Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
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  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to novel treatments and prevention of suppression of aging-related disorders, including sarcopenia.
• the present invention also provides compounds, compositions, medicaments, and therapeutic methods useful for novel treatment/prevention of sarcopenia-related diseases, disorders, symptoms, and the like.
• Non-Patent Document 1 Currently being developed by multiple companies, it mainly targets muscle differentiation and muscle cell death by targeting a factor of the TGF- ⁇ family called Myostatin/GDF-8. Therefore, not only sarcopenia but also muscular dystrophy is being developed as a target disease (Patent Documents 1 to 4, Non-Patent Document 1).
• bimagrumab a monoclonal antibody
• ACVR2B Activin Receptor
• phase 2 phase 2 has been completed in 2017.
• Bimagrumab increases muscle mass by inhibiting myostatin and activinA signals and promoting muscle differentiation.
• development was discontinued in 2018 because it did not dramatically improve sarcopenia symptoms, including walking speed and grip strength.
• a myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bones 2013 Sep;48(9):898-904.
• the present inventors In advancing research on novel treatment/prevention of sarcopenia-related diseases, disorders, symptoms, etc., the present inventors have found various compounds or pharmaceuticals thereof without being bound by conventionally studied molecular mechanisms and mechanisms of action. Intensive investigations and experiments have been repeated for many years on their salts or solvates thereof that are acceptable. The present inventor conducted extensive experiments on a compound that is used as an expectorant, among others, and unexpectedly found that it has the effect of increasing muscle strength and increasing cognitive ability. We have confirmed that the compound is suitable for use, and have found that the expectorant compound improves cognitive function, bone density, gray hair, and frailty including dermatitis, which are aging-related symptoms, and completed the present invention. rice field.
• the present invention provides sarcopenia-related diseases, disorders or conditions (or aging-related disorders including sarcopenia broadly, including so-called expectorants (including compounds or pharmaceutically acceptable salts or solvates thereof)).
• the present invention provides a composition for modulating, delaying, preventing or treating (the same applies hereinafter).
• Compounds constituting such expectorants include the compounds themselves or their pharmaceutically acceptable salts or solvates thereof. When it has an acidic group or a basic group, it can be converted into a basic salt or an acid salt by reacting with a base or an acid, so those salts are indicated.
• “pharmaceutically acceptable salts” include, for example, sodium salts, potassium salts, alkali metal salts such as lithium salts; magnesium salts, alkaline earth metal salts such as calcium salts; Organic base salts such as methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt, lysine salt, arginine Amino acid salts such as salts, ornithine salts, glutamates, aspartates, and the like.
• acid salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates, phosphorus inorganic acid salts such as acid salts; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; acetic acid organic acid salts such as salt, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine, lysine, arginine, Amino acid salts such as ornithine salts, glutamates, and aspartates are included.
• hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nit
• Expectorants include, for example, one or more compounds selected from the group consisting of L-ethylcysteine, ambroxol, L-carbocysteine and pharmaceutically acceptable salts thereof.
• the compound is L-ethylcysteine hydrochloride represented by the following general formula (1) and/or ambroxol hydrochloride represented by the following general formula (2) and their pharmaceutically acceptable
• One or more compounds selected from the group consisting of salts are preferred. ... (1) ...
• a disease, disorder or condition resulting from a disorder of muscle strength; a disease, disorder or condition resulting from a disorder of energy metabolism; a disease, disorder or condition resulting from a disorder of the nervous system and secretory organs A composition according to any one of the preceding clauses, comprising at least one selected from the group consisting of diseases, disorders or conditions resulting from the disorder. (Item 5) Any one of the preceding paragraphs, wherein said aging-related disorder including sarcopenia comprises at least one selected from the group consisting of primary sarcopeniasis, secondary sarcopeniasis and diseases, disorders or symptoms associated therewith.
• Age-related abnormalities including sarcopenia, are related lifestyle-related diseases (non-wasting diseases), wasting diseases, tumor-related diseases (including cancer cachexia), infectious diseases and related diseases such as COVID-19, exercise Selected from the group consisting of organic diseases, neurodegenerative diseases, cognitive impairment, and aging-related disorders (including malnutrition, frailty, spinal lung injury, inactivity, hypoactivity, disuse syndrome, and invasiveness such as trauma and surgery)
• Aging-related abnormalities, including said sarcopenia include the digestive system (such as the gastrointestinal tract), the circulatory system, the respiratory system (such as the vocal organs), the urinary system, the reproductive system, the endocrine system, the sensory system, the cranial nervous system, and the motor system.
• composition according to any one of the preceding clauses which is of a system selected from the group consisting of organ systems (bones, joints, ligaments, muscles, etc.).
• organ systems bones, joints, ligaments, muscles, etc.
• composition according to any one of the preceding paragraphs. (Item 11) 6. Any one of the preceding clauses, wherein said modulating, retarding, preventing or treating comprises modulating, retarding, preventing or treating at least one of loss of muscle mass and loss of (muscular) endurance. Composition.
• composition of the present invention may be administered in combination with at least one of exercise therapy, diet therapy and other drug therapy, or may be administered in combination with exercise therapy.
• the present invention provides a technology capable of treating or preventing sarcopenia and its related diseases, disorders and symptoms for the first time.
• the present invention also provides a technology capable of treating or preventing aging-related diseases, disorders and symptoms for the first time. That is, the present invention realizes a technology capable of novel treatment or prevention of suppression of aging-related disorders including sarcopenia. More specifically, the treatment and prevention according to the present invention also includes improvement of cognitive function, and covers all dementias including Alzheimer's disease. osteoporosis, including primary osteoporosis, secondary osteoporosis; Dermatitis, including urticaria; and hearing impairment, including age-related hearing loss; gray hair; hair loss, etc., may also be treated or prevented.
• FIG. 10 shows improvement in sarcopenia by administration of L-ethylcysteine hydrochloride, and endurance (muscular strength) in aged mice (79 weeks old) is measured using a treadmill.
• the administration of PBS phosphate-buffered saline
• FIG. 10 shows improvement in sarcopenia by administration of L-ethylcysteine hydrochloride, and endurance (muscular strength) in aged mice (79 weeks old) is measured using a treadmill.
• PBS phosphate-buffered saline
• FIG. 4 is a diagram showing gene regulation in muscles of mice administered with L-ethylcysteine hydrochloride, and shows a pathway analysis diagram of genes whose expression was increased by administration of L-ethylcysteine hydrochloride.
• FIG. 10 is a diagram showing gene regulation in muscles of mice administered with L-ethylcysteine hydrochloride, showing a pathway analysis diagram of genes whose expression was decreased by administration of L-ethylcysteine hydrochloride.
• FIG. 10 is a diagram showing gene regulation in the muscle of mice administered with L-ethylcysteine hydrochloride, showing upstream transcription factor analysis diagrams of genes in which changes in gene expression were observed.
• FIG. 11 shows a list of related diseases registered in MedlinePlus with altered expression gene associations with L-ethylcysteine hydrochloride.
• FIG. 10 shows improvement in sarcopenia by administration of ambroxol hydrochloride, and endurance (muscular strength) in aged mice (77 weeks old) is measured using a treadmill. In addition, the administration of PBS (phosphate-buffered saline) was also measured as a control.
• FIG. 10 is a diagram showing improvement of sarcopenia by ambroxol hydrochloride administration, in which cognitive ability in aged mice (77 weeks old) is measured using a contextual fear conditional test (CFC test). In addition, the administration of PBS (phosphate-buffered saline) was also measured as a control.
• CFC test contextual fear conditional test
• FIG. 5 shows the top 50 genes with altered gene expression in muscle of mice treated with ambroxol hydrochloride.
