KR20240029547A - Composition for improvement, prevention or treatment of muscular disorders, or improvement of muscular functions comprising quinic acid - Google Patents

Abstract

The present invention relates to a composition for improving, treating or preventing muscle disease, or improving muscle function, containing quinic acid as an active ingredient.
Quinic acid according to the present invention has an excellent effect in increasing the activity of mTOR, which is involved in muscle protein synthesis, and suppressing the mRNA expression of MuRF1 and atrogin-1, which are involved in muscle protein degradation. Additionally, by increasing muscle mass and improving muscle function, it is possible to prevent, treat, or improve muscle function decline and muscle loss caused by various diseases. Since the present invention is a natural product, it can be used safely without side effects and can be usefully used in the production of medicines, foods, cosmetics, or feed additives.

Description

Composition for improvement, prevention or treatment of muscular disorders, or improvement of muscular functions comprising quinic acid}

The present invention relates to a composition containing quinic acid for improving, treating or preventing muscle disease, or improving muscle function. More specifically, it relates to a composition containing quinic acid as an active ingredient for improving, treating or preventing muscle disease, Or it relates to a composition for improving muscle function.

Muscle atrophy is caused by a gradual decrease in muscle mass and refers to muscle weakness and degeneration (Cell, 119(7): 907-910, 2004). Muscle atrophy is promoted by inactivity, oxidative stress, and chronic inflammation, and weakens muscle function and exercise capacity (Clinical Nutrition, 26(5): 524-534, 2007). The most important factor determining muscle function is muscle mass, which is maintained by the balance of protein synthesis and breakdown. Muscular dystrophy occurs when protein degradation occurs more than synthesis (The International Journal of Biochemistry and Cell Biology, 37(10): 1985-1996, 2005).

Muscle size is controlled by intracellular signaling pathways that induce anabolism or catabolism within the muscle, and when signaling reactions that induce synthesis rather than decomposition of muscle proteins occur more often. Muscle protein synthesis is increased, which appears as an increase in muscle size (hypertrophy) or an increase in the number of muscle fibers (hyperplasia) due to an increase in muscle protein (The Korea Journal of Sports Science, 20(3): 1551-1561, 2011).

Factors involved in muscle protein synthesis induce protein synthesis by phosphorylating downstream proteins starting from stimulation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway within muscle cells. Activation of mammalian target of rapamycin (mTOR) by PI3K/Akt signaling is recognized as a central growth signaling factor that integrates various growth signals within cells. mTOR induces muscle protein synthesis by activating two factors that initiate mRNA translation, 4E-binding protein (4EBP1) and phosphorylated 70-kDa ribosomal S6 kinase (p70S6K), thereby contributing to increased muscle mass (The Korea Journal of Sports Science, 20(3): 1551-1561, 2011; The International Journal of Biochemistry and Cell Biology, 43(9): 1267-1276, 2011). Conversely, when the forhead box (FoxO), a transcription factor, moves from the cytoplasm into the nucleus, it increases the expression of atrogin-1 and MuRF-1, E3 ubiquitin ligase factors involved in protein degradation (Disease Models and Mechanisms, 6: 25 -39, 2013). As their expression level increases, protein breakdown within the muscle is promoted, resulting in a decrease in muscle mass. Therefore, promoting the activity of mTOR and suppressing the expression of atrogin-1 and MuRF-1 increases the amount of muscle protein and thus increases muscle mass.

Differentiation of muscle cells and muscle formation are regulated by various muscle regulatory factors. Among them, MyoD initiates the expression of muscle-specific genes and induces the differentiation of muscle satellite cells into myoblasts. Induction of myogenin expression by MyoD activity is the most important factor in the fusion of myogenic cells and is involved in the formation of myotube cells. Muscle fibers formed through this process form bundles and ultimately form muscles (Cellular and Molecular Life Sciences, 70: 4117-4130, 2013).

When there is injury or damage to a muscle, muscle satellite cells, which are precursors to muscle cells, play an important role in muscle regeneration. Normally, the muscle satellite cells located at the edge of the muscle fiber remain in a quiescent state, but when the muscle is physically or chemically damaged from the outside, various transcription factors are secreted to regenerate it. You enter the muscle regeneration phase.

Satellite cells self-renew by expressed transcription factors and form a satellite cell pool to be used for muscle regeneration. At this time, the number of satellite cells required for muscle regeneration is maintained at a constant level. To achieve this, the expression of Paired Box 7 (Pax7) increases. Increased expression of Pax7 is methylated by the coactivator-associated arginine methyltransferase 1 (CARM1) protein to form a Pax7-CARM1 complex, thereby promoting the expression of myogenic factor 5 (Myf5). Due to an increase in the expression level of the Myf5 factor, muscle satellite cells that were in a dormant state are activated and migrate to injured or damaged muscle areas. Afterwards, muscle fiber bundles are formed to create new muscles (Stem Cells Translational Medicine, 5: 282-290, 2016).

Quinic acid is a type of phenolic acid that exists in various plants and microorganisms (Evidence-Based Complementary and Alternative Medicine, 5602597, 2020). Quinic acid improves DNA repair by stimulating the synthesis of tryptophan and nicotinamide in the gastrointestinal tract (GIT) and inhibits the activation of NF-κB (nuclear transcription factor kappaB) (Phytotherapy Research, 23 (3):335-346, 2009). In addition, quinic acid has anti-neuroinflammatory (Evidence-Based Complementary and Alternative Medicine, 5602597, 2020), anti-diabetic (British Journal of Pharmacology, 176(17): 3250-3263, 2019), and anti-atherosclerosis (Biomedicine & Pharmacotherapy) properties. , 96: 563-571, 2017) and other biological activities have been reported.

However, prior to the present invention, nothing was known about quinic acid improving, treating or preventing muscle disease, or improving muscle function.

Accordingly, the present inventors searched for a natural substance that has excellent muscle function regulating activity and can be safely applied. As a result, quinic acid improved muscle disease by increasing the expression and activity of genes involved in muscle protein synthesis or genes involved in muscle function. The present invention was completed by confirming that it has a therapeutic or preventive effect, or an effect of improving muscle function.

The present invention provides a pharmaceutical composition for treating or preventing muscle disease containing quinic acid of Formula 1 as an active ingredient.

[Formula 1]

Another object of the present invention is to provide a food composition for improving or preventing muscle disease or improving muscle function containing quinic acid as an active ingredient.

Another object of the present invention is to provide a cosmetic composition for improving or preventing muscle disease or improving muscle function containing quinic acid of Formula 1 as an active ingredient.

Another object of the present invention is to provide a feed additive for improving or preventing muscle disease or improving muscle function containing quinic acid of Formula 1 as an active ingredient.

To achieve the above object, the present invention provides a pharmaceutical composition for treating or preventing muscle disease containing quinic acid represented by the following formula (1) as an active ingredient.

[Formula 1]

In addition, in order to achieve the above-described other objects, the present invention provides a food composition for improving or preventing muscle disease or improving muscle function containing quinic acid of Formula 1 as an active ingredient.

In addition, in order to achieve the above-described other objects, the present invention provides a cosmetic composition for improving or preventing muscle disease or improving muscle function containing quinic acid of Formula 1 as an active ingredient.

In addition, in order to achieve the above-described other objects, the present invention provides a feed composition for improving or preventing muscle disease or improving muscle function containing quinic acid of Formula 1 as an active ingredient.

