aerosols. The term "transdermal administration" as used in the present invention refers to the delivery of an effective amount of active ingredients contained in a pharmaceutical composition into the skin by administering the pharmaceutical composition topically to the skin.

[0054] When formulated as an inhalation dosing agent, the active ingredient included in the pharmaceutical composition of the present invention can be conveniently delivered in the form of an aerosol spray from a pressurized pack or atomizer by using a suitable propellant, e.g., dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosing unit can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges used in an inhaler or blower can be formulated to contain the compound and a powder mixture of a suitable powder base, such as lactose or starch.

[0055] The parenteral formulation is described in the literature (Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour), a prescription generally known in all pharmaceutical chemistry.

[0056] The amount of the pharmaceutical composition of the present invention used may vary depending on the age, gender, and weight of the subject being treated, and, above all, may depend on the condition of the subject being treated, the specific category or type of the disease being treated, the route of administration, and the properties of the therapeutic agent used.

[0057] The pharmaceutical composition of the present invention may be appropriately selected according to the absorption rate and excretion rate of the active ingredient in the body, the age and weight, sex and condition of the patient or animal to be treated, and the severity of the disease to be treated, but generally, it may be administered at a dose of 0.1 to 1,000 mg / kg per day, preferably 1 to 500 mg / kg, more preferably 5 to 250 mg / kg, and most preferably 10 to 100 mg / kg. In addition, the unit dosage form of the pharmaceutical composition of the present invention may be administered several times at regular time intervals as needed, and such dosage may be appropriately selected by a person skilled in the art.

[0058] The pharmaceutical composition of the present invention may be administered individually as a preventive agent or therapeutic agent, or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents.

[0059] According to one embodiment of the present invention, the anti-obesity agent may be a glucagon-like peptide-1 receptor agonist.

[0060] According to one embodiment of the present invention, the glucagon-like peptide-1 receptor agonist may be any one substance selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, benaglutide, polyethylene glycol loxenatide (PEG-loxenatide), efpeglenatide, vurolenatide, danuglipron (PF-06882961), and LY-3502970.

[0061] The glucagon-like peptide-1 receptor agonist according to the present invention may preferably be semaglutide.

[0062] Another objective of the present invention is to provide a method for preventing or treating obesity, comprising the step of administering the composition to a subject.

[0063] The pharmaceutical composition of the present invention may be administered orally or parenterally as intended, in an amount effective for the treatment or prevention of an individual or patient. It should be understood that the dosage for a specific individual or patient should be determined based on various relevant factors such as the patient's weight, age, race, gender, health status, diet, time of administration, method of administration, and severity of the disease, and that it may be appropriately adjusted by a professional. For example, a physician may start the dosage of the pharmaceutical composition of the present invention at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved, and may easily determine and prescribe the dosage as needed.

[0064] Another aspect of the present invention provides a kit for the prevention or treatment of obesity, wherein the composition comprises a racetam-class compound or a pharmaceutically acceptable salt thereof as a first pharmacological component; and an anti-obesity agent or a pharmaceutically acceptable salt thereof as a second pharmacological component.

[0065] To avoid excessive complexity caused by unnecessary repetition in this specification, common details are omitted.

[0066] The kit of the present invention allows for the simultaneous, sequential, or separate administration of a first pharmacological component and a second pharmacological component.

[0067] In addition to a preparation containing a first pharmacological component and a second pharmacological component, the kit of the present invention may include a packaging container, instructions for handling, accompanying documents, etc. The packaging container, instructions for handling, accompanying documents, etc. may describe combinations for using each pharmacological component in combination. Furthermore, the form of combination or mixture used when administering each pharmacological component, as well as the method of use and dosage, may be described.

[0068]

[0069] The present invention will be explained in more detail below through one or more embodiments. However, these embodiments are intended to illustrate the invention and the scope of the invention is not limited to these embodiments.

[0070]

[0071] Example 1. Diet-Induced Obesity (DIO) Animal Model and Experimental Design

[0072] To confirm the inhibitory effect of oxiracetam on muscle loss caused by the administration of GLP-1 receptor agonists (RA), a high-fat diet (HFD)-induced obesity animal model was prepared and an experiment was designed to verify the effect.