• FIG. 2 shows a pathway analysis diagram of genes whose gene expression is elevated in the muscle of mice to which ambroxol hydrochloride is administered.
• FIG. 10 is a diagram showing gene regulation in muscles of mice administered with ambroxol hydrochloride, and shows upstream transcription factor analysis diagrams of genes in which changes in gene expression were observed.
• FIG. 3 shows the top 30 genes with altered gene expression in myogenic cells of mice treated with ambroxol hydrochloride.
• FIG. 2 shows pathway analysis diagrams of genes whose gene expression is elevated in myogenic cells of mice to which ambroxol hydrochloride is administered.
• FIG. 2 shows pathway analysis diagrams of genes whose gene expression is reduced in myogenic cells of mice to which ambroxol hydrochloride is administered.
• FIG. 10 is a diagram showing gene regulation in myogenic cells of mice administered with ambroxol hydrochloride, and shows upstream transcription factor analysis diagrams of genes in which changes in gene expression were observed.
• the results of a frailty index test skin condition (hair, skin)) of ambroxol hydrochloride-administered mice are shown.
• the results of frailty index test muscular strength (grip strength)) of ambroxol hydrochloride-administered mice are shown.
• the results of frailty index test osteoporosis (physical/musculoskeletal)) of ambroxol hydrochloride-administered mice are shown.
• FIG. 3 shows the results of frailty index test (hearing loss) of ambroxol hydrochloride-administered mice.
• Fig. 2 shows evaluation results of frailty index test (alopecia) of L-carbocysteine-administered mice.
• Fig. 3 shows evaluation results of frailty index test (improvement of gray hair) of L-carbocysteine-administered mice.
• Fig. 2 shows evaluation results of frailty index test (improvement of hair loss) of L-carbocysteine-administered mice.
• Fig. 3 shows evaluation results of frailty index test (bone and muscle improvement) of L-carbocysteine-administered mice.
• Fig. 2 shows evaluation results of frailty index test (improvement of frailty) of L-carbocysteine-administered mice.
• sarcopenia refers to a disease diagnosed when 1. evidence supporting low muscle mass, 2. low muscle strength, or 3. low physical function is satisfied (European Working Group on Sarcopenia in Older People (EWGSOP)). Since the skeletal structure of Europeans and Americans differs from that of Asians, the AWGS (ASIAN working Group for SARCOPENIA) in 2014 created diagnostic criteria specific to Asians that can be used with Japanese physiques (Sportsmedicine 27(9), 2 -11, 2015-11, Bookhouse H.D.). Sarcopenia is classified into “primary sarcopenia” caused by aging and “secondary sarcopenia” caused by factors other than aging.
• muscles In addition to the function of "strength", muscles have the elements of "energy metabolism” and “secretory organs”.
• energy metabolism When muscle mass decreases or muscle function decreases, the functions of internal organs such as the heart and respiratory organs decrease from the viewpoint of "muscle strength", and joints suffer from arthritis due to the burden placed on the bones.
• energy metabolism obesity occurs due to the inability to use fat and sugar in the blood due to muscle deterioration.
• metabolic diseases such as myocardial infarction.
• NAMPT then synthesizes NAD from NMN in muscle. When NAD is lowered, brain function, metabolic function, etc. are lowered.
• Muscle mass is maintained through repeated synthesis and decomposition of muscle protein. Muscle mass is also reduced when the factors required for muscle protein synthesis decrease or when muscle protein breakdown exceeds muscle protein synthesis. Aging causes a decrease in sex hormones related to muscle growth, cell death (apoptosis), mitochondrial dysfunction, and exhaustion such as disuse, malnutrition, cancer and diabetes. Muscle atrophy (cachexia) due to sexually transmitted diseases combine to cause sarcopenia. In addition, loss of motor nerves that work to convey commands from the brain to the muscles, muscle damage such as corticosteroids, growth hormone (GH), insulin-like growth factor 1 (IGF-1), thyroid dysfunction, and insulin resistance. Sarcopenia also occurs due to hormonal influences associated with growth. Inflammatory cytokines are increased by suffering from each disease, and it is believed that the progression of muscle protein degradation also leads to the onset of sarcopenia.
• sarcopenia-related disease, disorder or symptom refers to a disease, disorder or symptom associated with one or more of sarcopenia and muscle strength disorders, energy metabolism disorders and secretory organ disorders that are characteristic of sarcopenia. say symptoms.
• Sarcopenia-related diseases, disorders or conditions are divided into diseases, disorders or conditions resulting from disorders of muscle strength; diseases, disorders or conditions resulting from disorders of energy metabolism; and diseases, disorders or conditions resulting from disorders of secretory organs. can be discussed (although there may be more than one disease, disorder or condition) and these are considered exhaustive.
• Sarcopenia-related diseases, disorders or conditions can also be discussed as primary sarcopeniases, secondary sarcopeniases and their accompanying diseases, disorders or conditions.
• the present invention broadly targets patients with sarcopenia, and sarcopenia-related diseases, disorders or symptoms include, for example, sarcopenia-related lifestyle-related diseases (non-debilitating diseases), debilitating diseases, tumor-related diseases (cancer disease), fluid quality), infectious diseases such as COVID-19, neurodegenerative diseases (including ALS), cognitive impairment, other related disorders (malnutrition, frailty, spinal lung injury, inactivity, (defined as including inactivity such as hypoactivity, disuse syndrome, trauma, surgery, etc.), and the like, but are not limited to these.
• aging-related disease, disorder or condition or “aging-related disease, disorder or condition” are used interchangeably and refer to a disease, disorder or condition that develops in association with aging.
• Aging-related diseases, disorders or conditions may include sarcopenia, lifestyle diseases (non-wasting diseases), wasting diseases, locomotory diseases, neurodegenerative diseases, cognitive impairment, and other related disorders, more particularly , sarcopenia, dementia (including short-term memory loss), metabolic disease, rheumatoid arthritis, osteoporosis, muscle mass loss, and hair loss.
• the term "disease, disorder or symptom caused by a muscle strength disorder” refers to any disease, disorder or symptom associated with a decrease in muscle quantity or quality (muscle function).
• muscle strength the function of internal organs such as the heart and respiratory organs is reduced, and joints include diseases, disorders or symptoms such as arthritis due to strain on the bones.
• Diseases, disorders or symptoms caused by muscle strength disorders include, for example, neurogenic muscular atrophy, myogenic muscular atrophy (muscular dystrophy, congenital myopathy, mitochondrial encephalomyopathy, myopathy due to congenital metabolic disorders, other myopathies, etc.) etc. can be mentioned.
• disease, disorder or symptom caused by disorder of energy metabolism refers to any disease, disorder or symptom caused by disorder of energy metabolism.
• a decline in muscle leads to obesity due to the inability to use fat and sugar in the blood, and an inability to metabolize fat leads to metabolic diseases such as myocardial infarction. to synthesize. Since a decrease in NAD leads to a decrease in brain function, metabolic function, etc., any disease resulting from such function should be listed as a disease, disorder or condition resulting from disturbances in energy metabolism in relation to sarcopenia. can be done.
• diseases, disorders or symptoms caused by disorders of energy metabolism include diabetes, dyslipidemia, obesity, metabolic syndrome, osteoporosis, fatty liver, hyperuricemia, hypertension and the like.
• disease, disorder or symptom caused by a disorder of a secretory organ refers to any disease, disorder or symptom associated with a disorder of muscle as a secretory organ secreted or produced from muscle.