In addition, in order to achieve the above-described other objects, the present invention provides the use of a pharmaceutical composition containing quinic acid of Formula 1 as an active ingredient for manufacturing a medicine for treating or preventing muscle diseases.

In addition, in order to achieve the above-described other objects, the present invention provides a method of treating muscle disease, which includes administering a pharmaceutical composition containing quinic acid of Formula 1 as an active ingredient to a patient with muscle disease.

Quinic acid according to the present invention increases the activity of p-mTOR, which is involved in muscle protein synthesis, suppresses the mRNA expression of MuRF1 and atrogin-1, which is involved in muscle protein degradation, and increases the mRNA expression of MyoD and Myogenin, which is involved in muscle differentiation. It has excellent effects. In addition, quinic acid increases muscle strength, muscle volume, and muscle weight, and has the effect of promoting muscle recovery from damaged muscles, preventing and treating muscle deterioration, muscle loss, and muscle damage caused by various diseases. Or it can be improved. Since the present invention is a natural product, it can be used safely without side effects and can be usefully used in the production of medicines, foods, cosmetics, or feed additives.

Figure 1 shows the results confirming the effect of increasing mTOR activity following quinic acid treatment in L6 muscle cells. Each graph represents the average value (means±SEM, n=3). * means there is a significant difference at p<0.05 compared to the control group (Duncan's test).
Figure 2 shows the results confirming the effect of increasing the protein expression levels of p-mTOR, p-p70S6K, and p-4EBP-1 according to quinic acid treatment in L6 muscle cells. Each graph represents the average value (means±SEM, n=3). ## indicates a significant difference at p<0.01 compared to the control group (Duncan's test), and * and ** indicate significant differences at p<0.05 and p<0.01, respectively, compared to the TNF-α treatment group. It means presence (Duncan's test).
Figure 3 shows the results confirming the effect of increasing the mRNA expression levels of MyoD and Myogenin due to quinic acid treatment in L6 muscle cells. Each graph represents the average value (means±SEM, n=3). ## indicates a significant difference at p<0.01 compared to the control group (Duncan's test), and * and ** indicate significant differences at p<0.05 and p<0.01, respectively, compared to the TNF-α treatment group. It means presence (Duncan's test).
Figure 4 shows the results confirming the effect of reducing the mRNA expression levels of MuRF1 and atrogin-1 according to quinic acid treatment in L6 muscle cells. Each graph represents the average value (means±SEM, n=3). ## means a significant difference at p<0.01 compared to the control group (Duncan's test), ** means a significant difference at p<0.01 compared to the TNF-α treatment group (Duncan's test) do.
Figure 5 shows the results confirming the effect of improving muscle strength due to quinic acid treatment in mice with induced muscle atrophy. Each graph represents the average value (means±SEM, n=10). ## means a significant difference at p<0.01 compared to the control group (Duncan's test), and ** means a significant difference at p<0.01 compared to the muscle atrophy group (Duncan's test).
Figure 6 shows the results confirming the effect of increasing muscle volume due to quinic acid treatment in mice with induced muscular atrophy. Each graph represents the average value (means±SEM, n=10). ## means a significant difference at p<0.01 compared to the control group (Duncan's test), and ** means a significant difference at p<0.01 compared to the muscle atrophy group (Duncan's test).
Figure 7 shows the results confirming the effect of increasing the weight of the tibialis anterior muscle due to quinic acid treatment in muscle atrophy-induced mice. Each graph represents the average value (means±SEM, n=10). ## means a significant difference at p<0.01 compared to the control group (Duncan's test), and ** means a significant difference at p<0.01 compared to the muscle atrophy group (Duncan's test).
Figure 8 shows the results confirming changes in gastrocnemius muscle tissue caused by muscle damage following quinic acid treatment. Each graph represents the average value (means±SEM, n=10). ## means a significant difference at p<0.01 compared to the control group (Duncan's test), and ** means a significant difference at p<0.01 compared to the muscle atrophy group (Duncan's test).

Hereinafter, the configuration of the present invention will be described in detail.

The present invention provides a pharmaceutical composition for treating or preventing muscle disease containing quinic acid as an active ingredient; or a food composition for improving or preventing muscle disease or improving muscle function containing quinic acid as an active ingredient; or for improving or preventing muscle disease containing quinic acid as an active ingredient; Or a cosmetic composition for improving muscle function; or feed additives for improving or preventing muscle disease, or improving muscle function, containing quinic acid; Alternatively, it provides a method of treating muscle disease comprising administering a pharmaceutical composition containing quinic acid as an active ingredient to humans or mammals other than humans.

In this specification, ‘quinic acid’ includes a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In this specification, 'muscle' comprehensively refers to tendons, muscles, and tendons, and 'muscle function' refers to the ability to exert force by contracting muscles, and the ability of muscles to exert maximum contractile force to overcome resistance. These include muscular strength, which is the ability to exercise, muscular endurance, which is the ability to express how long or how many times a muscle can repeat contraction and relaxation with a given weight, and quickness, which is the ability to exert strong force in a short period of time. The term 'improvement of muscle function' in this specification refers to improving muscle function better by increasing muscle mass.

As a result of treating L6 muscle cells with quinic acid, the activity of p-mTOR, which is involved in muscle protein synthesis, and the protein expression levels of p-mTOR, p-p70S6K, and p-4EBP-1, which are muscle protein synthesis biomarkers, were significant. It was confirmed that it increased (Figures 1 and 2). In addition, as a result of treating L6 muscle cells with quinic acid, it was confirmed that the mRNA expression of MyoD and Myogenin, which are involved in muscle differentiation, was increased (Figure 3). Additionally, as a result of treating L6 muscle cells with quinic acid, it was confirmed that the mRNA expression of MuRF1 and atrogin-1, which are involved in muscle protein degradation, was suppressed (Figure 4).

In addition, as a result of treating the immobilization mouse model using a skin stapler with quinic acid, muscle strength, muscle volume, and muscle weight each significantly increased compared to the muscle atrophy group (FIGS. 5 to 7). Additionally, as a result of treatment with quinic acid, recovery of damaged muscle tissue significantly increased (FIG. 8).

When the composition for treating or preventing muscle disease of the present invention is a pharmaceutical composition, it can be used for the prevention or treatment of muscle disease caused by muscle wasting or degeneration. Muscle wasting and degeneration occur due to genetic factors, acquired factors, aging, etc. Muscle wasting is characterized by gradual loss of muscle mass and weakness and degeneration of muscles, especially skeletal or voluntary muscles and cardiac muscles. Examples of diseases related to this include sarcopenia, muscular atrophy, muscular dystrophy, atony, muscle degeneration, myasthenia gravis, and cachexia. The composition of the present invention has the effect of increasing muscle mass, and the type of muscle is not limited.

The term ‘prevention’ in the present invention means anything that suppresses or delays the muscle disease.

The term ‘treatment’ of the present invention means reversing, alleviating, inhibiting the progression of, or preventing the symptoms of the muscle disease, unless otherwise specified.