[0073] Specifically, 7-week-old C57BL / 6 mice were purchased and used as an animal model. They were acclimatized for one week in an environment with a temperature of 23±2℃, humidity of 55±10%, and a 12-hour light-dark cycle before being used in the experiment. After acclimatization, obesity was induced by consuming a high-fat diet for 8 weeks, followed by the administration of oxiracetam (333 mg / kg, once daily, orally) and / or semaglutide (0.06 mg / kg, once daily, subcutaneous injection) for 6 weeks according to Table 1.

[0074]

[0075] Group | Diet | Administered Substance Nor Diet Group (Nor): General feed, 0.5% excipient (CMC) administered orally daily, and physiological saline administered subcutaneously daily High-Fat Diet Group (Veh): High-fat feed, 0.5% excipient (CMC) administered orally daily, and physiological saline administered subcutaneously daily Oxiracetam Monotherapy Group (Oxi): High-fat feed, oxiracetam (333 mg / kg) administered orally daily, and physiological saline administered subcutaneously daily Semaglutide Monotherapy Group (SEMA): High-fat feed, 0.5% excipient (CMC) administered orally daily, and semaglutide (0.06 mg / kg) administered subcutaneously daily Oxiracetam and Semaglutide Combination Group (Oxi+SEMA): High-fat feed, oxiracetam (333 mg / kg) administered orally daily, and semaglutide (0.06 mg / kg) administered subcutaneously daily

[0076]

[0077] Example 2. Confirmation of effects on dietary intake and body weight reduction following concomitant administration of semaglutide and oxiracetam

[0078] To confirm the effects of semaglutide and / or oxiracetam administration as GLP-1 RAs on diet intake and weight loss, an experiment was conducted for 6 weeks according to Example 1, with weight measured once a week and diet intake measured three times a week, and the mice of each group were photographed after the experiment was completed.

[0079] As a result, it was found that obesity was induced in the high-fat diet group and the oxiracetam monotherapy group, whereas the semaglutide monotherapy group and the oxiracetam and semaglutide combination therapy group exhibited a body shape similar to the normal diet group. In addition, it was confirmed that food intake and body weight decreased in the semaglutide monotherapy group and the oxiracetam and semaglutide combination therapy group compared to the high-fat diet group and the oxiracetam monotherapy group (Fig. 1).

[0080] Through these results, it was confirmed that oxiracetam alone has no effect on reducing dietary intake or body weight, but when used in combination with a GLP-1 RA such as semaglutide, it does not affect the dietary intake or body weight reduction effects of the GLP-1 RA.

[0081]

[0082] Example 3. Confirmation of the improving effect of oxiracetam on the side effect of semaglutide's muscle mass reduction

[0083] Muscle mass loss is known as a representative side effect of GLP-1 RAs such as semaglutide. Therefore, in order to determine whether the side effect of muscle mass loss that may occur with semaglutide monotherapy can be improved through the combined administration of oxiracetam and semaglutide, the lean mass and the diameter of the anterior tibialis muscle for each group were measured while conducting an experiment for 6 weeks according to Example 1.

[0084]

[0085] 3-1. Confirmation of the improved effect of oxiracetam on the reduction of semaglutide's lean body mass

[0086] Every two weeks, animal models from each group were anesthetized with 3% isoflurane and fixed to an imaging bed. Then, dual-energy X-ray absorptiometry (DEXA) was performed on the entire body using an iNSiGHT VET DXA (Osteosys, KR) device. During the DEXA imaging, adipose tissue was indicated in red and lean tissue in green, and the respiratory rate and body temperature of the animal models were measured using an animal monitoring system (SA instrument, USA). Subsequently, the lean body mass of the gastrocnemius muscle (GM) and tibialis anterior (TA) was measured and calculated from two-dimensional images of the muscles using a program with a region of interest (ROI).

[0087] As a result, it was confirmed that the total lean mass and inguinal white adipose tissue (iWAT) weight, which increased with a high-fat diet, were significantly reduced in the semaglutide monotherapy group and the oxiracetam and semaglutide combination therapy group. However, it was confirmed that the lean mass decreased 47% less in the oxiracetam and semaglutide combination therapy group compared to the semaglutide monotherapy group (Fig. 2).