• Muscles secrete inflammatory substances such as IL-6 and growth factors such as insulin-like growth factor 1 (IGF-1) and BDNF, which affect cancer, bone, nerve, and blood cell proliferation (Hoffmann et al. C, Weigert C. Skeletal Muscle as an Endocrine Organ: The Role of Myokines in Exercise Adaptations. Cold Spring Harb Perspect Med. 2017;7(11):a029793. Published 2017 Nov 1. doi:10.1101/cshperspect.
• IGF-1 insulin-like growth factor 1
• Diseases, disorders, or symptoms occur when their functions as secretory organs are impaired. Those related to these are included in diseases, disorders or conditions resulting from disorders of secretory organs. Diseases, disorders, or symptoms caused by disorders of secretory organs include, for example, diabetes, pancreatitis, ulcerative colitis, diarrhea, and the like.
• the term "disease, disorder or symptom caused by a disorder of the nervous system” refers to any disease, disorder or symptom associated with a disorder of nerves associated with muscles. Muscles contract in response to signals from the nervous system, and there is a close relationship between muscles and nerves. Disorders, disorders, or symptoms occur when these functions as the nervous system are impaired. Those related to these are included in diseases, disorders or conditions resulting from disorders of secretory organs. Diseases, disorders, or symptoms caused by disorders of the nervous system include, for example, neurodegenerative diseases (including ALS), cognitive impairment, and the like.
• primary sarcopenia refers to sarcopenia that has no obvious cause other than aging.
• secondary sarcopenia refers to sarcopenia that has causes other than aging, and activity-related sarcopenia (bedridden, inactive lifestyle, weightlessness that can cause ), disease-related sarcopenia (associated with severe organ failure (heart, lung, liver, kidney, brain), inflammatory diseases, malignancies and endocrine disorders), nutrition-related sarcopenia (malabsorption, gastrointestinal disease) , and those caused by insufficient intake of energy and/or protein accompanying the use of drugs that cause anorexia (use of drugs that cause anorexia).
• the compound refers to a compound represented by the above formula (1) and a compound represented by the above formula (2), a compound or a pharmaceutically acceptable salt or solvate thereof, defined elsewhere in the specification.
• exercise therapy refers to therapy by exercise.
• Non-pharmaceutical interventions for sarcopenia are exercise and dietary therapy such as vitamin D and omega-3.
• die therapy refers to therapy by diet.
• Non-pharmaceutical interventions for sarcopenia are exercise and dietary therapy such as vitamin D and omega-3.
• other drug therapy refers to drug therapy other than the "compound represented by the above formula (1) and the compound represented by the above formula (2)" of the present invention.
• the use of a plurality of compounds represented by the above formula (1) and the compound represented by the above formula (2) corresponds to the use of a plurality of the compounds of the present invention, etc., rather than other drug therapy.
• prevention is an act of administering the active ingredient of the present invention to a healthy person who has not developed a disease, for example, for the purpose of preventing the development of a disease. .
• treatment is the act of administering the active ingredient of the present invention to a person (patient) who has been diagnosed by a doctor as having a disease.
• the term “modulation” means that the subject's disease (e.g., sarcopenia-related disease, disorder, or symptom) develops a disease compared to when the compound of the present invention is not administered. It means that the condition is changed, preferably improved, at the time of administration.
• progression suppression means that the degree of a disease (eg, sarcopenia-related disease, disorder, or symptom) of a subject developing a disease does not worsen, preferably improves.
• the term "kit” refers to a unit that provides parts to be provided (for example, compounds, pharmaceuticals, compositions, etc., and instructions, etc.), usually divided into two or more compartments.
• This kit form is preferred when the purpose is to provide a composition that should not be provided in a mixed form for reasons such as stability, and is preferably used in a mixed form immediately before use.
• the kit is preferred when provided in combination with an agent for prior patient identification as a companion drug.
• the kit is provided with instructions or instructions describing how to use the parts provided or how to dispose of reagents or waste fluids after use. be.
• the kit when the kit is used as a pharmaceutical kit, the kit usually includes instructions and the like describing methods for administering pharmaceuticals and the like.
• the "instruction” describes the method of using the present invention for the user.
• the instructions include language that directs how to use (eg, administer) the compound, etc. of the present invention.
• This instruction shall, if necessary, be submitted to the regulatory authority of the country in which the invention is implemented (for example, the Ministry of Health, Labor and Welfare or the Ministry of Agriculture, Forestry and Fisheries in Japan, the Food and Drug Administration (FDA), the Department of Agriculture (USDA) in the United States. ), etc.), and clearly state that it has been approved by the competent authority.
• the instructions may be provided in a paper medium, but are not limited to that, and may also be provided in a form such as an electronic medium (for example, a home page provided on the Internet, e-mail, etc.).
• the pharmaceutical composition according to the present invention comprises an expectorant or a pharmaceutically acceptable salt or solvate thereof, wherein the expectorant is ethylcysteine, ambroxol, carbocysteine and pharmaceuticals thereof It includes one or more compounds selected from the group consisting of the above acceptable salts.
• the compound includes at least one of a compound represented by the following general formula (1) and a compound represented by general formula (2). ... (1) ... (2)
• the compound represented by the formula (1) has a generic name of Ethyl L-Cysteine Hydrochloride and a molecular formula of, for example, C 5 H 11 NO 2 S.HCl.
• the compound represented by Formula (2) has a generic name of Ambroxol Hydrochloride and a molecular formula of, for example, C 13 H 18 Br 2 N 2 O.HCl.
• the compounds of the present invention are not limited to these, but can be produced, for example, by the conventional production methods described below. These production methods can be appropriately improved based on the knowledge of those skilled in organic synthetic chemistry.
• the compounds used as starting materials may be salts thereof as long as they do not interfere with the reaction.
• the present invention also relates to such a manufacturing method.
• the object compound can be obtained by protecting the site other than the reaction site as necessary and deprotecting after the completion of the reaction or after performing a series of reactions.
• Protective groups used in these processes are described in the literature (T. W. Greene and P. G. M. Wuts, “Protective Group in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New York ( 1999)), etc., can be used.
• introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (eg, the methods described in the above literature) or a method analogous thereto.
• the starting materials and intermediates in the production method of the present invention can be purchased as commercial products, or can be obtained by synthesizing from known compounds according to methods described in known literature or known methods. Moreover, these starting materials and intermediates may be salts thereof as long as they do not interfere with the reaction.
• the intermediates and target compounds in the production method of the present invention can also be converted into other compounds included in the present invention by appropriately converting their functional groups.
• the transformation of the functional group at that time is a method commonly used in organic synthetic chemistry (for example, R. C. Larock, "Comprehensive Organic Transformations", 2nd Ed., John Wiley and Sons, Inc., New York (1999) described method, etc.) or a method based thereon.
• the present invention comprises or utilizes at least one of a compound represented by formula (1) above and a compound represented by formula (2) above to modulate a sarcopenia-related disease, disorder or condition.
• Compositions, medicaments, methods, compounds, uses, etc. for slowing, preventing, or treating , progression are provided.
• the compound represented by the above formula (1) and the compound represented by the above formula (2) unexpectedly modulate, delay progression, prevent or treat sarcopenia-related diseases, disorders or symptoms. It is completed and provided by discovering that it can be done.
• the compound used in the present invention is a compound represented by the above formula (1) and a compound represented by the above formula (2), a compound, or a pharmaceutically acceptable salt or solvate thereof (e.g., hydrates). Therefore, in a preferred embodiment, the compound of the present invention is a compound represented by formula (1) above and/or a compound represented by formula (2) above.
• sarcopenia-related diseases, disorders or conditions that can be modulated, delayed, prevented or treated in the present invention are diseases, disorders or conditions resulting from impairment of muscle strength; diseases, disorders or conditions resulting from impairment of energy metabolism; or symptoms; and at least one selected from the group consisting of diseases, disorders or symptoms caused by disorders of secretory organs.