The term ‘muscle damage’ in the present invention may mean exercise-induced muscle damage. Muscle damage can generally be defined as loss of muscle function due to physical destruction of muscle structure after an activity that causes a specific injury. Causes of muscle damage include trauma, excessive temperature, injury by myotoxins, ischemia, and muscle There are various reasons such as related diseases, inflammation, exercise, etc. Among these, exercise-induced muscle damage can be classified into primary muscle damage, which causes morphological or structural changes within the muscle, and secondary muscle damage, which causes inflammatory reactions and loss of calcium homeostasis. You can. Primary muscle damage causes structural destruction of sarcomeres and cytoskeletal elements, and weakens the development of muscle strength immediately after muscle damage. Secondary muscle damage occurs during the process of repairing primary damage. The inflammatory response causes delayed onset muscle soreness (DOMS), leakage of muscle proteins into the plasma, and a continuous decrease in muscle strength, resulting in temporary loss of muscle function. causes loss.

The muscle damage includes muscle strain, muscle rupture, muscle tearing, contusion, sprain, rotator cuff syndrome, and myositis. I can hear it.

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable salt of quinic acid. As used herein, the term 'pharmaceutically acceptable' refers to something that is physiologically acceptable and does not usually cause an allergic reaction or similar reaction when administered to humans, and the salt includes a pharmaceutically acceptable free acid (free acid). Acid addition salts formed by acid are preferred.

The pharmaceutically acceptable salt of quinic acid may be an acid addition salt formed using an organic acid or an inorganic acid, and the organic acids include, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, and maleic acid. Acids, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxy acetic acid, benzenesulfonic acid, Includes p-toluenesulfonic acid or methanesulfonic acid. Inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid or boric acid. The acid addition salt may preferably be in the form of hydrochloride or acetate, and more preferably in the form of hydrochloride.

The above-mentioned acid addition salts are general salts obtained by a) directly mixing quinic acid and the acid, b) dissolving and mixing it in a solvent or hydrous solvent, or c) placing quinic acid in the acid in a solvent or hydrous solvent and mixing them. It is manufactured using a manufacturing method.

Apart from the above, additional salt forms available include gaba salt, gabapentin salt, pregabalin salt, nicotinic acid salt, adipate salt, hemimalonate, cysteine salt, acetylcysteine salt, methionine salt, arginine salt, lysine salt, ornithine salt, or Aspartate, etc.

Additionally, the pharmaceutical composition for treating or preventing muscle disease or improving muscle function of the present invention may include a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Carriers for parenteral administration may also include water, suitable oils, saline solutions, aqueous glucose and glycols, and the like. Additionally, stabilizers and preservatives may be additionally included. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. As for other pharmaceutically acceptable carriers, those described in the following literature may be referred to (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The pharmaceutical composition of the present invention can be administered to mammals, including humans, by any method. For example, it can be administered orally or parenterally, and the parenteral administration method is not limited to this, but is intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, and intraperitoneal. , may be administered intranasally, enterally, topically, sublingually, or rectally.

The pharmaceutical composition of the present invention can be formulated into a formulation for oral administration or parenteral administration according to the administration route described above. When formulated, one or more buffers (e.g. saline or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g. EDTA or glutathione), fillers, bulking agents, binders, adjuvants (e.g. aluminum hydroxide) side), suspending agents, thickening agents, wetting agents, disintegrants or surfactants, diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, solutions, gels, syrups, slurries, suspensions or capsules, and such solid preparations may contain at least one excipient, for example, in the pharmaceutical composition of the present invention. , starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol, maltitol, cellulose. , methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropylmethyl-cellulose or gelatin can be mixed. For example, tablets or sugar tablets can be obtained by combining the active ingredient with a solid excipient, grinding it, adding suitable auxiliaries and processing it into a granule mixture.

In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, or syrups. In addition to the commonly used simple diluents such as water or liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, or preservatives may be included. .

In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, and preservatives may be additionally included. .

When administered parenterally, the pharmaceutical composition of the present invention can be formulated with a suitable parenteral carrier in the form of injections, transdermal administration, and nasal inhalation according to methods known in the art. The above injections must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. For injections, examples of suitable carriers include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), mixtures thereof, and/or vegetable oils. You can. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol, and 5% dextrose. etc. can be used. In order to protect the injection from microbial contamination, it may additionally contain various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. Additionally, in most cases, the injection may additionally contain an isotonic agent such as sugar or sodium chloride.

In the case of transdermal administration, forms such as ointments, creams, lotions, gels, external solutions, paste preparations, linear preparations, and aerol preparations are included. In the above, 'transdermal administration' means administering a pharmaceutical composition topically to the skin so that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.

For inhalation administration, the compounds used according to the invention may be packaged in pressurized packs or using a suitable propellant, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from a nebulizer. For pressurized aerosols, the dosage unit can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a text generally known in all pharmaceutical chemistry.

The pharmaceutical composition for treating or preventing muscle disease or improving muscle function of the present invention can provide desirable effects for treating and preventing muscle disease or improving muscle function when it contains an effective amount of quinic acid. In this specification, the term 'effective amount' refers to an amount that produces a greater response than the negative control, and preferably refers to an amount sufficient to improve muscle function. The pharmaceutical composition of the present invention may contain 0.01 to 99.99% of quinic acid, and the remaining amount may be comprised of a pharmaceutically acceptable carrier. The effective amount of quinic acid contained in the pharmaceutical composition of the present invention will vary depending on the form in which the composition is commercialized.

The total effective amount of the pharmaceutical composition of the present invention can be administered to a patient in a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease. For parenteral administration, the dosage is preferably 0.01 to 50 mg, more preferably 0.1 to 30 mg, per 1 kg of body weight per day based on quinic acid, and for oral administration, the dosage is 1 kg of body weight per day based on quinic acid. It can be administered in one to several divided doses so that the dose is preferably 0.01 to 100 mg, more preferably 0.1 to 50 mg. However, the effective dose for the patient is determined by considering various factors such as the patient's age, weight, health status, gender, severity of the disease, diet, and excretion rate, as well as the administration route and number of treatments of the pharmaceutical composition. Considering this, a person with ordinary knowledge in the art will be able to determine an appropriate effective dosage of quinic acid according to a specific use for treating and preventing muscle diseases. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route, and administration method as long as it exhibits the effects of the present invention.

The pharmaceutical composition for treating or preventing muscle disease or improving muscle function of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemical therapy, or biological response modifiers.

The pharmaceutical composition for treating or preventing muscle disease or improving muscle function of the present invention can also be provided in the form of an external preparation containing quinic acid as an active ingredient.

When the pharmaceutical composition for treating or preventing muscle disease or improving muscle function of the present invention is used as an external skin agent, it is additionally added with fatty substances, organic solvents, solubilizers, thickening agents, gelling agents, softeners, antioxidants, suspending agents, and stabilizers. Topicals, foaming agents, fragrances, surfactants, water, ionic emulsifiers, non-ionic emulsifiers, fillers, metal ion sequestrants, chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, It may contain adjuvants commonly used in the field of dermatology, such as hydrophilic active agents, lipophilic active agents, or any other ingredients commonly used in topical skin preparations, such as lipid vesicles. Additionally, the ingredients may be introduced in amounts commonly used in the field of dermatology.

When the pharmaceutical composition for treating or preventing muscle disease or improving muscle function of the present invention is provided as an external skin preparation, it is not limited thereto, but may be in the form of an ointment, patch, gel, cream, or spray.