[0088] Through these results, it was confirmed that the weight loss efficacy of GLP-1 RAs such as semaglutide is maintained, while muscle loss can be inhibited by oxiracetam.

[0089]

[0090] 3-2. Confirmation of the improving effect of oxiracetam on semaglutide's muscle mass reduction

[0091] For each group, two-dimensional images of the gastrocnemius muscle (GM) and tibialis anterior (TA) were taken using dual-energy X-ray absorptiometry, and lean body mass was measured and calculated.

[0092] As a result, in the semaglutide monotherapy group, it was confirmed that TA lean body mass gradually decreased at weeks 2, 4, and 6 compared to week 0 as the semaglutide treatment period continued. On the other hand, in the oxiracetam and semaglutide combination therapy group, it was confirmed that the gradual decrease in TA lean body mass was inhibited, and at week 6, it was confirmed that the TA lean body mass of the combination therapy group significantly increased compared to the semaglutide monotherapy group (Fig. 3).

[0093] Meanwhile, an analysis of the rate of change in lean body mass of the gastrocnemius and anterior tibialis muscles for each group at week 0 and week 6 of the experiment revealed that the lean body mass of the gastrocnemius and anterior tibialis muscles, which increased due to the high-fat diet, decreased in the semaglutide monotherapy group and the oxiracetam and semaglutide combination therapy group. However, compared to the semaglutide monotherapy group, the lean body mass of the gastrocnemius and anterior tibialis muscles decreased by 91% and 196% less, respectively, in the oxiracetam and semaglutide combination therapy group (Fig. 4).

[0094] Through these results, it was confirmed that muscle loss caused by GLP-1 RAs such as semaglutide can be inhibited by oxiracetam.

[0095]

[0096] Example 4. Confirmation of the improving effect of oxiracetam on the side effect of semaglutide's muscle strength reduction

[0097] In order to determine whether the side effect of decreased muscle strength that may occur with semaglutide monotherapy can be improved through the combined administration of oxiracetam and semaglutide, grip strength was measured for each group while conducting an experiment for 6 weeks according to Example 1.

[0098] Specifically, the tail of each animal model was held so that the device's rod could be grasped with both forelegs, and the maximum force at which the forelegs could no longer grasp the device's rod was considered as muscle strength (g) when the tail was pulled horizontally in this position. Measurements were taken once every two weeks.

[0099] As a result, it was found that grip strength at week 6 was significantly reduced in the semaglutide monotherapy group compared to the high-fat diet group, whereas no statistically significant difference was found in the oxiracetam and semaglutide combination therapy group (Fig. 5).

[0100] Through these results, it was confirmed that the decrease in muscle strength caused by GLP-1 RAs such as semaglutide can be inhibited by oxiracetam.

[0101]

[0102] Example 5. Confirmation of the improving effect of oxiracetam on the reduction of muscle protein expression by semaglutide

[0103] 5-1. Confirmation of the Inhibitory Effect of Oxiracetam on Semaglutide-Induced Reduction of Muscle Protein Synthesis

[0104] After the experiment according to Example 1 was completed, the change in p-Akt / Akt protein, which is the mechanism of muscle protein synthesis in the gastrocnemius muscle, was analyzed for each group.

[0105] Specifically, cells obtained from gastrocnemius tissue were lysed with lysis buffer to extract proteins, separated on a 10% SDS-PAGE gel, and transferred to a membrane. Then, p-Akt and Akt antibodies were added and left at 4°C for 16 hours, followed by the addition of a secondary antibody and left at room temperature for 1 hour, after which the samples were reacted with ECL and the expression levels of each protein were measured using a chemiluminescence image analyzer.

[0106] As a result, the relative expression level of p-Akt / Akt protein was found to be significantly reduced in the semaglutide monotherapy group compared to the high-fat diet group, whereas no statistically significant difference was found in the oxiracetam and semaglutide combination therapy group (Fig. 6).

[0107]

[0108] 5-2. Confirmation of the Inhibitory Effect of Oxiracetam on Increased Muscle Protein Degradation Induced by Semaglutide

[0109] After the experiment according to Example 1 was completed, the change in LC3A / B protein as an autophagy marker, which is a muscle protein degradation mechanism in the gastrocnemius muscle, was analyzed for each group.