• the sarcopenia-related disease, disorder or condition is sarcopenia-related lifestyle diseases (non-debilitating diseases), debilitating diseases, tumor-related diseases (including cancer cachexia), COVID-19 Infectious diseases and related diseases such as musculoskeletal diseases, neurodegenerative diseases (including ALS), cognitive impairment, other related disorders (malnutrition, frailty, spinal lung injury, inactivity, hypoactivity, disuse syndrome, trauma (defined as including invasiveness such as surgery and surgery).
• respiratory disease e.g. respiratory failure
• visceral disease or urinary system disease
• bone-related disease osteoporosis, etc.
• muscle-related disease dystrophy
• myofibrillar myopathy ALS, etc.
• Diseases, disorders or symptoms targeted by the present invention may be directly or indirectly related to sarcopenia, for example, digestive system (gastrointestinal tract), circulatory system, respiratory system, which may be related through muscle strength, energy metabolism or secretory system.
• Organ system including vocal organs
• urinary system including vocal organs
• reproductive system endocrine system
• sensory system including vocal organs
• nervous system including vocal organs
• motor system including muscle strength, energy metabolism or secretory system.
• neoplasm cancer, tumor, etc.
• the present invention provides a method for modulating, delaying progression, or slowing progression of aging-related diseases, disorders or symptoms comprising at least one of the compound represented by formula (1) above and the compound represented by formula (2) above.
• Compositions, methods, compounds or uses for prophylaxis or treatment are provided.
• the aging-related disease, disorder or condition is sarcopenia, lifestyle diseases (non-debilitating diseases), debilitating diseases, tumor-related diseases (including cancer cachexia), infections such as COVID-19 disease/related disease, locomotor system disease, neurodegenerative disease, cognitive impairment, and other related disorders (same as above).
• the aging-related disease, disorder or condition is selected from sarcopenia, dementia, metabolic disease, rheumatoid arthritis, osteoporosis, loss of muscle mass, hair loss.
• the compound used in the present invention is the compound represented by the above formula (1) and/or the compound represented by the above formula (2).
• the compound represented by formula (1) and/or the compound represented by formula (2) used in the present invention is orally administrable.
• modulation, retardation, prevention or treatment may be confirmed by modulation of at least one gene in said subject.
• the present invention regulates, delays progression of, or prevents aging-related diseases, disorders, or symptoms containing at least one of the compound represented by the above formula (1) and the compound represented by the above formula (2). or provide a composition for treatment.
• the aging-related disease, disorder or condition is sarcopenia, lifestyle diseases (non-debilitating diseases), debilitating diseases, tumor-related diseases (including cancer cachexia), infectious diseases such as COVID-19 ⁇ Related diseases, locomotory diseases, neurodegenerative diseases, cognitive impairment, and other related disorders (including malnutrition, frailty, spinal lung injury, inactivity, decreased activity, disuse syndrome, trauma, surgery, etc.) defined).
• the aging-related disease, disorder or condition is selected from sarcopenia, dementia, metabolic disease, rheumatoid arthritis, osteoporosis, loss of muscle mass, hair loss.
• the present invention provides a composition for use in diagnosing or testing a sarcopenia-related disease, disorder or condition in a subject, the composition comprising at least one gene selected from the group consisting of therapeutic genes.
• compositions are provided comprising means or reagents for identifying the presence, absence or level of expression of one gene.
• therapeutic gene clusters can be classified into various groups as conventionally known.
• a keratinization-related gene group and an extracellular structure tissue-related gene group as therapeutic gene groups.
• the present invention provides compositions for modulating, delaying progression, preventing or treating a sarcopenia-related disease, disorder or condition, comprising a substance or factor that modulates at least one gene.
• the present invention is a method for screening a substance or factor for modulating, delaying progression, preventing or treating a sarcopenia-related disease, disorder or condition, the method comprising: A) administering a candidate substance or factor to a subject; B) confirming regulation of at least one gene in said subject; C) identifying, based on the results of B), that the candidate substance or factor is a substance or factor that may have the ability to modulate, delay progression, prevent, or treat a sarcopenia-associated disease, disorder, or condition; provides a method that includes
• the compound represented by the above formula (1) and the compound represented by the above formula (2), medicament, composition, etc. of the present invention can be administered in any dosage form. Oral administration is preferred, but not limited thereto.
• a "subject” or “subject” to which administration is contemplated can be a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and/or other non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), commercially relevant mammals, e.g., cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys), reptiles, amphibians, and fish. not.
• the non-human animal is a mammal.
• Non-human animals can be male or female at any stage of development.
• a non-human animal can be a transgenic animal.
• the terms “treat,” “treating,” and “treatment” occur while a subject is suffering from a disease, disorder, or condition. Say things. As used herein, the act of reducing the severity of, or delaying or slowing the progression of, a disease, disorder, or symptom is termed “delaying progression,” and occurs before a subject begins to suffer from a disease, disorder, or , “prevention” is the act of inhibiting a disorder or symptom or reducing the severity of the disorder.
• an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, ie, treat the disorder. It will be appreciated by those skilled in the art that the effective amount of the compound of the invention will vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disorder to be treated, the mode of administration, as well as the age, health and subject, etc. can vary depending on the factors of Effective amounts include therapeutic and prophylactic treatments.
• a "therapeutically effective amount" of a compound is one that provides a therapeutic effect in treating a disorder or one or more symptoms associated with a disorder.
• An amount sufficient to delay or minimize A therapeutically effective amount of a compound means an amount of therapeutic agent that, alone or in combination with other therapies, provides a therapeutic effect in treating disorders.
• the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or prevents symptoms or causes of a disorder, or enhances the therapeutic effectiveness of another therapeutic agent.
• a prophylactically effective amount of a compound is an amount that prevents the disorder or one or more symptoms associated with the disorder, or prevents its recurrence. is sufficient for A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, that provides a prophylactic effect in preventing the disorder.
• prophylactically effective amount can encompass an amount that improves general prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• the sarcopenia-related disease, disorder or condition is a disease, disorder or condition resulting from an impairment of muscle strength; a disease, disorder or condition resulting from an impairment of energy metabolism; It includes at least one selected from the group consisting of symptoms and diseases, disorders or symptoms caused by disorders of secretory organs.
• the sarcopenia-related disease, disorder or condition comprises at least one selected from the group consisting of primary sarcopeniasis, secondary sarcopeniasis and diseases, disorders or conditions associated therewith.
• the sarcopenia-related disease, disorder or condition is sarcopenia-related lifestyle diseases (non-debilitating diseases), debilitating diseases, tumor-related diseases (including cancer cachexia), COVID-19, etc. infectious diseases and related diseases, locomotive diseases, neurodegenerative diseases (including ALS), cognitive impairment, other related disorders (malnutrition, frailty, spinal lung injury, inactivity, hypoactivity, disuse syndrome, trauma and any disorder defined as including an intervention such as surgery).
• the sarcopenia-related disease, disorder or condition is in the digestive system (such as the gastrointestinal tract), the cardiovascular system, the respiratory system (such as the vocal organs), the urinary system, the reproductive system, the endocrine system, the sensory system. , cranial nervous system, and motor system (bones, joints, ligaments, muscles, etc.).
• diseases, disorders or conditions resulting from impaired muscle strength that can be modulated, slowed, prevented or treated include neurogenic muscle atrophy, myogenic muscle atrophy (muscular dystrophy, congenital myopathy, mitochondrial muscle atrophy) encephalomyopathy, myopathy due to congenital metabolic disorder, other myopathies, etc.).
• myogenic muscle atrophy muscle dystrophy, congenital myopathy, mitochondrial muscle atrophy
• encephalomyopathy myopathy due to congenital metabolic disorder, other myopathies, etc.