Additionally, when the composition of the present invention is a food composition for improving and preventing muscle disease or improving muscle function, it can be used to prevent or improve muscle disease caused by muscle wasting or degeneration. Muscle wasting and degeneration occur due to genetic factors, acquired factors, aging, etc. Muscle wasting is characterized by gradual loss of muscle mass and weakness and degeneration of muscles, especially skeletal or voluntary muscles and cardiac muscles. Examples of diseases related to this include sarcopenia, muscular atrophy, muscular dystrophy, atony, muscle degeneration, myasthenia gravis, and cachexia. The composition of the present invention has the effect of increasing muscle mass, and the type of muscle is not limited.

The term ‘prevention’ in the present invention means anything that suppresses or delays the muscle disease.

The term 'improvement' in the present invention means at least reducing the degree of symptoms, for example, parameters related to the condition being treated by administration of the composition comprising quinic acid of the present invention.

The food composition of the present invention includes all forms of functional food, nutritional supplement, health function food, food additives, and feed, including humans or livestock. Animals are used as food. Food compositions of this type can be prepared in various forms according to conventional methods known in the art.

Food compositions of this type can be prepared in various forms according to conventional methods known in the art. General foods include, but are not limited to, beverages (including alcoholic beverages), fruits and their processed foods (e.g. canned fruit, bottled foods, jam, mamalade, etc.), fish, meat and their processed foods (e.g. ham, sausages, etc.) corned beef, etc.), bread and noodles (e.g. udon, buckwheat noodles, ramen, spagate, macaroni, etc.), fruit juice, various drinks, cookies, taffy, dairy products (e.g. butter, cheese, etc.), edible vegetable oil, margarine , can be manufactured by adding quinic acid to vegetable proteins, retort foods, frozen foods, and various seasonings (e.g., soybean paste, soy sauce, sauce, etc.). In addition, nutritional supplements are not limited to this, but can be manufactured by adding quinic acid to capsules, tablets, pills, etc. In addition, the health functional food is not limited to this, but for example, quinic acid can be prepared in the form of tea, juice, and drinks and consumed by liquefying, granulating, encapsulating, and powdering so that it can be consumed (health beverage). Additionally, in order to use quinic acid in the form of a food additive, it can be prepared and used in the form of powder or concentrate. Additionally, it can be prepared in the form of a composition by mixing quinic acid with known active ingredients that are known to be effective in improving and preventing muscle disease or improving muscle function.

When the composition for improving and preventing muscle disease or improving muscle function of the present invention is used as a health drink composition, the health drink composition may contain various flavoring agents or natural carbohydrates as additional ingredients, like ordinary drinks. . The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; It may be sugar alcohol such as xylitol, sorbitol, or erythritol. Sweeteners include natural sweeteners such as thaumatin and stevia extract; Synthetic sweeteners such as saccharin and aspartame can be used. The proportion of the natural carbohydrate is generally about 0.01 to 10.0 g, preferably about 0.1 to 5.0 g, per 100 mL of the composition of the present invention.

Quinic acid may be contained as an active ingredient in a food composition for improving or preventing muscle disease or improving muscle function, and the amount is specifically limited to an amount effective to achieve the action for improving or preventing muscle disease or improving muscle function. However, it is preferably 0.01 to 100% by weight based on the total weight of the entire composition. The food composition of the present invention can be prepared by mixing quinic acid with other active ingredients known to be effective in compositions for improving and preventing muscle disease or improving muscle function.

Additionally, the composition for improving or preventing muscle disease or improving muscle function of the present invention may also be a cosmetic composition. The cosmetic composition of the present invention contains quinic acid as an active ingredient, and together with dermatologically acceptable excipients, it can be used as a basic cosmetic composition (toilet water, cream, essence, face wash such as cleansing foam and cleansing water, pack, body oil), color cosmetic composition ( It can be manufactured in the form of foundation, lipstick, mascara, makeup base), hair product composition (shampoo, rinse, hair conditioner, hair gel), and soap.

The excipients are not limited thereto, but may include, for example, skin emollients, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners, and solvents. In addition, it may additionally contain fragrances, pigments, disinfectants, antioxidants, preservatives, and moisturizers, and may include thickeners, inorganic salts, synthetic polymer materials, etc. for the purpose of improving physical properties. For example, when preparing face wash and soap with the cosmetic composition of the present invention, they can be easily produced by adding quinic acid to a regular face wash and soap base. When manufacturing cream, it can be produced by adding quinic acid to a general oil-in-water (O/W) cream base. Here, synthetic or natural materials such as proteins, minerals, and vitamins can be added for the purpose of improving physical properties, such as fragrances, chelating agents, pigments, antioxidants, and preservatives.

The content of quinic acid contained in the cosmetic composition of the present invention is not limited to this, but is preferably 0.001 to 10% by weight, more preferably 0.01 to 5% by weight, based on the total weight of the entire composition. If the content is less than 0.001% by weight, the desired effect cannot be expected, and if the content is more than 10% by weight, there may be difficulties in safety or formulation manufacturing.

Additionally, when the composition of the present invention is a feed additive for improving and preventing muscle disease or improving muscle function, it can be used to prevent or improve muscle disease caused by muscle wasting or degeneration in animals.

In the present invention, the term 'feed additive' refers to a substance added to feed for the purpose of various effects such as supplementing nutrients and preventing weight loss, improving digestibility of fiber in feed, improving milk quality, preventing reproductive disorders and improving conception rate, and preventing high temperature stress in the summer. Includes. The feed additive of the present invention corresponds to supplementary feed under the Feed Management Act, and includes mineral preparations such as sodium bicarbonate, bentonite, magnesium oxide, and complex minerals, mineral preparations such as trace minerals such as zinc, copper, cobalt, and selenium, and kerotene. , vitamins such as vitamins A, D, E, nicotinic acid, and vitamin B complex, protective amino acids such as methionine and lysine, protective fatty acids such as fatty acid calcium salts, probiotics (lactic acid bacteria), yeast cultures, and live bacteria such as mold fermentation products, Yeast agents, etc. may be additionally included.

In the present invention, the term 'feed' refers to any natural or artificial diet, meal, etc., or an ingredient of the meal, for or suitable for eating, ingestion, and digestion by animals, and to prevent or improve muscle disease according to the present invention. Feed containing the composition as an active ingredient can be manufactured from various types of feed known in the art, and may preferably include concentrated feed, roughage and/or special feed, but is not limited thereto.

Concentrated feed includes seeds and fruits, including grains such as wheat, oats, and corn; bran, which includes rice bran, bran, and barley bran, which are by-products obtained from refining grains; soybeans; oil, sesame seeds, linseed, and coco oil; It is a product made by concentrating residues such as residual starch, which is the main component of the starch residue remaining after removing the starch from the by-products such as seed jelly, sweet potatoes, and potatoes, fishmeal, fish residue, and fresh liquid obtained from fish. Fish soluble, meat meal, blood meal, feather meal, skim milk powder, animal feed such as dried whey, which is the residue from the production of cheese from milk and casein from skim milk, yeast, These include, but are not limited to, chlorella and seaweed.

Forage includes raw grass feed such as wild grass, grass, and green cuttings, turnips for feed, beets for feed, root vegetables such as rutterbearger, a type of turnip, raw grass, green cuttings, and grains, etc., in silos. These include, but are not limited to, silage, which is stored feed that has been filled and fermented with lactic acid, field grass, hay made by cutting and drying grass, straw from breeding crops, and leaves from legumes. Special feeds include mineral feeds such as oyster shells and rock salt, urea feeds such as urea and its derivative diureide isobutane, and mixed feeds to supplement ingredients that are likely to be lacking when mixing only natural feed ingredients, or to increase the storability of the feed. Substances added in trace amounts include feed additives and dietary supplements, but are not limited to these.

