WO2022250365A1 - Composition pharmaceutique contenant du triéthiodure de gallamine en tant que principe actif pour la prévention ou le traitement de maladies musculaires - Google Patents

Composition pharmaceutique contenant du triéthiodure de gallamine en tant que principe actif pour la prévention ou le traitement de maladies musculaires Download PDF

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WO2022250365A1
WO2022250365A1 PCT/KR2022/007112 KR2022007112W WO2022250365A1 WO 2022250365 A1 WO2022250365 A1 WO 2022250365A1 KR 2022007112 W KR2022007112 W KR 2022007112W WO 2022250365 A1 WO2022250365 A1 WO 2022250365A1
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muscle
muscles
present
pharmaceutical composition
health
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PCT/KR2022/007112
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Korean (ko)
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김보경
정승효
이경진
김수정
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건국대학교 글로컬산학협력단
주식회사 케이에스비튜젠
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Publication of WO2022250365A1 publication Critical patent/WO2022250365A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/316—Foods, ingredients or supplements having a functional effect on health having an effect on regeneration or building of ligaments or muscles
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of muscle diseases comprising gallamine triethiodide as an active ingredient, and more particularly, to a pharmaceutical composition comprising gallamine triethiodide, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition capable of preventing or treating muscle diseases such as skeletal muscle atrophy and sarcopenia caused by various causes by effectively controlling atrophy and reduction of muscles.
  • Skeletal muscle atrophy can be caused by a variety of causes, such as immobility, muscle disease, space travel, denervation, sepsis, administration of dexamethasone, reduced weight bearing, and reduced food intake. It is characterized by a decrease in mass and muscle fiber cross-sectional area. In addition, it is known to be caused by peripheral neuropathy pain, decline in muscle function that inevitably accompanies aging, and treatment such as plaster cast performed on patients with surgical damage.
  • the occurrence of the above-mentioned skeletal muscle atrophy can deteriorate the patient's quality of life due to problems such as weakness, induction of activity disorder, and extension of functional recovery period. It is one of the immediate problems that must be resolved in order to pursue a healthy and humane life and move toward a welfare state.
  • muscle loss can also be caused by the aging process and various chronic diseases. As aging progresses, some of the newly generated skeletal muscle is replaced with fibrous tissue, resulting in sarcopenia in which the body's skeletal muscle mass and strength are reduced, and hypertension, impaired glucose tolerance and diabetes, obesity, dyslipidemia, It is known that muscle loss appears even in chronic diseases, such as atherosclerosis and cardiovascular disease, whose incidence increases with age (Pharmacol Res. 2015, 99, 86).
  • a general method for preventing the above-mentioned skeletal muscle atrophy is to prevent muscle loss through exercise, but there is no fundamental treatment currently on the market, and the development of countermeasures, preventive agents, therapeutic agents, and improvement agents that can prevent this can be mentioned. There is a need for research on this.
  • the pharmaceutical composition according to the present invention can be usefully used for the prevention, treatment, and improvement of skeletal muscle atrophy and muscle diseases, and furthermore, identification of the active ingredient material is thought to be of great help in the future development of medicine and pharmacology.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating muscle diseases, comprising gallamine triethiodide represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • Another object of the present invention is to provide a health food composition for the prevention or improvement of muscle diseases comprising the gallamine triethiodide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a health functional food composition for preventing or improving muscle diseases, comprising the gallamine triethiodide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating muscle diseases, comprising gallamine triethiodide represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • the present invention provides a health food composition for the prevention or improvement of muscle diseases comprising the gallamine triethiodide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving muscle diseases, comprising the gallamine triethiodide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Gallamine triethiodide according to the present invention can effectively control skeletal muscle atrophy or muscle loss, and can treat muscle diseases caused by various causes, such as skeletal muscle atrophy and sarcopenia. It can be used as a preventive, therapeutic or ameliorative agent for diseases such as the back.
  • 1 is a photograph of the anterior tibialis anterior muscle of a dexamethasone-treated model (Dexamethasone) and a normal model (Normal).
  • Figure 5 is a graph measuring the body weight of the dexamethasone treatment model (Dexamethasone) and the group treated with gallamine triethiodide (Gallamine triethiodide) of the present invention.
  • the X-axis unit of FIG. 5 is 'Day'.
  • Figure 6 is a graph measuring the grip strength of groups treated with a dexamethasone treatment model (Dexamethasone) and gallamine triethiodide of the present invention.