• diseases, disorders or conditions resulting from impaired energy metabolism that may be modulated, slowed, prevented or treated include diabetes, dyslipidemia, obesity, metabolic syndrome, osteoporosis, fatty liver, hypertension Examples include uricemia, hypertension, and the like.
• diseases, disorders or conditions resulting from disorders of secretory organs that can be modulated, slowed, prevented or treated can include diabetes, pancreatitis, ulcerative colitis, diarrhea, and the like.
• diseases, disorders or conditions resulting from disorders of the nervous system can include neurodegenerative diseases (including ALS), cognitive impairment, and the like. .
• sarcopenia-related diseases, disorders or conditions can be divided into primary and secondary.
• the sarcopenia-related disease, disorder, or symptom includes at least one selected from the group consisting of primary sarcopeniasis, secondary sarcopeniasis, and diseases, disorders, or symptoms associated therewith.
• the disease, disorder or symptom associated with primary sarcopeniasis and/or secondary sarcopeniasis that can be modulated, slowed, prevented or treated is bedridden, inactive lifestyle, poor physical condition, Severe organ failure, inflammatory disease, malabsorption, gastrointestinal disease, anorexia and the like can be mentioned.
• the compound of the present invention may be selected from compounds represented by formula (1) above and compounds represented by formula (2) above.
• the compounds of the present invention or compounds or pharmaceutically acceptable salts or solvates thereof are orally administrable.
• the pharmaceutical composition of the present invention may be characterized by being administered in combination with at least one of exercise therapy, diet therapy and other drug therapy.
• the pharmaceutical compositions of the invention may be characterized as being administered in combination with exercise therapy.
• the modulating, slowing progression, preventing or treating is modulating, slowing progression, preventing in at least one of loss of muscle mass, loss of (muscle) endurance, loss of short-term memory, loss of bone mineral density and osteoporosis. or may include therapy.
• modulating, slowing progression, preventing or treating may comprise modulating, slowing progression, prevention or treatment of at least one of loss of muscle mass and loss of (muscular) endurance.
• the administration route of the compounds, medicaments, compositions, etc. of the present invention may be oral administration, parenteral administration or rectal administration, and the daily dose depends on the type of compound, administration method, symptoms and age of patients. etc.
• oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per 1 kg body weight of humans or mammals can be administered in 1 to several divided doses.
• parenteral administration such as intravenous injection, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per 1 kg body weight of humans or mammals can be administered.
• compositions relate primarily to pharmaceutical compositions for administration to humans, it will be appreciated by those skilled in the art that such compositions are generally applicable to animals of all kinds. suitable for administration to Modification of pharmaceutical compositions for administration to various animals is well understood, and the ordinary veterinary pharmacologist can design and/or perform such modifications with no more than routine experimentation.
• the compounds, medicaments, compositions, etc. of the present invention can be administered orally or parenterally by formulation or preparation using an appropriate dosage form.
• dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices, and the like.
• Formulations are manufactured by known methods using pharmaceutically acceptable additives. Additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , fragrance, etc. can be used.
• lactose mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, stearin.
• carmellose calcium croscarmellose sodium
• hydroxypropylcellulose hydroxypropylmethylcellulose
• polyvinyl alcohol stearin.
• Magnesium acid sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc and the like.
• pharmaceutically acceptable excipients include any and all solvents, dispersion media, diluents, or other liquid bases, dispersing or suspending aids, surfactants, etc. Tonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like are included as appropriate to the particular dosage form desired.
• Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, (Lipponcott, Williams & Wilkins, Baltimore, MD, 2006) describes various excipients used in formulating pharmaceutical compositions and their preparation. A known technique for this is disclosed. Any conventional carrier medium is incompatible with a substance (e.g., producing any undesirable biological effect, or otherwise any other component(s) of the pharmaceutical composition. ) is considered within the scope of the present invention, except insofar as it adversely interacts with ).
• the pharmaceutically acceptable excipient is at least 95%, 96%, 97%, 98%, 99%, or 100% pure.
• the additive is approved for human and veterinary use.
• the excipient is approved by the US Food and Drug Administration.
• the excipient is pharmaceutical grade.
• the excipient meets the standards of the United States Pharmacopoeia (USP), European Pharmacopoeia (EP), British Pharmacopoeia, Japanese Pharmacopoeia (JP) and/or International Pharmacopoeia.
• compositions used in the preparation of pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifying agents, disintegrants, binders, preservatives, buffers. agents, lubricants, and/or oils, but are not limited thereto.
• additives may optionally be included in the formulations of the invention. Additives such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents can be present in the composition according to the judgment of the formulator.
• Exemplary diluents are calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol. , sodium chloride, dry starch, corn starch, powdered sugar, and combinations thereof.
• Exemplary granulating and/or dispersing agents are potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins.
• Exemplary surfactants and/or emulsifiers include natural emulsifiers such as acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, waxes, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate).
• natural emulsifiers such as acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, waxes, and lecithin
• Exemplary binders include starches (such as cornstarch and starch paste), gelatin, sugars (such as sucrose, glucose, glucose, dextrin, molasses, lactose, lactitol, mannitol), natural and synthetic gums (such as acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol shell mucus, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, polyvinylpyrrolidone, silicic acid. aluminum magnesium (Vegum), and larch arabogalactan), alginic acid, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohols, and combinations thereof.
• starches such as cornstarch and starch paste
• gelatin such as sucrose, glucose
• Exemplary preservatives can include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives, and other preservatives.
• Exemplary antioxidants are alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, Including, but not limited to, sodium bisulfite, sodium pyrosulfite, and sodium sulfite.
• Exemplary chelating agents are ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and Contains trisodium edetate.
• Exemplary antimicrobial preservatives are benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea.
• Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid, but but not limited to them.
• Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoic acid, and phenylethyl alcohol.
• Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
• Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), lauryl ether.
• the preservative is an antioxidant. In another embodiment the preservative is a chelating agent.
• Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium glucoheptonate, calcium gluconate, D-gluconate.
• Exemplary lubricants are magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, behanate glyceryl, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, lauryl sulfate Including, but not limited to, magnesium, sodium lauryl sulfate, and combinations thereof.
• oils include almond, apricot kernel, avocado, babassu, bergamot, black currant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton.
• oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. but not limited to them.
• Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, mixtures thereof, and the like.
• inert diluents commonly used in the art, such as water or other solvents, so
• the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• the complexes of the invention are mixed with solubilizers such as cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
• Injectable preparations such as sterile injectable aqueous or oleagenous suspensions, can be formulated according to the known art using dispersing or wetting agents and suspending agents.
• the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. .
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution, USP, and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• Injectable formulations are prepared, for example, by filtration through a bacteria-retaining filter, or with a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. It can be sterilized by incorporation.
• compositions for rectal or vaginal administration are typically suppositories, in which the complexes of the invention are mixed with nonirritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository wax.
• nonirritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository wax.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active ingredient is admixed with at least one inert pharmaceutically acceptable excipient or carrier.
• inert pharmaceutically acceptable excipient or carrier are for example sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as carboxymethylcellulose, (c) humectants such as glycerol; (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) dissolution retardants such as paraffin; (f) absorption enhancers such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin and
• Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules, using additives such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents, and can be of a composition that they release the active ingredient(s) exclusively or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
• Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules, using additives such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.
• the active ingredient can be in microencapsulated form with one or more additives as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active ingredient may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may, as is normal practice, contain additional substances other than inert diluents, such as tableting lubricants and other tabletting aids, such as magnesium stearate and microcrystalline cellulose.
• the dosage form may contain buffering agents.