The feed additive for preventing or improving muscle disease according to the present invention can be manufactured by adding quinic acid in an appropriate effective concentration range according to various feed manufacturing methods known in the art.

The feed additive according to the present invention can be applied without limitation to any object aimed at preventing or improving muscle disease. For example, it can be applied to any entity, including non-human animals such as cows, horses, pigs, goats, sheep, dogs, cats, rabbits, birds, and fish.

Additionally, the present invention provides a method of treating muscle disease comprising administering to a mammal a pharmaceutical composition containing an effective amount of quinic acid as an active ingredient.

As used herein, the term 'mammal' refers to a mammal that is the subject of treatment, observation or experiment, and preferably refers to a human.

As used herein, the term 'effective amount' refers to the amount of an active ingredient or pharmaceutical composition that, as believed by a researcher, veterinarian, physician, or other clinician, induces a biological or medical response in a tissue system, animal, or human. It includes amounts that induce relief of symptoms of a disease or disorder. The effective amount and frequency of administration of the active ingredient of the present invention may vary depending on the desired effect. Therefore, the optimal dosage to be administered can be easily determined by a person skilled in the art, and can be determined based on the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, the type of dosage form, and the patient's age, weight, and general health. It can be adjusted according to various factors, including condition, gender and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs. In the prevention, improvement or treatment method of the present invention, for adults, it is preferable to administer quinic acid at a dose of 0.001 g/kg to 10 g/kg once or several times a day.

In the treatment method of the present invention, the composition containing quinic acid as an active ingredient is administered in a conventional manner through oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, intraocular or intradermal routes. can do.

Hereinafter, quinic acid according to the present invention will be described in detail through examples.

However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.

[Example 1] Effect of increasing mTOR activity, a key biomarker for muscle protein synthesis

It is known that when mTOR protein is phosphorylated and activated, it can induce the activation of proteins involved in muscle protein synthesis and muscle mass increase in the PI3K/Akt signaling pathway within muscle cells. Therefore, in order to confirm the muscle creation-inducing activity of quinic acid, the activity of mTOR was confirmed using the mTOR Sandwich ELISA kit (Cell Signaling Technology, Beverly, MA, USA).

L6 myoblasts (ATCC; Manassas, VA, USA) were cultured in 6-well plates at 1 After seeding, the cells were cultured for 24 hours to reach 10 ⁵ cells/well. After culture, the medium in the well was removed, replaced with DMEM (Hyclone) containing 2% horse serum (HS; Hyclone), and cultured for an additional 6 days to differentiate L6 cells into myotube cells. Next, quinic acid was dissolved in DMEM (Hyclone) at concentrations of 20 μM and 40 μM, respectively, and then treated with cells and cultured for 12 hours. After culturing, cells were lysed by treatment with cell lysis buffer. The protein in the obtained cell lysate was quantified at a concentration of 1 mg/mL using Bradford (Bio-Rad Laboratories Inc., Hercules, CA, USA). 50 μL of cell lysate was dispensed into each microwell with anti-mTOR antibody attached and left at 37°C for 2 hours. After washing a total of 4 times with washing buffer, treatment with detection antibody and leaving at 37°C for 1 hour, washing again with washing buffer a total of 4 times, horseradish peroxidase ) conjugated secondary antibody was added and left at 37°C for 30 minutes. Finally, after washing a total of four times with the washing buffer solution, TMB substrate was added to each well, left at 37°C for 10 minutes, and stop buffer solution was added to stop the TMB reaction. After 2 minutes, the absorbance was measured at a wavelength of 450 nm to measure the level of mTOR in the myotube cells treated with quinic acid (Figure 1). The experiment was repeated a total of three times, and each measured value was calculated as a percentage (%) of the control group and expressed as mean ± standard deviation. Differences between groups were confirmed through Duncan multi-range analysis using one-way analysis of variance using the SPSS25.0 statistical package (SPSS Inc., Chicago, IL, USA). At this time, if the p value was less than 5%, it was indicated as statistically significant.

Looking at Figure 1, it was confirmed that when L6 muscle cells were treated with quinic acid according to Example 1 of the present invention, the activity of mTOR increased significantly (*p < 0.05) compared to the control group. This means that the quinic acid of the present invention has an excellent ability to promote muscle protein synthesis within muscle cells.

[Example 2] Effect of increasing expression of muscle protein synthesis biomarkers

L6 myoblast (ATCC), a muscle cell, was placed in a 6-well plate with DMEM (Hyclone) containing 10% FBS (Hyclone) at 1 Х 10 ⁵ cell/mL. When the cell density reached approximately 80-85%, the medium in the well was removed and the cells were treated with DMEM (Hyclone) containing 2% HS (Hyclone) to induce myotube differentiation. Differentiation was carried out for a total of 4 days, with new medium replaced every 2 days. After differentiation, quinic acid was dissolved in DMEM (Hyclone) containing 50 ng/mL tumor necrosis factor alpha (TNF-α; PeproTech, Rocky Hills, NJ, USA) at concentrations of 20 μM and 40 μM, respectively, and then treated with cells. and cultured for 24 hours. After incubation, cells were lysed with NP-40 buffer solution (ELPIS-Biotech, Daejeon, Korea) containing protease inhibitor cocktail (Sigma-Aldrich St. Louis, MO, USA) to obtain cell lysates. The obtained cell lysate was centrifuged at 13,000 rpm for 10 minutes to obtain the supernatant. The protein concentration in the supernatant was quantified using Bradford (Bio-Rad Laboratories Inc.), and then the protein was separated by heating for 5 minutes and running on a 10% sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) gel. The separated proteins were transferred to a nitrocellulose membrane. Then, p-mTOR, mTOR, p-p70S6K, p70S6K, p-4EBP1, 4EBP1, or α-tubulin antibodies (Cell Signaling Technology) were each diluted in 2.5% bovine serum albumin (BSA) at a ratio of 1:1000 and nitro-activated. The protein transferred to the cellulose membrane was reacted at room temperature for 20 hours. After reacting with the primary antibody, the nitrocellulose membrane was washed three times for 10 minutes using Tris-buffer Saline Tween20 (TBST). A secondary antibody (Bethyl Laboratories, Inc., Montgomery, TA, USA) conjugated with horseradish peroxidase (HRP), which recognizes the primary antibody, was diluted 1:5000 in 2.5% BSA and incubated on a nitrocellulose membrane at room temperature for 2 hours. It was reacted in and washed three times for 10 minutes each using TBST. The protein band was developed using ECL Western blot detection reagent (GE Healthcare, Piscataway, NJ, USA), and the colored protein band was confirmed using the G;BOX EF imaging system (Syngene, Cambridge, UK) (Figure 2 ).

As a result, as shown in Figure 2, the protein expression levels of p-mTOR, p-p70S6K, and p-4EBP-1, which are involved in muscle protein synthesis in L6 muscle cells by TNF-α, were significant ( ^## p < 0.01), while the protein expression levels of p-mTOR, p-p70S6K, and p-4EBP-1 were confirmed to increase significantly ( ^* p < 0.05, ^** p < 0.01) with quinic acid treatment. This means that the quinic acid of the present invention has an excellent ability to increase the expression of biomarkers involved in muscle protein synthesis in muscle cells.

