KR102368217B1 - Composition for preventing or treating muscle atrophy or Sarcopenia comprising 14-deoxyandrographolide succinate - Google Patents

Abstract

The present invention relates to a composition for the prevention or treatment of muscle aging-related diseases comprising sacopenia, containing 14-deoxyandrographolide succinate as an active component. By containing a compound of the present invention, 14-deoxyandrographolide succinate, and a combination formulation comprising the same as the active component, it is possible to promote or induce differentiation from myoblasts to myotube cells, and thus alleviate, prevent or treat diseases that can be caused by muscle-related diseases including muscle aging-related sarcopenia and skeletal muscle sarcopenia according to the same.

Description

TECHNICAL FIELD [0001] Composition for preventing or treating muscle atrophy or Sarcopenia comprising 14-deoxyandrographolide succinate comprising sarcopenia containing 14-deoxyandrographolide succinate as an active ingredient

The present invention relates to a composition for preventing or treating skeletal muscle atrophy or sarcopenia comprising sacopenia containing 14-deoxyandrographolide succinate as an active ingredient.

The present invention effectively controls skeletal muscle atrophy and sarcopenia using 14-deoxyandrographolide succinate as an active ingredient in various animal models and cell test methods to effectively control muscular diseases caused by various causes, especially It relates to a pharmaceutical composition and its use as an agent for preventing, treating and ameliorating skeletal muscle atrophy.

Skeletal muscle atrophy can be caused by various causes, such as immobility, muscle disease, space travel, denervation, sepsis, dexamethasone administration, weight loss, decreased dietary intake, etc. It is characterized in that the area is reduced. It is also known to be caused by treatment such as peripheral neuropathic pain, a decrease in muscle function that inevitably accompanies aging, and a treatment such as a plaster cast performed on a surgically injured patient. The occurrence of such muscle atrophy can lead to a decrease in the quality of life of the patient due to problems such as weakness, induction of activity impairment, and prolongation of the recovery period. In particular, aging, which is rapidly increasing worldwide, and overcoming of degenerative diseases are one of the immediate problems that must be solved in order to pursue a healthy and humane life and move forward to a welfare state.

In the muscle, anabolic and catabolic effects are balanced and muscle generation is controlled. When a signal transduction reaction that induces synthesis rather than degradation of muscle protein is activated, the synthesis of muscle protein is increased, leading to an increase in muscle size (hypertrophy, hypertrophy) or an increase in the number of muscle fibers (hyperplasia), resulting in excessive muscle production.

Progressive muscle weakness and loss of function threatens the quality of life and lowers the survival rate of cancer patients. More than 30% of cancer patients die due to weight loss due to muscle loss, and this loss of muscle function is due to degeneration of myo-proteins, muscle fiber cross-sectional area, and muscle strength. ), the number of muscle fibers (nuclear number of myofibers) and insulin responsiveness are commonly accompanied.

In addition to cancer, muscle loss can also be caused by aging and various chronic diseases. As aging progresses, sarcopenia, in which a portion of newly created skeletal muscle is replaced with fibrous tissue, decreases the amount and strength of skeletal muscle in the human body. In addition, muscle loss occurs in chronic diseases that increase with age, such as hypertension, impaired glucose tolerance, diabetes, obesity, dyslipidemia, atherosclerosis, and cardiovascular disease (Pharmacol Res. 2015, 99, 86). ).

A general method for preventing muscle atrophy is prevention of muscle loss through exercise, but there is no fundamental treatment currently on the market. At a time when a clear treatment for these patients with muscular atrophy has not been developed, it is necessary to study the development of countermeasures and prevention/treatment/improvement agents that can prevent muscular atrophy. Therefore, it is considered that the pharmaceutical composition according to the present invention will be usefully used for the prevention, treatment and improvement of these muscular atrophy diseases. Furthermore, the identification of the active ingredient is thought to be of great help to the development of pharmaceutical science in the future.

Andrographolide is a major component of Andrographis paniculata along with andrographiside, Andropanoside, Andrographin, Panicolin, etc. there is. Andrographolide is a Labdane (= natural bicyclic diterpene) diterpenoid isolated from the stem and leaves of Andrographis paniculata. Labdane is a natural bicyclic diterpene. It forms the structural core of various natural medicines collectively known as Labdanes or Labdane diterpenes, and this ingredient has been found to have a great hepatoprotective function. It has been confirmed through research and is used as an anti-inflammatory and anticancer agent.