  • the X-axis unit of FIG. 6 is 'Day'.
  • FIG. 7 is a photograph of the tibialis anterior muscle of a group treated with a dexamethasone treatment model (Dexamethasone) and gallamine triethiodide of the present invention.
  • Figure 8 is a graph measuring the length of the Tibialis Anteriors (TA) of the group treated with a dexamethasone treatment model (Dexamethasone) and gallamine triethiodide of the present invention.
  • FIG. 9 is a graph measuring lean body mass in groups treated with a dexamethasone treatment model (Dexamethasone) and gallamine triethiodide of the present invention.
  • the X-axis unit of FIG. 9 is 'Day'.
  • Figure 10 is a graph measuring the muscle mass of the gastrocnemius (GS) of the dexamethasone treatment model (Dexamethasone) and the group treated with gallamine triethiodide (Gallamine triethiodide) of the present invention.
  • the X-axis unit of FIG. 10 is 'Day'.
  • Figure 11 is a graph measuring the muscle mass of the tibialis anterior bone (TA) of a group treated with a dexamethasone treatment model (Dexamethasone) and gallamine triethiodide of the present invention.
  • Figure 12 is a graph measuring the ATP activity of the control group (Control) and the group treated with gallamine triethiodide (Gallamine triethiodide) of the present invention by Luminescence assay.
  • FIG. 13 is an image of myotubes observed under an optical microscope in a control group, a TNF- ⁇ treatment group, and a group treated with gallamine triethiodide of the present invention.
  • FIG. 14 is a graph measuring the length of myotubes in a control group, a TNF- ⁇ treatment group, and a group treated with gallamine triethiodide of the present invention.
  • One aspect of the present invention provides a pharmaceutical composition for preventing or treating muscle diseases, comprising gallamine triethiodide represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient:
  • Gallamine triethiodide is known as a non-depolarising muscle relaxant.
  • Gallamine is known to be the first synthetic neuromuscular blocking drug used clinically and exhibits anticholinesterase effects. By inhibiting cholinesterase, it prevents the degradation of acetylcholine and As an indirect cholinergic agonist by inhibiting choline (acetylcholine), it acts on autonomic ganglia, parasympathetic postganglionic fibers, and skeletal muscle endplates. Furthermore, gallamine triethiodide is widely used for the treatment of rheumatic diseases accompanying musculoskeletal disorders, neuralgia after neurogenic hyperkinesia, pain caused by spinal cord injury, and muscle spasms.
  • the gallamine triethiodi binds to muscarinic acetylcholine receptors in the post-synaptic membrane of the motor end plate, in particular, to cholinergic receptor sites and Nicotine presynaptic acetylcholine receptors that bind and competitively block the transmission of acetylcholine, blocking muscle neurotransmission, preventing activation of muscle contraction processes, and inhibiting the release of acetylcholine (acetylcholine receptors).
  • the present inventors effectively control the skeletal muscle atrophy and muscle loss of gallamine triethiodide through animal models and cell experiments to prevent, treat, and improve muscle diseases caused by various causes, especially skeletal muscle atrophy. confirmed and completed the present invention.
  • the muscular disease is atony, muscular atrophy, muscular dystrophy, muscle degeneration, muscle stiffness, amyotrophic axonal sclerosis, myasthenia, cachexia, skeletal muscle It may be at least one selected from the group consisting of muscle atrophy and senile sarcopenia, for example, skeletal muscle atrophy or senile sarcopenia.
  • the gallamine triethiodide can promote mitochondrial functional activity, facial muscles, neck muscles, back muscles, arm muscles, shoulder muscles, chest muscles, abdominal muscles, gluteal muscles, back muscles, It may be characterized in that it is delivered to one or more target tissues selected from the group consisting of leg muscles, foot muscles, hand muscles, and intrinsic muscles of the hand, for example, leg muscles.
  • prevention refers to any activity that inhibits or delays the occurrence, spread, and recurrence between households by administration of the pharmaceutical composition according to the present invention
  • treatment refers to gallamine triethiodide of the present invention. Or a pharmaceutically acceptable salt thereof, or any action that improves or beneficially changes the symptoms of muscle disease by administering a composition containing the same.
  • degree of improvement, enhancement and treatment will be able to determine the degree of improvement, enhancement and treatment by knowing the exact criteria of the disease for which the composition of the present application is effective by referring to the data presented by the Korean Medical Association, etc. will be.