• opacifying agents may optionally contain opacifying agents, and can be of a composition that they release the active ingredient(s) exclusively or preferentially in a certain part of the intestinal tract, optionally in a delayed manner.
• embedding compositions include polymeric substances and waxes.
• Dosage forms for topical and/or transdermal administration of the compounds, salts, solvates and compositions of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or or may contain a patch.
• the active ingredient may be admixed in a sterile environment with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as may be required.
• the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
• Such dosage forms can be prepared, for example, by dissolving and/or formulating the active ingredient in the proper medium.
• the rate can be controlled by providing a rate controlling membrane and/or dispersing the active ingredient in a polymer matrix and/or gel.
• Suitable devices for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Pat. Including things.
• Intradermal compositions may be administered by devices that limit the effective penetration length of the needle into the skin, such as those described in PCT Publication No. WO99/34850 and functional equivalents thereof. Jet injection devices are disclosed in, for example, U.S. Pat. 12,335, 5,503,627, 5,064,413, 5,520,639, 4,596,556, 4,790,824, 4,941,880, 4,940,460 and PCT publication WO97 /37705 and WO97/13537.
• a conventional syringe can be used for the classic Mantoux method of intradermal administration.
• Formulations for external administration include liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or or suspensions including but not limited to.
• Topically administrable formulations may contain, for example, from about 1% to about 10% (w/w) of the active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
• Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
• the pharmaceutical composition of the present invention can be prepared, packaged, and/or sold as a formulation for transpulmonary administration from the oral cavity.
• Such formulations may comprise dry particles containing the active ingredient having diameters ranging from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
• Such compositions are conveniently prepared using a device containing a dry powder reservoir (to which a propellant stream can be directed to disperse the powder) and/or a self-propelled solvent/powder dispenser container (e.g. a closed container). It is in the form of a dry powder for administration using a device containing the active ingredient dissolved and/or suspended in a low-boiling propellant.
• Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
• Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in unit dosage form.
• the propellant may further contain additional ingredients such as liquid nonionic and/or solid anionic surfactants and/or solid diluents, which may have a particle size of the same order as the particles comprising the active ingredient. can contain.
• a pharmaceutical composition of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
• Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic, optionally sterile solutions and/or suspensions containing the active ingredient, conveniently either nebulized and /or may be administered using an atomizing device.
• Such formulations may further comprise one or more additional ingredients, including flavorings such as sodium saccharin, volatile oils, buffers, surfactants and/or preservatives such as methylhydroxybenzoic acid, but not limited to them.
• Droplets provided by this route of administration can have an average diameter ranging from about 0.1 to about 200 nanometers.
• formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions of the invention.
• Another formulation for intranasal administration is a coarse powder, containing the active ingredient and having an average particle size of about 0.2-500 micrometers. Such formulations are administered in the manner snuffed, ie, by rapid nasal inhalation from a container of powder held near the nostril.
• Formulations for nasal administration may contain, for example, from about 0.1-100% (w/w) of active ingredient, and may include one or more of the additional ingredients described herein.
• a pharmaceutical composition of the invention may be prepared, packaged, and/or sold in a formulation for buccal administration.
• Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods and may contain, for example, 0.1-20% (w/w) of active ingredient, the balance being orally administered.
• Formulations for buccal administration may instead comprise a powder and/or an aerosolized and/or atomized solution and/or suspension containing the active ingredient.
• Such powdered, aerosolized and/or aerosolized formulations can have an average particle size and/or droplet size ranging from about 0.1 to about 200 nanometers when dispersed and are described herein. may further comprise one or more of the additional components of
• the pharmaceutical composition of the present invention can be prepared, packaged, and/or sold as a formulation for ocular administration.
• Such formulations may, for example, be in the form of eye drops and contain, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier.
• Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
• Other ophthalmically administrable formulations that are useful include those containing the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
• the pharmaceutical compositions of the invention can be administered to the patient for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 hours, at least 7 weeks, or at least 8 weeks. In certain embodiments, the pharmaceutical compositions of the invention can be administered to the patient for at least 4 weeks. Typically, the effects of sarcopenia can be assessed in about 4 weeks.
• compositions described herein can be prepared by any method known or later developed in the field of pharmacology. Generally, such methods of preparation involve combining the active ingredient with additives and/or one or more other adjunct ingredients and then, if necessary and/or desired, producing the desired product. forming and/or packaging into single or multiple dose units.
• a pharmaceutical composition of the invention may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
• a "unit dose" is discrete amount of the pharmaceutical composition containing a predetermined amount of the active ingredient.
• the amount of active ingredient is generally equal to the dose of active ingredient administered to a subject and/or a convenient fraction of such dose (eg, 1/2 or 1/3 of such dose).
• the relative amounts of active ingredient, pharmaceutically acceptable excipients, and/or any additional ingredients in the pharmaceutical compositions of the present invention will depend on the make-up, size, and/or disorder of the subject being treated. It will also vary depending on the route by which the composition is administered. For example, a composition can contain from 0.1% to 100% (w/w) of active ingredient.
• the compounds of the invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It should be understood, however, that the total daily usage of the pharmaceutical composition of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific therapeutically effective dose level for any particular subject will depend on a variety of factors. They include the disease, disorder or disorder to be treated and the severity of the disorder, the activity of the specific active ingredients used, the age, weight, general health, sex and diet of the subject, the specific Including time of administration, route of administration, and rate of excretion of the active ingredient, length of treatment, drugs used in combination with or concurrently with the particular active ingredient employed, and similar factors well known in the medical arts.
• the compounds of the present invention can be administered by any route.
• a pharmaceutical composition comprising a powders, ointments, creams and/or drops), mucosal, nasal, bucal, enteral, sublingual, intratracheal instillation, intrabronchial instillation and/or inhalation and/or oral spray, nasal as a spray, and/or as an aerosol).
• Specifically contemplated routes are systemic intravenous injection, local administration by blood and/or lymph transfusion, and/or administration directly to the affected area.
• the most suitable route of administration will depend on various factors. These include properties of the agent (eg its stability in the environment of the gastrointestinal tract) and/or subject disorders (eg whether the subject is able to tolerate oral administration).
• properties of the agent eg its stability in the environment of the gastrointestinal tract
• subject disorders eg whether the subject is able to tolerate oral administration.
• oral and/or nasal spray and/or aerosol routes are most commonly used to deliver therapeutic agents directly to the lungs and/or respiratory system.
• the present invention takes into account possible advances in the science of drug delivery and encompasses delivery of the pharmaceutical compositions of the invention by any suitable route.
• Compounds, salts, solvates, pharmaceutical compositions of the present invention may range from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg. kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg of the subject Body weight/day can be delivered one or more times daily and administered at a dosage level sufficient to obtain the desired therapeutic effect.
• the desired dose can be delivered three times a day, twice a day, once a day, every two days, every three days, every week, every two weeks, every three weeks, or every four weeks.
• the desired dose is achieved using multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or more doses). can be delivered via
• the dosage ranges described herein provide guidance for the administration of provided pharmaceutical compositions to adults.
• the amount administered to a child or adolescent can be determined by a medical practitioner or person of ordinary skill in the art, and can be lower than or the same as that administered to an adult.
• the precise amount of the compound, salt, solvate, composition of the invention required to achieve an effective amount will depend, for example, on the species of interest, age, and severity of the disorder, side effects or disorders in general, the specific Varies from subject to subject depending on the identity of the compound(s), mode of administration, and the like.
• the present invention encompasses "therapeutic cocktails” comprising the compounds, salts, solvates and pharmaceutical compositions of the present invention.
• the compounds, salts, solvates, pharmaceutical compositions of the invention comprise a single species capable of binding multiple targets.