[Example 3] Effect of increasing the expression level of muscle differentiation biomarkers

L6 myoblast (ATCC), a muscle cell, was placed in a 6-well plate with DMEM (Hyclone) containing 10% FBS (Hyclone) at 1 Х 10 ⁵ cell/mL. When the cell density reached approximately 80-85%, the medium in the well was removed and 20 μM and quinic acid were added to DMEM (Hyclone) containing 50 ng/mL TNF-α (PeproTech) and 2% HS (Hyclone). After dissolving to a concentration of 40 μM, myotube differentiation was induced by treating cells. Differentiation was carried out for a total of 4 days, with new medium replaced every 2 days. At this time, the group containing cells in DMEM (Hyclone) containing 2% HS (Hyclone) but not containing TNF-α was used as the control group. After 24 hours, total RNA was isolated using TRIzol reagent (Takara). The isolated total RNA was quantified using NanoDrop 1000 (Thermo Fisher Scientific Inc.). 16 μL of quantified RNA was synthesized into cDNA using Reverse Transcriptase Premix (ELPIS-Biotech) and a PCR machine (Gene Amp PCR System 2700; Applied Biosystems) under the conditions of 42°C, 55 minutes and 70°C, 15 minutes. Repeat 35 times at 95°C for 30 seconds, 60°C for 30 seconds, and 72°C for 45 seconds with 1 μL of cDNA among 16 μL of generated cDNA, specific primers (Bioneer) listed below, and PCR premix (ELPIS-Biotech). Then, PCR was performed.

MyoD

Forward primer: 5'-GGTGTAACAACCATACCCCACT-3' (SEQ ID NO: 1)

Reverse primer: 5'-TGCCTCGGAGATAAATACAGCC-3' (SEQ ID NO: 2)

Myogenin

Forward primer: 5'-AGAGAGCCCCTTGTTAATGC-3' (SEQ ID NO: 3)

Reverse primer: 5'-GGCCACTCACTGTCTCTCAAA-3' (SEQ ID NO: 4)

β-Actin:

Forward primer: 5'-CTGTGTGGATTGGTGGCTCTATC-3' (SEQ ID NO: 5)

Reverse primer: 5'-AAACGCAGCTCAGTAACAGTCC-3' (SEQ ID NO: 6)

As a result of PCR, the amplified cDNA was separated by electrophoresis using a 1.5% agarose gel, and the cDNA band was confirmed using the G;BOX EF imaging system (Syngene) (Figure 3).

As a result, as shown in Figure 3, the mRNA expression of MyoD and Myogenin, which was significantly ( ^## p < 0.01) decreased by treatment with TNF-α, was significantly ( ^* p < 0.05, ^** p) by treatment with quinic acid. < 0.01). This means that the quinic acid of the present invention has an excellent ability to promote muscle differentiation.

[Example 4] Effect of suppressing the expression level of muscle protein degradation biomarkers

L6 myoblast (ATCC), a muscle cell, was placed in a 6-well plate with DMEM (Hyclone) containing 10% FBS (Hyclone) at 1 Х 10 ⁵ cell/mL. When the cell density reached approximately 80-85%, the medium in the well was removed and the cells were treated with DMEM (Hyclone) containing 2% HS (Hyclone) to induce myotube differentiation. Differentiation was carried out for a total of 6 days, with new medium replaced every 2 days. After differentiation, quinic acid was dissolved in DMEM (Hyclone) containing 50 ng/mL TNF-α (PeproTech) at concentrations of 20 μM and 40 μM, respectively, and then treated with the cells. After 12 hours, total RNA was isolated using TRIzol reagent (Takara, Otsu, Japan). The isolated total RNA was quantified using NanoDrop 1000 (Thermo Fisher Scientific Inc., Waltham, MA, USA). 16 μL of quantified RNA was incubated at 42°C for 55 minutes and at 70°C for 15 minutes using Reverse Transcriptase Premix (ELPIS-Biotech) and a PCR machine (Gene Amp PCR System 2700; Applied Biosystems, Foster City, CA, USA). cDNA was synthesized under these conditions. Among 16 μL of generated cDNA, 1 μL of cDNA, the following specific primers (Bioneer, Daejeon, Korea), and PCR premix (ELPIS-Biotech) were used for 30 seconds at 95°C, 30 seconds at 60°C, and 45 seconds at 72°C. PCR was repeated 35 times.

MuRF1

Forward primer: 5'-CCGGACGGAAATGCTATGGA-3' (SEQ ID NO: 7)

Reverse primer: 5'-AGCCTGGAAGATGTCGTTGG-3' (SEQ ID NO: 8)

Atrogin-1

Forward primer: 5'-CTCATACGGGAACTTCTCCAGAC-3' (SEQ ID NO: 9)

Reverse primer: 5'-CAGTGTAGAGTGGTCTCCATTCG-3' (SEQ ID NO: 10)

β-Actin:

Forward primer: 5'-CTGTGTGGATTGGTGGCTCTATC-3' (SEQ ID NO: 5)

Reverse primer: 5'-AAACGCAGCTCAGTAACAGTCC-3' (SEQ ID NO: 6)

As a result of PCR, the amplified cDNA was separated by electrophoresis using a 1.5% agarose gel, and the cDNA band was confirmed using the G;BOX EF imaging system (Syngene, Cambridge, UK) (Figure 4).

As a result, as shown in Figure 4, the mRNA expression levels of MuRF1 and atrogin-1, which are involved in muscle protein degradation by TNF-α, increased significantly ( ^## p < 0.01), while treatment with quinic acid decreased MuRF1 and atrogin-1. It was confirmed that the mRNA expression level of atrogin-1 was significantly ( ^** p < 0.01) decreased. This means that the quinic acid of the present invention has an excellent ability to inhibit the expression of biomarkers involved in muscle protein degradation in muscle cells.

[Example 5] Effect of quinic acid on increasing muscle function and muscle mass in an animal model inducing muscle atrophy

<5-1> Raising animals and inducing muscle atrophy

As experimental animals, 8-week-old male mice (C57BL/6N; Samtako Bio, Korea) were purchased and tested. The breeding room environment for all animals was maintained at a temperature of 23 ± 2°C and a relative humidity of 55 ± 10%. Before starting the experiment, a total of 30 mice were divided into normal group, muscle atrophy group, and 50 mg/kg quinic acid administration group and randomly assigned to 10 mice per group. After a week of adaptation, anesthesia was induced by intraperitoneal injection of 325 mg/kg tribromoethanol (Sigma-Aldrich). After anesthesia, the gastrocnemius muscle of the right hindlimb and the right sole of the rats in the muscle atrophy group and the sample administration group were stapled using a skin stapler (Unidus, Chungcheongbuk-do, Korea). The right hind leg was damaged and unable to move, and this condition was maintained for a week. One week later, the stapler core fixed to the gastrocnemius muscle and sole was removed, and 50 mg/kg quinic acid was administered orally every day for 7 days for another week to induce muscle regeneration. At this time, the normal group and the muscle atrophy group were orally administered saline solution instead of the sample.

<5-2> Confirmation of the muscle strength improvement effect of quinic acid

After the oral administration period was over, the muscle strength of the mice was measured using a muscle strength meter (Panlab, Barcelona, Spain). The tail of the mouse was pulled with a constant force until the mouse released the last part of the muscle strength measuring device, and a total of 5 consecutive tests were performed per mouse.