[0110] Specifically, the expression levels of each protein were measured in the same manner as in Example 5-1, except that LC3A / B-I and LC3A / B-II antibodies were used as primary antibodies, and then the ratio of LC3A / B-II to LC3A / B-I (LC3A / B II / I ratio) was calculated.

[0111] As a result, the LC3A / B II / I ratio was found to have significantly increased in the semaglutide monotherapy group compared to the high-fat diet group, whereas it was found to have significantly decreased in both the oxiracetam monotherapy group and the oxiracetam and semaglutide combination therapy group (Fig. 7).

[0112]

[0113] 5-3. Confirmation of the inhibitory effect of oxiracetam on the reduction of mitochondrial metabolism induced by semaglutide

[0114] After the experiment according to Example 1 was completed, the change in succinate dehydrogenase (SDHA), a major factor in mitochondrial metabolism, was analyzed in the epididymal white adipose tissue (EWAT) of each group.

[0115] Specifically, the expression levels of each protein were measured in the same manner as in Example 5-1, except that SDHA antibody was used as the primary antibody.

[0116] As a result, the relative expression level of SDHA protein was found to be decreased in the semaglutide monotherapy group compared to the high-fat diet group, whereas it was found to be significantly increased in the oxiracetam monotherapy group and the oxiracetam and semaglutide combination therapy group (Fig. 8).

[0117]

[0118] Through these results, it was confirmed that muscle protein degradation and muscle atrophy induced by GLP-1 RA can be inhibited by the administration of oxiracetam. Therefore, it was confirmed that oxiracetam according to the present invention can be effectively used in combination with GLP-1 RA for the prevention or treatment of sarcopenia, muscular dystrophy, and cachexia, as well as muscle atrophy caused by GLP-1 RA.

[0119]

[0120] Example 6. Statistical Analysis

[0121] Statistical analysis of Examples 2 to 5 was performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA). The results of each replicate experiment were expressed 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.

[0122]

[0123] Hereinafter, examples of the preparation of pharmaceuticals and foods containing oxiracetam according to the present invention as an active ingredient for concomitant use with a GLP-1 RA are described; however, the present invention is not intended to be limited but merely to be described in detail. Using oxiracetam, which has excellent therapeutic or preventive effects without side effects when used in combination with the glucagon-like peptide-1 (GLP-1) receptor agonist, pharmaceutical and food compositions of Preparation Examples 1 and 2 were prepared according to the following compositional ingredients and compositional ratios using conventional methods.

[0124]

[0125] Preparation Example 1. Pharmaceutical

[0126] 1-1. Mountain Ritual

[0127] 50 mg of Oxiracetam and 2 g of crystalline cellulose of the present invention were mixed and then filled into an airtight bag according to a conventional method for manufacturing powders to produce a powder.

[0128]

[0129] 1-2. Refining

[0130] 50 mg of Oxiracetam, 400 mg of crystalline cellulose, and 5 mg of magnesium stearate of the present invention were mixed, and then tablets were manufactured by compressing them according to a conventional tablet manufacturing method.

[0131]

[0132] 1-3. Capsules

[0133] 30 mg of Oxiracetam, 100 mg of whey protein, 400 mg of crystalline cellulose, and 6 mg of magnesium stearate of the present invention were mixed and then filled into a gelatin capsule according to a conventional capsule manufacturing method to produce a capsule.

[0134]

[0135] Preparation Example 2. Food

[0136] 2-1. Manufacturing of Health Foods

[0137] The present invention can be prepared by mixing 1000 mg of Oxiracetam, 70 µg of Vitamin A acetate, 1.0 mg of Vitamin E, 0.13 mg of Vitamin B1, 0.15 mg of Vitamin B2, 0.5 mg of Vitamin B6, 0.2 µg of Vitamin B12, 10 mg of Vitamin C, 10 µg of Biotin, 1.7 mg of Nicotinamide, 50 µg of Folic Acid, 0.5 mg of Calcium Pantothenate, 1.75 mg of Ferrous Sulfate, 0.82 mg of Zinc Oxide, 25.3 mg of Magnesium Carbonate, 15 mg of Monopotassium Phosphate, 55 mg of Disodium Phosphate, 90 mg of Potassium Citrate, 100 mg of Calcium Carbonate, and 24.8 mg of Magnesium Chloride; the mixing ratio may be modified arbitrarily. After mixing the above ingredients according to a conventional method for manufacturing health foods, the granules It can be manufactured and used in the manufacture of health food compositions according to conventional methods.