• different compounds, salts, solvates, pharmaceutical compositions of the invention contain different targeting moieties, and the different targeting moieties may all bind the same target.
• different compounds, salts, solvates, pharmaceutical compositions of the invention contain different targeting moieties, and all of the different targeting moieties may bind different targets.
• such different targets may be associated with the same cell type.
• such different targets may be associated with different cell types.
• the compounds, salts, solvates and pharmaceutical compositions of the present invention can be used for combination therapy.
• the specific combination of therapies (therapeutic agents or treatments) for use in a combination regimen will be determined as appropriate, taking into consideration the suitability of the desired therapeutic agents and/or treatments and the desired therapeutic effect to be achieved. good.
• the therapy used may have the desired effect for the same purpose (e.g., a conjugate of the invention useful for detecting tumors may be administered concurrently with another agent useful for detecting tumors). or they may achieve a different effect (eg control of any side effects).
• compositions of the invention can be administered alone or in combination with one or more therapeutically active agents.
• combination with is not intended that the agents must necessarily be administered and/or formulated for delivery together, although those methods of delivery are within the scope of the invention.
• the compositions may be administered simultaneously, prior to, or subsequent to one or more other desired therapeutic agents or medical treatments.
• each agent can be administered at the dose and/or time schedule determined for that agent.
• the present invention provides agents capable of improving their bioavailability, decreasing and/or modifying their metabolism, inhibiting their excretion, and/or modifying their biodistribution.
• compositions of the present invention includes delivery of the pharmaceutical composition of the present invention in combination with It will also be appreciated that the therapeutically active agents and the compounds, salts, solvates, pharmaceutical compositions of the invention used in this combination may be administered together as a single composition or administered separately as different compositions. obtain.
• therapeutically active agent refers to any substance used as a medicament for the treatment, prevention, delay, reduction, or amelioration of a disorder; Refers to useful substances.
• Therapeutically active agents also include compounds that increase the effect or effectiveness of another compound, for example, by enhancing the effect or reducing the side effects of a compound, salt, solvate, pharmaceutical composition of the invention.
• the therapeutically active agent is an anticancer agent, an antibiotic, an antiviral agent, an anti-HIV agent, an antiparasitic agent, an antiprotozoal agent, an anesthetic, an anticoagulant, an inhibitor of an enzyme, a steroidal agent, a steroidal or non-steroidal agent.
• Steroidal anti-inflammatory drugs antihistamines, immunosuppressants, antitumor agents, antigens, vaccines, antibodies, decongestants, sedatives, opioids, analgesics, antipyretics, contraceptives, hormones, prostaglandins, progesterone agonists , antiglaucoma drugs, ophthalmic drugs, anticholinergic drugs, analgesics, antidepressants, antipsychotics, neurotoxins, hypnotics, tranquilizers, anticonvulsants, muscle relaxants, antiparkinsonian drugs, anticonvulsants, muscle constrictors, channel blockers, miotics, antisecretory agents, antithrombotic agents, anticoagulants, anticholinergics, beta-adrenergic blockers, diuretics, cardiovascular agents, vasoactive agents, vasodilators, antihypertensive agents, angiogenic agents, modulators of cell-extracellular matrix interactions (eg cell growth inhibitors and anti-adhesion
• kits containing one or more of the compounds, salts, solvates, pharmaceutical compositions of the present invention are provided.
• the invention provides kits comprising compounds, salts, solvates, pharmaceutical compositions of the invention and instructions for use.
• a kit may contain a plurality of different compounds, salts, solvates, pharmaceutical compositions of the invention.
• the kit may contain any of several additional components or reagents in any combination. Although not all of the various combinations are explicitly shown, each combination is within the scope of the invention.
• the kit comprises, for example, (i) one or more compounds, salts, solvates, pharmaceutical compositions, and optionally one or more specific compounds of the invention to be delivered. therapeutically active agent, (ii) instructions for administration to a subject in need thereof.
• Kits typically include instructions, which may include, for example, protocols and/or preparation of a compound, salt, solvate, pharmaceutical composition of the invention, administration of a compound of the invention to a subject in need thereof, Administration of salts, solvates, pharmaceutical compositions, diseases, disorders or conditions for the design of novel compounds, salts, solvates, pharmaceutical compositions of the invention may be described.
• Kits generally include one or more vessels or containers, which may be adapted to separately house some or all of the individual components and reagents.
• the kit may also include a means for commercial packaging of the individual containers in relatively close proximity, such as a plastic box. It may contain instructions, packaging material, such as Styrofoam®, and the like.
• Identifiers such as bar codes, radio frequency identification (ID) tags, etc.
• ID radio frequency identification
• the identifier can be used to uniquely identify the kit, eg, for quality control, inventory control, tracking, transfer between workstations purposes.
• Example 1 L-ethylcysteine hydrochloride
• Example 1-1 Effect of compound and effect of combined use with exercise therapy
• L-ethylcysteine hydrochloride represented by formula (1) could be used to treat various related diseases, disorders or symptoms related to sarcopenia in the following mouse model.
• mice C57BL/6J (purchased from Oriental Yeast) (purchased from Oriental Yeast)
• muscle strength (endurance) in 79-week-old aged mice was tested according to the following procedure. It was confirmed by a red mill test. Mice were trained for 3 days to habituate them to the equipment before recording their performance. The electrical stimulation grid was adjusted to 1 mA and the slope was set to 15 degrees. On the first day of training, mice were allowed to walk on a treadmill at a speed of 10 m/min for 10 min, rest for 10 min, and then walk at a speed of 10 m/min for 10 min.
• the first two steps were performed under the same conditions as on the first day, after which the subject started walking at 10 m/min and increased the speed by 1 m/min every minute to a maximum speed of 20 m/min. .
• maximal exercise endurance was measured.
• Six mice were placed on the treadmill and the belt speed was started at 5 m/min for 5 minutes to warm up the mice. The speed was increased by 1 m/min to a maximum of 20 m/min. After running for 5 minutes, the speed was increased from 20 m/min to 21 m/min for 10 minutes. Mice were then forced to run at 22 m/min until they remained on the electrical stimulation grid for 10 seconds, and the distance they ran for 10 seconds was measured. As a result, in the treadmill test, the running distance of mice, so-called endurance, decreased significantly with aging.
• Muscle strength increase in aged mice by administration of L-ethylcysteine hydrochloride L-ethylcysteine hydrochloride was orally administered to aged mice from 40 to 79 weeks of age. The dose was 1000 mg/kg/day. No significant changes in body weight or behavioral abnormalities were observed during the administration period. After administration of L-ethylcysteine hydrochloride at 79 weeks of age, muscle strength (endurance) was measured by a treadmill test. Figure 1).
• L-ethylcysteine hydrochloride increases muscle mass in aged mice, and in particular, the effect was maximized when the aged mice administered with L-ethylcysteine hydrochloride were exercised. rice field. This result indicates that L-ethylcysteine hydrochloride increases muscle strength in aged mice. It was also shown that the administration of L-ethylcysteine hydrochloride in combination with exercise significantly restores muscle mass. This indicated that L-ethylcysteine hydrochloride could be useful as a therapeutic agent for sarcopenia.
• Example 1-2 Changes in gene expression in muscle by administration of L-ethylcysteine hydrochloride
• Example 1-2 Changes in gene expression in muscle by administration of L-ethylcysteine hydrochloride
• RNA-seq Genetic analysis (RNA-seq) was performed in aged mice administered with L-ethylcysteine hydrochloride, which improved muscle strength (gastrocnemius or soleus) and muscle mass.
• the method and reagents used are as follows. Quality checking of all reads was performed using FastQC v0.11.8 and removal of low quality reads was performed using Trimomatic (ver 0.38).