As a result, as shown in Figure 5, the muscle strength was significantly ( ^## p < 0.01) decreased in the muscle atrophy group compared to the normal group, but when 50 mg/kg of quinic acid was administered, the muscle strength was significantly ( ^*) compared to the muscle atrophy group. ^* p < 0.01) was confirmed to have increased. This means that the quinic acid of the present invention has an excellent effect in increasing muscle strength reduced due to muscle atrophy.

<5-3> Confirmation of the effect of quinic acid on increasing muscle volume

Before sacrifice, mice were anesthetized with isoflurane and the volume and density of right hind limb muscles were measured using positron emission tomography/computed tomography/single photon emission tomography (microPET/CT/SPECT; Siemens Inveon, Knoxville, TN, USA). did.

As a result, as shown in Figure 6, the muscle volume of the muscular atrophy group was significantly ( ^## p < 0.01) reduced compared to the normal group, but when treated with 50 mg/kg of quinic acid, the muscle volume was significantly lower than that of the muscular atrophy group. ( ^** p < 0.01) was confirmed to have increased. This means that the quinic acid of the present invention is excellent in increasing the volume of muscles reduced due to muscle atrophy.

<5-4> Confirmation of the effect of quinic acid on increasing muscle weight

After muscle strength measurements were completed, the experimental animals were anesthetized by intraperitoneal injection of 325 mg/kg of tribromomethanol (Sigma-Aldrich) and then sacrificed through cardiac blood sampling. After confirming that the heartbeat had stopped, the undamaged tibialis anterior muscle was removed from the right hind leg and its weight was measured.

As a result, as shown in Figure 7, the weight of the tibialis anterior muscle in the muscle atrophy group was significantly ( ^## p < 0.01) reduced compared to the normal group, but when treated with 50 mg/kg of quinic acid, the weight was significant compared to the muscle atrophy group. It was confirmed that there was a significant increase ( ^* p < 0.05). This means that the quinic acid of the present invention is excellent in increasing the weight of muscles reduced due to muscle atrophy.

<5-5> Confirmation of the effect of quinic acid in promoting damaged muscle regeneration

In Example 5-4, from the mouse from which the tibialis anterior muscle of the right hind limb was removed, the gastrocnemius muscle of the right hind limb, which was directly physically damaged by a stapler, was extracted. A portion of the extracted gastrocnemius muscle tissue was fixed in 10% formalin to create a paraffin block. After fixation, hematoxylin & eosin staining was performed to measure muscle recovery from a histological perspective, and the stained tissue was examined under a photochemical microscope equipped with an eXcope T500 camera (DIXI Science, Daejeon, Korea). (CK40; Olymupus, Tokyo, Japan).

As a result, as shown in Figure 8, compared to the normal group, the nucleus of the satellite cell in the muscle atrophy group was located in the middle of the muscle fiber rather than the edge of the muscle fiber, whereas when quinic acid was administered, the nucleus was located at the edge of the muscle fiber. In addition, compared to the normal group, the muscle fiber cross-sectional area was significantly ( ^## p<0.01) decreased in the muscle atrophy group, but when treated with 50 mg/kg of quinic acid, the muscle fiber cross-sectional area was significantly ( ^** p<0.01) compared to the muscle atrophy group. It was confirmed that it increased. This means that the quinic acid of the present invention is excellent in promoting the regeneration of damaged muscles.

Below, an example of the preparation of a composition containing quinic acid of the present invention will be described, but the present invention is not intended to be limited, but merely explained in detail.

<Manufacturing Example 1> Medicine

Production Example 1-1. manufacture of powders

Quinsan 50mg

crystalline cellulose 2g

lactose 100mg

Talc 10mg

The above ingredients are mixed and filled into an airtight bubble to prepare a powder.

Production Example 1-2. manufacture of tablets

Quinsan 50mg

crystalline cellulose 400mg

Magnesium stearate 5mg

After mixing the above ingredients, tablets are manufactured by compressing them according to a typical tablet manufacturing method.

Production Example 1-3. Manufacturing of capsules

Quinsan 50mg

whey protein 100mg

crystalline cellulose 400mg

Magnesium stearate 6mg

Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a typical capsule manufacturing method.

Production Example 1-4. Manufacturing of injectable drugs

Quinsan 50mg

Mannitol 180mg

Sterile distilled water for injection 2974mg

Na ₂ HPO ₄ ,12H ₂ O 26 mg

It is prepared with the above ingredients per ampoule according to the usual manufacturing method for injections.

Production Example 1-5. Manufacture of liquid

Quinsan 50mg

Iseonghwadang 10g

Mannitol 5 g

Purified water Appropriate amount

According to the usual liquid preparation method, add and dissolve each ingredient in purified water, add an appropriate amount of lemon flavor, mix the above ingredients, add purified water, adjust the total to 100g by adding purified water, and then fill it in a brown bottle and sterilize it. to produce a liquid.

Production Example 1-6. Manufacture of granules

Quinsan 50mg

vitamin mixture Appropriate amount

Vitamin A Acetate 70 ㎍

Vitamin E 1.0mg

Vitamin B1 0.13mg

Vitamin B2 0.15mg

Vitamin B6 0.5mg

Vitamin B12 0.2 μg

Vitamin C 10mg

biotin 10 μg

Nicotinic acid amide 1.7mg

folic acid 50 μg

Calcium Pantothenate 0.5mg

mineral mixture Appropriate amount

Ferrous sulfate 1.75mg

zinc oxide 0.82mg

Magnesium Carbonate 25.3 mg

Potassium Phosphate Monobasic 15mg

Dibasic Calcium Phosphate 55mg

potassium citrate 90mg

calcium carbonate 100mg

Magnesium chloride 24.8mg

The composition ratio of the above vitamin and mineral mixture is a mixture of components relatively suitable for granules in a preferred embodiment, but the mixing ratio may be modified arbitrarily. The above components are mixed according to a typical granule manufacturing method, and then the granules are mixed. It can be prepared and used to manufacture a health functional food composition according to a conventional method.

<Production Example 2> Food

Manufacturing Example 2-1. Manufacturing of health foods

Quinic acid 1000 mg, Vitamin A acetate 70 ug, Vitamin E 1.0 mg, Vitamin B1 0.13 mg, Vitamin B2 0.15 mg, Vitamin B6 0.5 mg, Vitamin B12 0.2 ug, Vitamin C 10 mg, Biotin 10 ug, Nicotinamide 1.7 mg, Folic acid 50 ug, calcium pantothenate 0.5 mg, ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, monobasic potassium phosphate 15 mg, dicalcium phosphate 55 mg, potassium citrate 90 mg, calcium carbonate 100 mg, chloride It can be manufactured by mixing 24.8 mg of magnesium, and the mixing ratio can be modified arbitrarily. After mixing the above ingredients according to a normal health food manufacturing method, granules are manufactured, and the health food is prepared according to a normal method. It can be used to prepare a composition.

Manufacturing Example 2-2. Manufacturing of health drinks

Add purified water to 1000 mg of quinic acid, 1000 mg of citric acid, 100 g of oligosaccharides, 2 g of plum concentrate, and 1 g of taurine to make a total of 900 mL. Mix the above ingredients according to the usual health drink manufacturing method, and then stir at 85°C for about 1 hour. After heating, the resulting solution is filtered, placed in a sterilized 2 L container, sealed, sterilized, stored in the refrigerator, and then used to manufacture a health drink composition.