  • the term "therapeutically effective amount" used in combination with an active ingredient means an effective amount to prevent or treat a target disease
  • the therapeutically effective amount of the composition of the present invention depends on several factors, such as the method of administration. , target site, condition of the patient, etc. may vary. Therefore, when used in the human body, the dosage should be determined in an appropriate amount considering both safety and efficiency. It is also possible to estimate the amount to be used in humans from the effective amount determined through animal experiments. These considerations in determining an effective amount can be found, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martined., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount that is sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects
  • the effective dose level is the patient's Factors including health status, type of muscle disease, cause of muscle disease, severity, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, drugs used in combination or concurrently, and It may be determined according to other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer the amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the pharmaceutical composition of the present invention may further include a carrier, diluent, excipient, or a combination of two or more thereof commonly used in biological preparations, for example, a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable” means exhibiting non-toxic properties to cells or humans exposed to the composition.
  • the pharmaceutically acceptable carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc. , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components may be mixed and used. Customary additives may be added.
  • diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate formulations for injection, such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
  • formulations for injection such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
  • it can be preferably formulated according to each disease or component by using an appropriate method in the art or by using a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
  • the pharmaceutical composition is one or more selected from the group consisting of oral dosage forms, external preparations, suppositories, sterile injectable solutions and sprays, for example, capsules, solutions, injections, soft capsules, and granules. , Or it may be a tablet formulation, more preferably an oral or injection formulation.
  • administration means providing a predetermined substance to an individual or patient by any suitable method, and parenteral administration (eg, intravenous, subcutaneous, intraperitoneal) according to the desired method or applied topically as an injectable formulation) or administered orally.
  • parenteral administration eg, intravenous, subcutaneous, intraperitoneal
  • the active substance of the present invention can be administered in various oral and parenteral formulations during clinical administration, and when formulated, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used. It is manufactured by
  • Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, etc., and these solid preparations contain one or more active substances of the present invention and at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used.
  • Liquid formulations for oral administration include suspensions, internal solutions, emulsions, or syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. can
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, freeze-dried formulations, suppositories, and the like.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • injectable esters such as ethyl oleate
  • a base for suppositories witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used.
  • the effective dosage of the active substance of the present invention for the human body may vary depending on the patient's age, weight, sex, dosage form, health condition and disease degree, and is generally about 0.001-100 mg/kg/day, Preferably it is 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg/day, preferably 0.7-2500 mg/day, and once or twice a day at regular intervals according to the judgment of a doctor or pharmacist. It may be divided into several doses.
  • the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell.
  • Preferred administration methods and formulations include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like.
  • Injections include aqueous solvents such as physiological saline and ring gel solutions, non-aqueous solvents such as vegetable oils, higher fatty acid esters (eg, oleic acid ethyl, etc.), alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.).
  • Stabilizers e.g., ascorbic acid, sodium hydrogensulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
  • a pharmaceutical carrier such as a preservative (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
  • the term "subject” refers to monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, including humans who have or may develop the above muscle disease. or all animals including guinea pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject.
  • the pharmaceutical composition of the present invention may be administered in parallel with existing therapeutic agents.
  • the pharmaceutical composition of the present invention may further include pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate. , Lactose, Mannitol, Taffy, Gum Arabic, Pregelatinized Starch, Corn Starch, Powdered Cellulose, Hydroxypropyl Cellulose, Opadry, Sodium Starch Glycolate, Carnauba Lead, Synthetic Aluminum Silicate, Stearic Acid, Magnesium Stearate, Aluminum Stearate, Calcium stearate, white sugar, dextrose, sorbitol and talc may be used.
  • the pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 part by weight to 90 parts by weight based on the composition, but is not limited thereto.
  • the active substance of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • pharmaceutically acceptable salt refers to a concentration that has an effective effect that is relatively non-toxic and harmless to patients. It means inorganic addition salt.
  • inorganic and organic acids can be used as free acids, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, and fumarin as organic acids.
  • Acids gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesul
  • phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid may be used.
  • these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.) and the like.
  • acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malic Eight, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharide Lates, stearates, succinates, tartrates, tosylates,
  • the acid addition salt according to the present invention is obtained by dissolving an active material in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. by a conventional method, for example, filtering and drying the precipitate produced by adding an organic or inorganic acid. It can be prepared by distillation of a solvent and excess acid under reduced pressure, followed by drying or crystallization in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the present invention includes not only active substances and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, isomers, optical isomers and the like that can be prepared therefrom.