• Filtering conditions are as follows. LEADING: 20 (remove bases with a quality score less than 20 from the beginning of the read), TRAILING: 20, SLIDING WINDOW: 4:15 (window size 4, average quality 15), MINLEN: 36 (remove reads less than 3 bases) )
• Each read obtained after filtering was mapped to the reference genome GRCm38 using STAR (ver2.7.0.f). Mapping was performed with the default value of STAR. Since it was a paired-end with a length of 150 bp, an index for STAR for the reference genome GRCm38 was created according to the length of 150, and mapping was performed.
• Index creation is as follows. Run Mode; Genome Generate Reference; GRCm38 Annotation file; genecode version M24 sjdbOverhang;150 Alignment was performed using the index created above. In addition, the default values were used without any options. (Basic options are as follows.) genomeDir; index created above
• featurecount (ver 1.6.4) was used to calculate the number of counts, and the number of counts was calculated for each gene name defined by the symbolname. At this time, counting was performed in gene symbol units defined in genecode version M24. With respect to the calculated count number, filtering was performed for genes with count data of 0 in all samples, TMM normalization was performed using edgeR (ver 3.22.3), and correction between samples was performed.
• edgeR ver 3.22.3
• Example 1-3 Changes in muscle expression genes and diseases caused by administration of L-ethylcysteine hydrochloride
• diseases related to the top genes showing altered expression were found in model mice by matching with NIH MedlinePlus (Fig. 6).
• Example 2 Ambroxol hydrochloride
• Example 2-1 Effect of compound and effect of combined use with exercise therapy
• Ambroxol hydrochloride was orally administered to aged mice from 50 to 77 weeks of age. The dose was 9.21 mg/kg/day. No significant changes in body weight or behavioral abnormalities were observed during the administration period.
• muscle strength was measured by a treadmill test. As a result, an increase in muscle strength was observed specifically in aged mice due to administration of ambroxol hydrochloride (Fig. 7). ).
• Example 2-2 Improvement of cognitive function
• CFC test Contextual fear conditional test
• memory is evaluated by two types of memory: fear memory and spatial memory.
• fear memory is evaluated by the time during which the animal freezes and stops moving after being given an electric shock. Immediately after the electrical stimulation, it freezes, but the next day, if you put it in the machine that gives you an electric shock and you don't remember what happened the day before, the freezing time will be reduced (Reference: https://www. ncbi.nlm.nih.gov/books/NBK5223/).
• fear memory was evaluated in the CFC test.
• ambroxol hydrochloride was administered to the 77-week old mice of Example 2-2.
• fear memory was evaluated by CFC.
• administration of ambroxol hydrochloride improved the CFC freezing score, and an increase in cognitive ability was observed specifically in aged mice due to administration of ambroxol hydrochloride (Fig. 8).
• Example 2-3 Changes in gene expression in muscle by administration of ambroxol hydrochloride
• Example 2-3 Changes in gene expression in muscle by administration of ambroxol hydrochloride
• FIGS. 9-12 Administration of ambroxol hydrochloride increased 164 genes and markedly decreased 204 genes (Fig. 9), showing changes in gene clusters related to intercellular signals and nerves (Figs. 10 and 11).
• FIG. 10 is a diagram showing the top 30 genes with altered gene expression in the muscle of mice administered with ambroxol hydrochloride
• FIG. 11 shows a pathway analysis diagram of genes with increased expression. From the upstream transcription factor analysis shown in FIG. 12, new transcription factors involved in differentiation and cell senescence were observed as upstream factors. This result suggests the possibility of developing diagnostic and therapeutic agents for sarcopenia with new targets.
• Example 2-4 Gene expression control in cultured cells
• FIG. 13 to 17 The results are shown in FIGS. 13 to 17.
• FIG. 14 is a diagram showing the top 30 genes with altered gene expression in the muscles of mice administered ambroxol hydrochloride
• FIG. 16 shows a pathway analysis diagram of genes whose gene expression is decreased in the muscle of ambroxol hydrochloride-administered mice
• FIG. 17 is a diagram showing gene regulation in muscle of mice administered with ambroxol hydrochloride (with C2C12 cell culture), and shows upstream transcription factor analysis diagrams of genes in which gene expression changes were observed. From the upstream transcription factor analysis shown in FIG. 17, new transcription factors involved in differentiation and cell senescence were observed as upstream factors. This result suggests the possibility of developing diagnostic and therapeutic agents for sarcopenia with new targets.
• Example 2-5 Suppression of frailty by administration of ambroxol hydrochloride
• 1000 mg/kg/day of ambroxol hydrochloride was orally administered to the above model mice from 50 weeks of age to 81 weeks of age, and age-related frailty was confirmed by a frailty index test.
• FIG. 18 shows skin condition (hair, skin)
• FIG. 19 shows muscle strength (grip strength)
• FIG. 20 shows osteoporosis (physical/musculoskeletal)
• FIG. 21 shows evaluation results for hearing loss.
• Grip strength was evaluated by measurement of grip strength called a grip test, and a muscle strength measuring device (Muromachi Kikai, MK-380S) was used for the test. Specifically, a wire mesh was grasped by the forelimbs and hind limbs, and the tail was gradually pulled back horizontally until the wire mesh was released. The maximum muscle strength at that time was measured. From these results, it was confirmed that the administration of ambroxol hydrochloride improved the skin, muscle strength, osteoporosis, coat, and the like.
• Example 3 L-carbocysteine
• Example 3-1 Suppression of frailty by administration of L-carbocysteine
• 307.2 mg/kg/day of L-carbocysteine was administered to the drinking water for 23 weeks from 49 weeks of age, and frailty, etc. associated with aging was performed by the frailty index test in the same manner as in Example 2-5 above. It was confirmed.
• FIG. 22 is the evaluation result of alopecia
• Figure 23 is the evaluation result of fur color loss (improvement of gray hair)
• Figure 24 is the evaluation result of hair condition (improvement of hair loss)
• Figure 25 is the body condition score (bone and muscle improvement)
• FIG. 26 shows the total value of the frailty index test (frailty improvement). From these results, administration of L-carbocysteine improved dermatitis, hair loss, and white hair, and improved physical conditions. In addition, since improvement is seen in the total value, suppression of frailty is expected.
• the pharmaceutical composition of the present invention is effective against age-related sarcopenia. It is understood that the pharmaceutical composition according to the present invention restores muscle atrophy and muscle function deterioration due to stem cell dysfunction, muscle fiber type imbalance, and the like. Therefore, it is speculated that the pharmaceutical composition of the present invention is also effective for sarcopenia such as cancer cachexia (sarcopenia due to metabolic abnormality), infectious diseases (sarcopenia due to inflammation), chronic renal failure (sarcopenia due to metabolic abnormality), and the like. be.
• cancer cachexia sarcopenia due to metabolic abnormality
• infectious diseases sarcopenia due to inflammation
• chronic renal failure sarcopenia due to metabolic abnormality
• the pharmaceutical composition according to the present invention can be used for osteoporosis, including primary osteoporosis, secondary osteoporosis; Dermatitis including eczema vulgaris, chronic lichen simplex, erythroderma, psoriasis, and urticaria; hearing impairment including age-related deafness; gray hair;
• the present invention can improve sarcopenia-related diseases, disorders, or symptoms, and is expected to be suitably used and applied in related industries.
• TECHNICAL FIELD The present invention relates to novel treatment/prevention of sarcopenia-related diseases, disorders, or symptoms. offer. Therefore, the compounds, compositions, and medicaments according to the present invention can be used (combinedly) for purposes such as exercise promotion and rehabilitation, and can be widely applied not only to humans but also to animals. , for example, can be applied by being mixed in food or feed.

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