[0138]

[0139] 2-2. Preparation of Health Drinks

[0140] 1000 mg of Oxiracetam, 1000 mg of Citric Acid, 100 g of Oligosaccharide, 2 g of Plum Concentrate, and 1 g of Taurine of the present invention are mixed with purified water according to a conventional method for making 900 ml of health drinks, then stirred and heated at 85°C for about 1 hour, and then the resulting solution is filtered, taken into a sterilized 2 L container, sealed and sterilized, and then stored in a refrigerator to be used in making a health drink composition.

[0141]

[0142] 2-3. Chewing Gum

[0143] Chewing gum was prepared by combining 20% ​​by weight of gum base, 76.9% by weight of sugar, 1% by weight of flavoring, and 2% by weight of water with 0.1% by weight of the Oxiracetam of the present invention using a conventional method.

[0144]

[0145] 2-4. Candy

[0146] A candy was prepared by combining 60% by weight of sugar, 39.8% by weight of corn syrup, and 0.1% by weight of flavoring with 0.1% by weight of the Oxiracetam of the present invention using a conventional method.

[0147]

[0148] 2-5. Biscuits

[0149] A biscuit was prepared by a conventional method by combining 25.59 wt% of cake flour Grade 1, 22.22 wt% of gravity flour Grade 1, 4.80 wt% of refined sugar, 0.73 wt% of salt, 0.78 wt% of glucose, 11.78 wt% of palm shortening, 1.54 wt% of ammonium, 0.17 wt% of baking soda, 0.16 wt% of sodium bisulfite, 1.45 wt% of rice flour, 0.0001 wt% of vitamin B, 0.04 wt% of milk flavor, 20.6998 wt% of water, 1.16 wt% of whole milk powder, 0.29 wt% of milk substitute, 0.03 wt% of dicalcium phosphate, 0.29 wt% of spray salt, and 7.27 wt% of spray oil with 0.8301 wt% of the oxiracetam of the present invention.

[0150]

[0151] The present invention has been described above with reference to its embodiments. Those skilled in the art will understand that the present invention may be embodied in modified forms without departing from the essential characteristics of the invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the invention is defined by the claims, not by the foregoing description, and all variations within the scope of the claims should be interpreted as being included in the invention.

Claims

1. A pharmaceutical composition for the prevention or treatment of obesity, The above composition is, A racetam-class compound or a pharmaceutically acceptable salt thereof as a first pharmacological component; and A pharmaceutical composition for the prevention or treatment of obesity, comprising an anti-obesity agent or a pharmaceutically acceptable salt thereof as a second pharmacological component.

2. A pharmaceutical composition for the prevention or treatment of obesity according to claim 1, wherein the racetam-based compound improves or inhibits the muscle-reducing side effects of the anti-obesity agent.

3. A pharmaceutical composition for the prevention or treatment of obesity according to claim 1, wherein the anti-obesity agent is accompanied by one or more side effects selected from the group consisting of muscle atrophy, sarcopenia, muscular dystrophy, and cachexia.

4. A pharmaceutical composition for the prevention or treatment of obesity, wherein, in claim 3, the anti-obesity agent is a glucagon-like peptide-1 receptor agonist.

5. A pharmaceutical composition for the prevention or treatment of obesity according to claim 1, wherein the racetam-series compound is Oxiracetam.

6. A pharmaceutical composition for the prevention or treatment of obesity according to claim 1, wherein the pharmaceutically acceptable salt is any one salt selected from the group consisting of hydrochloride, sulfate, nitrate, phosphate, hydrobromide, and hydroiodide.

7. A pharmaceutical composition for the prevention or treatment of obesity according to claim 4, wherein the glucagon-like peptide-1 receptor agonist is semaglutide.

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