  • One aspect of the present invention provides a health food and health functional food composition for preventing or improving muscle diseases comprising Gallamine triethiodide represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient do:
  • Examples of foods to which the active substance of the present invention can be added are dairy products including drinks, meat, sausages, bread, biscuits, rice cakes, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, chewing gum, ice cream,
  • dairy products including drinks, meat, sausages, bread, biscuits, rice cakes, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, chewing gum, ice cream
  • soups, beverages, alcoholic beverages and vitamin complexes, dairy products and milk-processed products, etc. and includes both health foods and health functional foods in a conventional sense.
  • Health food and health functional food compositions containing active substances according to the present invention may be added to food as it is or used together with other foods or food ingredients, and may be appropriately used according to conventional methods.
  • the mixing amount of the active substance may be appropriately determined according to its purpose of use (for prevention or improvement).
  • the amount of the composition in health food and health functional food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of food.
  • the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.
  • the health food and health functional food composition of the present invention is not particularly limited in other ingredients except for containing the active substance of the present invention as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates are added as additional ingredients like conventional beverages.
  • the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents thaumatin, stevia extract (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can advantageously be used.
  • the ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 of the health functional food composition of the present invention.
  • the health food and health functional food composition containing the active substances of the present invention are various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.) ), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like.
  • the health food and health functional food composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages.
  • the ratio of these additives is not so critical, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.
  • a pharmaceutical composition, health food composition, and health functional food composition for preventing, treating, or improving muscle diseases comprising Gallamine triethiodide or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention, is a composition for skeletal muscle atrophy or As it can effectively control muscle loss, it can be used as an agent for preventing, treating, or improving muscle diseases caused by various causes, such as skeletal muscle atrophy and sarcopenia.
  • Gallamine triehiodide represented by Formula 1 below was used by purchasing a commercially available (Med Chem Express, USA) reagent:
  • a dexamethasone treatment model was prepared by inducing skeletal muscle atrophy or muscle loss by administering dexamethasone to mice for 14 days, and the effects of the dexamethasone treatment on skeletal muscle atrophy are shown in FIGS. 1 to 4 .
  • muscle function indexes such as grip strength, tibialis anteriors (TA) length, and lean muscle mass (lean body mass) are reduced. I was able to confirm.
  • gallamine triethiodide was orally administered at a concentration of 30 mg/kg to increase skeletal muscle atrophy or muscle reduction efficacy in terms of muscle strength Test (Grip Strength), Tibialis Anteriors (TA) Length (Diameter), Lean Body Mass, Gastrocnemius Muscle (GS) and Tibialis Anteriors (TA) Muscle Mass (Lean Mass) ) was confirmed, and the results are shown in FIGS. 5 to 11.
  • Gallamine triethiodide was tested in body weight, grip strength in terms of muscle function, and muscle diameter in Tibialis Anteriors (TA). It was confirmed that the administered group had an effect.
  • myoblasts myoblasts
  • ATP ATP which is intracellular energy
  • the protective effect of gallamine triethiodide against skeletal muscle cell atrophy was demonstrated by increasing mitochondrial activity using luminescence assay and optical microscope.
  • Myotubes formed after differentiation were treated with TNF- ⁇ and gallamine triethiodide, and 2 days later, luminescence assay and optical microscopy were performed.
  • the functional activity of mitochondria is judged by the length and area of the myotube and the activity of generating ATP, and the myotube atrophy defense effect is judged.
  • Myotube atrophy at 10 ⁇ M of Gallamine triethiodide It was confirmed that this was suppressed.
  • the active substance according to the present invention can be formulated in various forms depending on the purpose.
  • the following exemplifies some formulation methods containing the active substance according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • the powder was prepared by filling in an airtight bag.
  • tablets were prepared by tableting according to a conventional tablet manufacturing method.
  • capsules were prepared by filling gelatin capsules according to a conventional capsule preparation method.
  • the active substance according to the present invention was dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, and the volume was adjusted with sodium chloride BP for injection, followed by thorough mixing. .
  • the solution was filled into a 5 ml type I ampoule made of transparent glass, sealed under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 DEG C for 15 minutes or more to prepare an injection solution.
  • each component is dissolved in purified water, lemon flavor is added, the above components are mixed, and purified water is added to adjust the total volume to 100 mL, and then filled in a brown bottle and sterilized to prepare a liquid formulation.
  • the active substance according to the present invention can be manufactured into various types of health food depending on the purpose.