Andrographolide succinate is one of the main ingredients of Andrographis paniculata along with Andrographolide. There are no studies on skeletal muscle atrophy and sarcopenia.

Accordingly, the present inventors effectively control skeletal muscle atrophy and sarcopenia of 14-deoxyandrographolide succinate through various animal models and cell test methods to effectively control muscular diseases caused by various causes, especially skeletal muscle atrophy. prevention, treatment and improvement of

Korean Patent Publication No. 10-2019-0070844

The inventor of the present invention observes and compares the muscle size, strength, and performance from dexamethasone treated or aged animal models as a method for evaluating the effectiveness of skeletal muscle atrophy recovery drugs, and the drug effectively reduces skeletal muscle atrophy. The present invention was completed by confirming that the

Accordingly, an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of muscle aging-related diseases comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[Formula 1]

In addition, an object of the present invention is to provide a food composition for preventing or improving muscle aging-related diseases, comprising the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating muscle aging-related diseases, comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient do.

[Formula 1]

In addition, the present invention provides a food composition for preventing or improving muscle aging-related diseases comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[Formula 1]

In one embodiment of the present invention, the muscle aging-related disease is senile sarcopenia, atony, muscular atrophy, muscle degeneration, myositis, amyotrophic axonal sclerosis, myasthenia gravis, myositis, muscle It may be selected from the group consisting of calcification, muscle ossification, muscle weakness related diseases and cachexia.

In one embodiment of the present invention, the composition may promote mitochondrial functional activity.

In one embodiment of the present invention, the composition may be administered by one or more methods selected from the group consisting of intravenous, intradermal, inhalation, transdermal (topical), intraorbital, subcutaneous, intramuscular, oral and transmucosal administration. .

In one embodiment of the present invention, the composition is composed of orbicularis muscle, masticatory muscle, tongue and neck muscle, rib cage and arm muscle, arm and shoulder, hand intrinsic muscle, lower extremity and leg muscle, forelimb and foot muscle can be delivered to one or more target tissues selected from the group.

In one embodiment of the present invention, the disease may be induced by steroids or atrophic factors.

The present invention relates to a composition for treating diseases related to muscle aging, and the like, wherein the compound of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof has an effect of effectively preventing, improving and treating skeletal muscle atrophy or sarcopenia. Therefore, the present invention containing the compound can be usefully applied to related pharmaceutical and health functional food fields.

1 is a result showing the effect on skeletal muscle atrophy by dexamethasone treatment.
Figure 2 is andrographolide (Androglapholide) 30mg / kg oral administration and 14-deoxyandrographolide succinate (14-deoxyandrographolide succinate) 30mg / kg intraperitoneal administration body weight (Body Weight) and muscle function (Grip Strength) ) is a result showing the effect on
3 shows the inhibitory effect on skeletal muscle atrophy according to the administration method at the same concentration of 30 mg/kg of androglapholide and 14-deoxyandrographolide succinate on lean body mass (Lean Body). Mass), Lean Mass of Tibialis Anteriors, TA, and Lean Mass of Gastrocnemius Muscle, GS.
4 shows the inhibitory effect on skeletal muscle atrophy according to the administration method at the same concentration of 30 mg/kg of androglapholide and 14-deoxyandrographolide succinate. , TA) is the result shown by Muscle Diameter T1.
Figure 5 shows the effect of androglapholide and 14-deoxyandrographolide succinate on skeletal muscle atrophy according to the same concentration of 30 mg/kg and the same intraperitoneal administration (IP) method on body weight, Results showing the grip strength and treadmill tests, which are muscle functions.
6 shows the effect of androglapholide and 14-deoxyandrographolide succinate on skeletal muscle atrophy according to the same 30mg/kg concentration and the same intraperitoneal administration (IP) method. These are the results of checking the lean body mass, the lean mass of the anterior tibialis anteriors (TA), and the lean mass of the gastrocnemius muscle (GS).
7 shows the effect of androglapholide and 14-deoxyandrographolide succinate on skeletal muscle atrophy according to the same concentration (30 mg/kg) and the same intraperitoneal administration (IP). This is the result shown by Muscle Diameter T1 of the anterior tibialis anteriors (TA).
8 is anterior view of the skeletal muscle atrophy or muscle reduction effect according to oral administration of 14-deoxyandrographolide succinate at a concentration of 30 mg/kg and administration of 60 mg/kg IP for 14 days in a 20-month-old aging mouse. These are the results showing the efficacy of lean mass and length (Diameter) of the bone (Tibialis Anteriors, TA), and functional aspects of the muscle with a grip strength test.
9 is a result showing the effects of androglapholide and 14-deoxyandrographolide succinate on skeletal muscle mitochondrial function and on skeletal muscle cell atrophy.