Manufacturing Example 2-3. chewing gum

Chewing gum was prepared in a conventional manner by mixing 20% by weight of gum base, 76.9% by weight of sugar, 1% by weight of flavor, 2% by weight of water, and 0.1% by weight of quinic acid.

Manufacturing Example 2-4. candy

Candy was prepared in a conventional manner by mixing 60% by weight of sugar, 39.8% by weight of starch syrup, 0.1% by weight of flavor, and 0.1% by weight of quinic acid.

Manufacturing Example 2-5 Biscuit

Power grade 1 25.59% by weight, gravity grade 1 22.22% by weight, refined sugar 4.80% by weight, table salt 0.73% by weight, glucose 0.78% by weight, palm shortening 11.78% by weight, ammonium 1.54% by weight, sodium bicarbonate 0.17% by weight, sodium bisulfite 0.16% by weight , 1.45% by weight of rice flour, 0.0001% by weight of vitamin B, 0.04% by weight of milk flavor, 20.6998% by weight, 1.16% by weight of whole milk powder, 0.29% by weight of powdered milk, 0.03% by weight of monobasic calcium phosphate, 0.29% by weight of spray salt and spray. Biscuits were prepared in a conventional manner by mixing 7.27% by weight of oil and 5% by weight of quinic acid.

<Production Example 3> Cosmetics

Production Example 3-1. Nutritional lotion (milk lotion)

Nutritional lotion was prepared according to a conventional method using the quinic acid of the present invention according to the nutritional lotion formulation ratio shown in Table 1 below.

Ingredients Manufacturing Example 3-1
(weight%) Quinsan 2.0 squalane 5.0 beeswax 4.0 Polysorbate 60 1.5 Sorbitan sesquioleate 1.5 liquid paraffin 0.5 Caprylic/Capric Triglyceride 5.0 glycerin 3.0 Butylene glycol 3.0 propylene glycol 3.0 Carboxy vinyl polymer 0.1 Triethanolamine 0.2 Preservatives, coloring, flavoring Appropriate amount Purified water to 100

Production Example 3-2. Soft lotion (skin lotion)

Soft lotion was prepared according to a conventional method using the quinic acid of the present invention in the softening lotion formulation ratio shown in Table 2 below.

Ingredients Manufacturing Example 3-2
(weight%) Quinsan 2.0 glycerin 3.0 Butylene glycol 2.0 propylene glycol 2.0 Carboxy vinyl polymer 0.1 PEG 12 nonylphenyl ether 0.2 Polysorbate 80 0.4 ethanol 10.0 Triethanolamine 0.1 Preservatives, coloring, flavoring Appropriate amount Purified water to 100

Production Example 3-3. Nutrition cream

A nutritional cream was prepared according to a conventional method using the quinic acid of the present invention according to the nutritional cream formulation ratio shown in Table 3 below.

Ingredients Manufacturing Example 3-3
(weight%) Quinsan 2.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 PEG60 hydrogenated castor oil 2.0 liquid paraffin 10 squalane 5.0 Caprylic/Capric Triglyceride 5.0 glycerin 5.0 Butylene glycol 3.0 propylene glycol 3.0 Triethanolamine 0.2 antiseptic Appropriate amount pigment Appropriate amount Spices Appropriate amount Purified water to 100

Manufacturing Example 3-4. massage cream

A massage cream was prepared according to a conventional method using the quinic acid of the present invention in the massage cream formulation ratio shown in Table 4 below.

Ingredients Manufacturing Example 3-4
(weight%) Quinsan 1.0 beeswax 10.0 Polysorbate 60 1.5 PEG 60 hydrogenated castor oil 2.0 Sorbitan sesquioleate 0.8 liquid paraffin 40.0 squalane 5.0 Caprylic/Capric Triglyceride 4.0 glycerin 5.0 Butylene glycol 3.0 propylene glycol 3.0 Triethanolamine 0.2 Preservatives, coloring, flavoring Appropriate amount Purified water to 100

Production Example 3-5. pack

A pack was prepared according to a conventional method using the quinic acid of the present invention in the pack formulation ratio shown in Table 5 below.

Ingredients Manufacturing Example 3-5
(weight%) Quinsan 1.0 polyvinyl alcohol 13.0 Sodium Carboxymethylcellulose 0.2 glycerin 5.0 allantoin 0.1 ethanol 6.0 PEG 12 nonylphenyl ether 0.3 Polysorbate 60 0.3 Preservatives, coloring, flavoring Appropriate amount Purified water to 100

Production Example 3-6. gel

A gel was prepared according to a conventional method using the quinic acid of the present invention in the gel formulation ratio shown in Table 6 below.

Ingredients Manufacturing Example 3-6
(weight%) Quinsan 0.5 Sodium ethylenediamine acetate 0.05 glycerin 5.0 Carboxy vinyl polymer 0.3 ethanol 5.0 PEG 60 hydrogenated castor oil 0.5 Triethanolamine 0.3 Preservatives, coloring, flavoring Appropriate amount Purified water to 100

In the table above, 'appropriate amount' means that an appropriate amount can be added depending on preference, and 'to 100' means that the remaining weight% after subtracting the sum of the weight% of the remaining mixing ingredients excluding purified water from the total 100% by weight is added to the purified water. This means that it can be done in weight percent.

Although the present invention has been described in terms of the above-mentioned preferred embodiments, various modifications and variations can be made without departing from the gist and scope of the invention. Furthermore, the appended claims cover such modifications or variations as fall within the subject matter of the present invention.

As described above, the present invention provides a composition containing quinic acid for improving, treating or preventing muscle disease, or improving muscle function. More specifically, quinic acid of the present invention improves muscle mass and strength by increasing the activity of mTOR, increasing the mRNA expression level of MyoD and Myogenin, and decreasing the mRNA expression level of MuRF1 and atrogin-1, thereby improving and treating muscle diseases. Alternatively, it is effective for prevention or improving muscle function. Therefore, quinic acid of the present invention has high industrial applicability because it can provide a composition showing excellent effects for improving, treating or preventing muscle diseases, or improving muscle function.

Claims (7)

A pharmaceutical composition for treating or preventing muscle disease, or improving muscle function, containing quinic acid represented by the following formula (1) as an active ingredient.
[Formula 1]

According to clause 1,
The muscle disease is characterized in that it is at least one selected from the group consisting of atony, muscular atrophy, muscular dystrophy, muscle degeneration, myasthenia gravis, cachexia, and sarcopenia. Pharmaceutical composition for treating or preventing muscle disease or improving muscle function. A pharmaceutical composition for treating or preventing muscle damage containing quinic acid represented by the following formula (1) as an active ingredient.
[Formula 1]
. According to clause 3,
The muscle damage consists of muscle strain, muscle rupture, muscle tearing, contusion, sprain, rotator cuff syndrome, and myositis. A pharmaceutical composition for treating or preventing muscle damage, comprising at least one selected from the group. A food composition for improving or preventing muscle disease or muscle damage, or improving muscle function, containing quinic acid represented by the following formula (1) as an active ingredient.
[Formula 1]
. A cosmetic composition for improving or preventing muscle disease or muscle damage, or improving muscle function, containing quinic acid represented by the following formula (1) as an active ingredient.
[Formula 1]
. A feed additive for improving or preventing muscle disease or muscle damage, or improving muscle function, containing quinic acid represented by the following formula (1) as an active ingredient.
[Formula 1]
.