  • the following exemplifies methods for producing some health foods containing the active substances according to the present invention as active ingredients, but the present invention is not limited thereto.
  • Brown rice, barley, glutinous rice, and adlay were alphanized by a known method, dried, roasted, and then prepared into a powder having a particle size of 60 mesh using a grinder.
  • Black beans, black sesame seeds, and perilla seeds were also steamed and dried by a known method, roasted, and then prepared into powder with a particle size of 60 mesh by a grinder.
  • the active substance of the present invention was concentrated under reduced pressure in a vacuum concentrator to obtain a dry powder. It was prepared by blending the dry powder of grains, seeds and active substances prepared above in the following ratio.
  • Seeds (7 parts by weight of perilla seeds, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds),
  • the active substance according to the present invention can be manufactured into various types of health functional food depending on the purpose.
  • the following exemplifies a method for producing some health functional foods containing the active substance according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • Vitamin A Acetate 70 ⁇ g
  • Vitamin B6 0.5 mg
  • Vitamin B12 0.2 ⁇ g
  • composition ratio of the above vitamin and mineral mixture was prepared by mixing ingredients suitable for relatively health functional foods in a preferred embodiment, the mixing ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health functional food manufacturing method. Then, granules can be prepared and used in the preparation of health functional food compositions according to conventional methods.
  • the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized, and then refrigerated according to the present invention. It is used in the manufacture of health beverage compositions.
  • the composition ratio is a mixture of ingredients suitable for a relatively favorite beverage in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the class of demand, the country of demand, and the purpose of use.
  • Gallamine triethiodide according to the present invention can effectively control skeletal muscle atrophy or muscle loss, and can treat muscle diseases caused by various causes, such as skeletal muscle atrophy and sarcopenia. It can be useful as a preventive, therapeutic or ameliorative agent for diseases such as the back.

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Abstract

Le triéthiodure de gallamine selon la présente invention permet de lutter efficacement contre l'atrophie des muscles squelettiques ou la perte musculaire, et peut ainsi être utilisé en tant qu'agent pour prévenir, traiter ou soulager des maladies musculaires ayant diverses causes, par exemple, des maladies telles que l'atrophie des muscles squelettiques ou la sarcopénie.
PCT/KR2022/007112 2021-05-27 2022-05-18 Composition pharmaceutique contenant du triéthiodure de gallamine en tant que principe actif pour la prévention ou le traitement de maladies musculaires WO2022250365A1 (fr)

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KR1020210068255A KR102605800B1 (ko) 2021-05-27 2021-05-27 갈라민트리에티오디드를 유효성분으로 포함하는 근육질환의 예방 또는 치료용 약학적 조성물
KR10-2021-0068255 2021-05-27

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1362585A2 (fr) * 2001-01-26 2003-11-19 Osmotica Corp. Compositions pharmaceutiques contenant un inhibiteur de cox-ii et un relaxant musculaire
KR20040049044A (ko) * 2002-12-03 2004-06-11 화일약품주식회사 1,2,3-트리스(2-디에틸아미노에톡시)벤젠의 제조방법
KR100447929B1 (ko) * 2001-08-21 2004-09-08 주식회사 삼오제약 갈라민 트리에치오다이드의 신규 제조 방법
KR20050064809A (ko) * 2003-12-24 2005-06-29 (주)코스타 월드 갈라민 트리에치오다이드의 신규 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1362585A2 (fr) * 2001-01-26 2003-11-19 Osmotica Corp. Compositions pharmaceutiques contenant un inhibiteur de cox-ii et un relaxant musculaire
KR100447929B1 (ko) * 2001-08-21 2004-09-08 주식회사 삼오제약 갈라민 트리에치오다이드의 신규 제조 방법
KR20040049044A (ko) * 2002-12-03 2004-06-11 화일약품주식회사 1,2,3-트리스(2-디에틸아미노에톡시)벤젠의 제조방법
KR20050064809A (ko) * 2003-12-24 2005-06-29 (주)코스타 월드 갈라민 트리에치오다이드의 신규 제조방법

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HINMAN C.L., G E DAMBACH, R A HUDSON, H C RAUCH: "Response to gallamine: An indicator of diminished neuromuscular function in experimental autoimmune myasthenia gravis", JOURNAL OF NEUROSCIENCE RESEARCH, vol. 14, no. 2, 1 January 1985 (1985-01-01), pages 271 - 278, XP093008530, DOI: 10.1002/jnr.490140212 *

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