Hereinafter, the present invention will be described in detail.

Provided is a pharmaceutical composition for preventing or treating muscle aging-related diseases, comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[Formula 1]

In the present invention, the muscle aging-related disease may mean a disease that causes muscle weakness or loss. The muscle weakness or loss is not limited to the aging of the individual and may be caused by hypoxia, chemicals and drugs, physical factors, infectious factors, immune or inflammatory reactions, infectious factors, nutritional imbalance, space travel, and steroids or alcohol It is a concept including those induced by drugs, such as.

In the present invention, "pharmaceutically acceptable salt" means a salt formed with any inorganic or organic acid or base that does not cause serious irritation to the administered organism and does not impair the biological activity and physical properties of the compound. As the salt, a salt commonly used in the art may be used, such as an acid addition salt formed with a pharmaceutically acceptable free acid. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic acids and organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium.

In the present invention, “hydrate” refers to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to which water is bound by a non-covalent intermolecular force, and may include a stoichiometric or non-stoichiometric amount of water. . Specifically, the hydrate may contain water in a ratio of about 0.25 mole to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, about 2 mole, about 2.5 moles, about 3 moles, about 5 moles, and the like.

As used herein, the term “prevention” refers to any action that suppresses symptoms or delays the onset of symptoms by administration of the pharmaceutical composition according to the present invention.

As used herein, the term “treatment” refers to any action in which symptoms are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.

The pharmaceutical composition according to the present invention includes the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is commonly used in formulation, and includes, but is not limited to, saline, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome, and the like. It does not, and may further include other conventional additives, such as antioxidants and buffers, if necessary. In addition, diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules, or tablets. Regarding suitable pharmaceutically acceptable carriers and formulations, formulations can be preferably made according to each component using the method disclosed in Remington's literature. The pharmaceutical composition of the present invention is not particularly limited in dosage form, but may be formulated as an injection or oral ingestion, and when an injection is used, it may be formulated in a form in which the durability of the active ingredient is improved.

The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously or subcutaneously) according to a desired method, and the dosage may vary depending on the patient's condition and weight, the degree of disease, drug form, Although it varies depending on the route and time of administration, it may be appropriately selected by those skilled in the art.

In one embodiment, the composition according to the present invention can be prepared as an aqueous solution for parenteral administration, preferably a buffered solution such as Hank's solution, Ringer's solution or physically buffered saline. can be used Aqueous injection suspensions may contain a substrate capable of increasing the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.

The composition of the present invention may be administered systemically or locally, and may be formulated into a formulation suitable for such administration by a known technique. For example, for oral administration, it may be administered by mixing with an inert diluent or an edible carrier, sealing it in a hard or soft gelatin capsule, or pressing it into a tablet. For oral administration, the active compound can be mixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.

Various formulations for injection, parenteral administration, etc. can be prepared according to techniques known in the art or commonly used techniques. Androglapholide and 14-deoxyandrographolide succinate were dissolved in saline or buffer and stored in a freeze-dried state, and then an effective amount of Androglapholide and 14- Deoxyandrographolide succinate (14-deoxyandrographolide succinate) may be administered in a form suitable for intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., formulated in a solution immediately before administration in saline or buffer solution.

Meanwhile, subjects to which the pharmaceutical composition of the present invention can be administered may include all animals.

The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , can be determined according to factors including sensitivity to drug, administration time, administration route and excretion rate, duration of treatment, concurrent drugs, and other factors well known in the medical field. The composition according to the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the patient, and may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, and the like.

In the present invention, the muscle aging-related diseases are senile sarcopenia, atony, muscular atrophy, muscle degeneration, muscle stiffness, amyotrophic axonal sclerosis, myasthenia gravis, myositis, muscle calcification, muscle ossification, It may be one or more diseases selected from the group consisting of muscle weakness-related diseases and cachexia.

In the present invention, the muscle weakness-related disease refers to any disease that can occur due to muscle weakness, and is a disease in which the differentiation ability of myoblasts is reduced or weakened due to a decrease in myocytes in the body or a decrease in satellite cell activity. It means a disease that can be prevented, improved, or treated through

In the present invention, the composition may promote mitochondrial functional activity.

In the present invention, the composition may be administered by one or more methods selected from the group consisting of intravenous, intradermal, inhalation, transdermal (topical), intraorbital, subcutaneous, intramuscular, oral and transmucosal administration.

In the present invention, the composition is one selected from the group consisting of orbicularis muscle, masticatory muscle, tongue and neck muscle, thoracic rib cage and arm muscle, arm and shoulder, hand intrinsic muscle, lower extremity and leg muscle, forelimb and foot muscle It can be delivered to more than one target tissue.

In the present invention, the disease may be induced by steroids or atrophic factors.

In the present invention, steroid is a generic term for compounds having a generic steroid nucleus structure in which one cyclopentyl ring is attached to three cyclohexyl rings, and may preferably refer to a cortisol steroid.

In the present invention, cell atrophy may be expressed in the form of adaptation of cells due to cell damage. These cell damage factors can be caused by hypoxia, chemicals and drugs, physical factors, infectious factors, immune or inflammatory reactions, infectious factors, and nutritional imbalance. , IL-6, TNF-α, NF-κB, Dexamethasone, and the like.

In another aspect, the present invention provides a food composition for preventing or improving muscle aging-related diseases, comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[Formula 1]

The food composition is a concept including health functional food.

As used herein, the term “improvement” refers to any action that at least reduces a parameter related to a condition to be treated, for example, the severity of symptoms.

In the food composition of the present invention, the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof may be added to food as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method. there is. The mixed amount of the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof may be suitably determined depending on the purpose of its use (for prevention or improvement). In general, in the production of food or beverage, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw material. However, in the case of long-term intake for health and hygiene or health control, the amount may be less than or equal to the above range.

The health functional food composition of the present invention is not particularly limited in other ingredients other than containing the above ingredients as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. . Examples of the above-mentioned 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 dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate can be appropriately determined by the selection of a person skilled in the art.

In addition to the above, the health functional food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, colorants and thickeners (cheese, chocolate, etc.), pectic acid and salts thereof, Alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like may be contained. These components may be used independently or in combination. The proportion of these additives may also be appropriately selected by those skilled in the art.

Without conflict, the description of the pharmaceutical composition may be applied to the description of the food composition.

Hereinafter, the present invention will be described in more detail through examples. However, the following examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

Example 1.

Commercially available (Xianjiatianbio, China) and 14-deoxyandrographolide succinate reagents having the structure of Formula 1 were purchased and used.

<Test Example>

Differentiation of myoblasts (myoblasts) into myotubes is preceded by the activity of ATP, which is an intracellular energy, and the increase in ATP activity can accelerate the rate of differentiation by increasing the activity of mitochondria in myoblasts. Luminescence assay confirmed that androglapholide and 14-deoxyandrographolide succinate induce ATP activity and promote myoblast differentiation by increasing mitochondrial activity. did In addition, the protective effect against skeletal muscle cell atrophy caused by the atrophic factor TNF-α in myotubes that have been differentiated was also demonstrated using luminescence assay and light microscopy. Effect of androglapholide and 14-deoxyandrographolide succinate on dexamethasone treatment and skeletal muscle atrophy by aging model. Weight, grip strength and skeletal muscle atrophy. Suppression and recovery of tibialis anterior muscle loss, inhibition and recovery of lean muscle mass loss, and recovery of gastrocnemius muscle were confirmed using dual energy X-ray absorptiometry (DEXA).

Test Example 1. Dexamethasone treatment confirmed the effect on skeletal muscle atrophy in mice

In the dexamethasone-induced sarcopenia model, skeletal muscle atrophy or muscle reduction was induced by intraperitoneal administration of 100 μl of dexamethasone at a concentration of 10 mg/kg to 8-week-old male ICR mice for 12 days.

As shown in FIG. 1 , the grip strength, which is an index of muscle function, was measured by dexamethasone using a mouse experimental grip strength meter (Jeongdo BNP Grip strength meter, Korea). The measurement method is the measurement value when the experimenter holds the tail while gently holding the body of the mouse and then pulls the tail at a constant speed and releases both front feet was recorded. The highest tension out of a total of 5 measurements was considered as the grip strength (g). The anterior tibialis anterior muscle and lean body mass were measured using dual energy X-ray absorptiometry (DEXAmetry). As a result, it was confirmed that all of the indicators shown in Figure 1 were reduced by dexamethasone.

Test Example 2. Skeletal muscle atrophy or sarcopenia according to the administration method at the same concentration of androglapholide and 14-deoxyandrographolide succinate using a dexamethasone-treated skeletal muscle atrophy mouse model comparison of the preventive or therapeutic effects of

In the dexamethasone-induced mouse sarcopenia model, 14-deoxyandrographolide succinate was administered simultaneously with administration of dexamethasone for 12 days and oral administration at a concentration of androglapholide 30mg/kg. ) 30mg/kg IP to evaluate the efficacy of skeletal muscle atrophy or muscle reduction by body weight, grip strength and lean body mass in terms of muscle function, and Lean of Tibialis Anteriors (TA) The mass, the lean mass of the gastrocnemius muscle (GS), and the length (Diameter) of the anterior tibialis anteriors (TA) were confirmed.

As a result, as shown in Figure 2, in the grip strength test (Grip Strength) and muscle loss measurement index in terms of muscle function, body weight, 30 mg/kg concentration I.P. It was confirmed that 14-deoxyandrographolide succinate of the administration method has a superior effect than androglapholide.

In addition, as shown in FIG. 3 , in lean mass of lean body mass and anterior tibialis anteriors (TA), 30 mg/kg concentration of I.P. 14-deoxyandrographolide succinate of the administration method and 30 mg/kg concentration of oral administration method androglapholide were confirmed to have similar effects, but gastrocnemius muscle, In Lean Mass of GS), it was confirmed that 14-deoxyandrographolide succinate had a superior effect.

Furthermore, as shown in Figure 4, in the length (Diameter) of the anterior shin tibialis anteriors (Tibialis Anteriors, TA), 30mg / kg concentration I.P. It was confirmed that 14-deoxyandrographolide succinate of the administration method and androglapholide of the oral administration method of 30 mg/kg have similar effects.

Test Example 3. Skeletal muscle atrophy or muscle according to the same concentration and administration method of androglapholide and 14-deoxyandrographolide succinate using a dexamethasone-treated skeletal muscle atrophy mouse model Comparison of the effects of prevention or treatment of nephropathy

In the dexamethasone-induced mouse sarcopenia model, dexamethasone was administered for 12 days and at the same time, androglapholide and 14-deoxyandrographolide succinate were administered at a concentration of 30 mg/kg I.P. By administration, the efficacy of skeletal muscle atrophy or muscle reduction was evaluated by body weight, lean body mass, lean mass of Tibialis Anteriors (TA), lean mass of gastrocnemius muscle (GS) and Diameter of the anterior shinbone (Tibialis Anteriors, TA) was checked, and grip strength and treadmill tests were performed in terms of muscle function. The Treadmill test had mice run on a treadmill at 14 m/min at an inclination of 5˚, increasing the speed by 2 m/min every 1 min until it reached 20 m/min, and the end of the measurement was a mechanical stab stimulation and Refusal to run despite electric shock stimulation was set as the end point of the measurement.

As a result, as shown in FIG. 5, at the same concentration (30 mg/kg) and the same administration method (IP) of androglapholide and 14-deoxyandrographolide succinate 14-deoxyandrographolide succinate showed a superior effect than androglapholide in the body weight, grip strength test, and treadmill test in terms of muscle function. confirmed to exist.

In addition, as shown in FIG. 6, 14-deoxyandrographol in Lean Mass, Lean Mass of Tibialis Anteriors, TA, and Lean Mass of Gastrocnemius Muscle, GS Ride succinate (14-deoxyandrographolide succinate) was confirmed to have a superior effect than andrographolide (Androglapholide).

Furthermore, 14-deoxyandrographolide succinate is superior to androglapholide in the length (Diameter) of the anterior tibialis anteriors (TA) as shown in FIG. It was confirmed that there was an effect.

Test Example 4. Results of prevention or treatment of skeletal muscle atrophy or sarcopenia of 14-deoxyandrographolide succinate using an aged mouse model

Oral administration of 14-deoxyandrographolide succinate (14-deoxyandrographolide succinate) at a concentration of 30 mg/kg and 60 mg/kg I.P. The efficacy of skeletal muscle atrophy or muscle reduction by administration, the grip strength test in terms of muscle function, and the lean mass and length (Diameter) of the anterior tibialis anteriors (TA) were confirmed.

As a result, as shown in FIG. 8, the grip strength in the functional aspect of the muscle was 14-deoxyandrographolide succinate 60 mg/kg I.P. It was confirmed that the administration showed a superior effect, and the lean mass and length (Diameter) of the anterior tibialis anteriors (TA) were also confirmed to excellently inhibit atrophy or decrease in the skeleton of aging mice.

Test Example 5. Promoting differentiation of myoblasts and protective effect against skeletal muscle cell atrophy induced by the atrophic factor TNF-α in the differentiated myoblast Myotube

To promote the differentiation of myoblasts, the C2C12 mice myoblast cell line was dispensed at a concentration of 5x10 ³ cells/well in a 96-well cell culture plate, 70-80% confluence was confirmed, and then the culture medium and differentiation medium were changed. The differentiation medium was treated with androglapholide and 14-deoxyandrographolide succinate, and ATP activity was measured during differentiation for 5 days by Luminescence assay. To measure the protective effect against skeletal muscle cell atrophy, C2C12 mice myoblasts were dispensed at 5x10 ³ cells/well and 2x10 ⁵ cells/well, respectively, in a 6-well cell culture plate and a 6-well culture plate, 80-90% confluency was confirmed, and the differentiation medium was cultured. TNF-α and TNF-α in Myotube formed after 5 days of differentiation Treated with androglapholide and 14-deoxyandrographolide succinate, suction the medium 2 days later, and dispense 2.0 CellTiter (promega) reagent 100 μL on weel after 10-12 After a minute reaction time, it was measured with a luminescence measuring instrument, and TNF-α and After 2 days of treatment with androglapholide and 14-deoxyandrographolide succinate, 5 random pictures were taken under an optical microscope (magnification: 40×, 100×).

As a result, as shown in FIG. 9, androglapholide and 14-deoxyandrographolide succinate were treated to protect against atrophy of skeletal muscle cells and promote differentiation of skeletal muscle cells. It was confirmed that ATP produced by mitochondrial activity had a concentration-dependent protective effect against the atrophy of cells caused by TNF-α in the luminescence assay measurement result and the fully differentiated Myotube.

In addition, as shown in Figure 9, myoblasts are differentiated into myotube cells, and when treated with androglapholide and 14-deoxyandrographolide succinate, myoblasts from myotubes It was confirmed that differentiation into cells is promoted (Luminescence is increased). In addition, it was confirmed that androglapholide inhibited Myotube atrophy from 1 μM or more to 14-deoxyandrographolide succinate from 10 μM or more (tube length and area and ATP production) activity is judged by the functional activity of mitochondria).

Claims (11)

As a pharmaceutical composition for the prevention or treatment of muscle aging-related diseases comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient,
The muscle aging-related diseases are senile sarcopenia, dystonia (atony), muscular atrophy, muscle degeneration, muscle stiffness, amyotrophic axonal sclerosis, myasthenia gravis, myositis, muscle calcification, muscle ossification and cachexia (cachexia) ) is one or more diseases selected from the group consisting of,
The composition comprises one or more target tissues selected from the group consisting of orbicularis muscle, masticatory muscle, tongue and neck muscle, thoracic rib cage and arm muscle, arm and shoulder, intrinsic muscle of hand, lower extremity and leg muscle, forelimb and foot muscle A pharmaceutical composition for the prevention or treatment of muscle aging-related diseases delivered to.
[Formula 1]

delete The pharmaceutical composition according to claim 1, wherein the composition promotes mitochondrial functional activity.
The pharmaceutical composition according to claim 1, wherein the composition is administered by one or more methods selected from the group consisting of intravenous, inhalational, transdermal, intraorbital, oral and transmucosal administration.
delete The pharmaceutical composition according to claim 1, wherein the disease is induced by steroids or atrophic factors.
As a health functional food composition for the prevention or improvement of muscle aging-related diseases comprising a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient,
The muscle aging-related diseases are senile sarcopenia, dystonia (atony), muscular atrophy, muscle degeneration, muscle stiffness, amyotrophic axonal sclerosis, myasthenia gravis, myositis, muscle calcification, muscle ossification and cachexia (cachexia) ) is one or more diseases selected from the group consisting of,
The composition comprises one or more target tissues selected from the group consisting of orbicularis muscle, masticatory muscle, tongue and neck muscle, thoracic rib cage and arm muscle, arm and shoulder, intrinsic muscle of hand, lower extremity and leg muscle, forelimb and foot muscle A health functional food composition for the prevention or improvement of muscle aging-related diseases delivered to.
[Formula 1]

delete The health functional food composition according to claim 7, wherein the composition promotes mitochondrial functional activity.
delete The health functional food composition according to claim 7, wherein the disease is induced by steroids or cell atrophic factors (Atrophic factor).

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