KR20230055668A - Composition for preventing or treating sarcopenia comprising reboxetine as an active ingredient - Google Patents

Abstract

The present invention relates to a composition comprising reboxetine as an active ingredient for prevention or treatment of sarcopenia. In the present invention, reboxetine is identified to have an effect of alleviating the atrophy of myotubes formed in myoblasts and as such, is provided as a novel medication for prevention, treatment, or alleviation of sarcopenia.

Description

Composition for preventing or treating sarcopenia comprising reboxetine as an active ingredient

The present invention relates to a composition for preventing or treating sarcopenia comprising reboxetine as an active ingredient.

Sarcopenia caused by degeneration of spinal nerves, motor nerves, or skeletal muscle fibers is one of the representative intractable diseases whose causes have not yet been identified. According to studies so far, motor nerves that induce contraction of skeletal muscle are degenerated so that contraction of skeletal muscle does not progress, or the expression of proteins involved in muscle contraction in skeletal muscle is reduced (sarcopenia), or the protein is modified It is known that normal skeletal muscle contraction does not proceed, and in the long term, the motor nerve or skeletal muscle is transformed into fibrous tissue.

Among sarcopenia, degenerative sarcopenia is defined as a decrease in muscle mass associated with aging, and is increasingly recognized as having an important effect on the quality of life in old age. Degenerative sarcopenia occurs in 13-24% of people under the age of 70, but occurs in more than 50% of those over the age of 80. is known to be associated with an increase in Patients suffering from sarcopenia experience difficulties in daily life, such as lower grip strength or reduced walking speed, while skeletal muscle index is below the standard. Body composition shows a marked loss of muscle mass, while a tendency for body fat to increase.

As a treatment for sarcopenia, nutritional approaches and exercise training methods are being studied. Treatment using protein compounds such as appetite stimulants and testosterone has been proposed, but the therapeutic effect is not satisfactory. Exercise training is difficult to see as an appropriate alternative because it is often difficult for the elderly with sarcopenia to even try to exercise. As a method of slowing down the progress of sarcopenia pharmaceutically, a method of inhibiting muscular atrophy caused by degeneration or progressive mutation of muscle cells, which is a type of sarcopenia, is mainly used.

Korean Registered Patent Publication No. 10-1944985 (2019. 02. 01. Announcement)

In order to solve the above problems, an object of the present invention is to provide a new pharmaceutical composition capable of preventing, treating or improving sarcopenia, the effect of which reboxetine improves the atrophy of the root canal formed in myoblasts. By confirming that it represents, it is to provide reboxetine (reboxetine) as a new drug for the prevention, treatment or improvement of sarcopenia.

The present invention provides a pharmaceutical composition for preventing or treating sarcopenia comprising reboxetine as an active ingredient.

In addition, the present invention provides a health functional food composition for preventing or improving sarcopenia comprising reboxetine as an active ingredient.

In addition, the present invention provides a method for treating sarcopenia comprising administering the pharmaceutical composition to a subject suffering from sarcopenia in a pharmaceutically effective amount.

According to the present invention, reboxetine (reboxetine) can be provided as a new drug for preventing, treating or improving sarcopenia because it exhibits an effect of improving atrophy of myoblasts.

1 is a result of staining Myosin heavy chain (MYH) and nuclei by Immunocytochemistry (ICC) in order to evaluate the effect of reboxetine on the myotube formation process of myoblasts.
2 is a result of evaluating a myotube area and a fusion index in order to evaluate the effect of reboxetine on the process of myoblast myotube formation.

The terms used in this specification have been selected from general terms that are currently widely used as much as possible while considering the functions in the present invention, but these may vary depending on the intention of a person skilled in the art, precedent, or the emergence of new technologies. In addition, in a specific case, there is also a term arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the invention. Therefore, the term used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, not simply the name of the term.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in this application, it should not be interpreted in an ideal or excessively formal meaning. don't

Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout this specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.

Hereinafter, the present invention will be described in more detail.

The present invention provides a pharmaceutical composition for preventing or treating sarcopenia comprising reboxetine or a pharmaceutically acceptable salt thereof as an active ingredient.

The reboxetine is a compound represented by Formula 1 below, (2S)-2-[(S)-(2-ethoxyphenoxy)-phenylmethyl]morpholine[(2S)-2-[( S)-(2-ethoxyphenoxy)-phenylmethyl]morpholine; (S,S)-reboxetine], was discovered by Farmitalia-Carlo Erba as a norepinephrine reuptake inhibitor, and was first published in 1984. Reboxetine has been commercialized on the market as an antidepressant by Pfizer and has been studied to be used for panic disorder or ADHD, but it is a compound that has not yet been approved for use in the United States.

[Formula 1]

The reboxetine (reboxetine) can improve one or more symptoms of sarcopenia selected from the group consisting of reduced body weight, skeletal muscle weight, grip strength, and expression levels of muscle protein-related genes due to sarcopenia.

The muscle protein-related gene is a gene that produces a muscle protein, which is a gene encoding MyoD or Myogenin, or Myostatin, Atrogin-1, or MuRF1. It may be a gene that destroys muscle protein, which is a gene encoding (Muscle RING-finger protein-1), but is not limited thereto.

The reboxetine can improve root canal atrophy.

The sarcopenia includes degenerative muscle weakness or muscular dystrophy. The sarcopenia may be degenerative sarcopenia, and refers to a decrease in muscle mass of skeletal muscle due to a decrease in the number and cross-sectional area of muscle fibers for various reasons such as aging. The muscular atrophy refers to a disease in which muscles atrophy, and specifically, a disease in which the muscles of the limbs gradually atrophy almost symmetrically, and may include amyotrophic lateral sclerosis or spinal progressive muscular atrophy.

In the present invention, the pharmaceutically acceptable salt is composed of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethylaminium salt and pyridinium salt. It may be one or more basic salts selected from the group, but is not limited thereto.

In addition, the pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid , It may be one or more acid salts selected from the group consisting of glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and aspartic acid, but Note that it is not limited.

The pharmaceutical composition according to the present invention can be prepared in unit dose form by formulating using a pharmaceutically acceptable carrier according to a method that can be easily performed by those skilled in the art or by putting it into a multi-dose container. there is.

The pharmaceutically acceptable carrier is one commonly used in formulation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. The pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like, in addition to the above components.

In the present invention, the content of the additives included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the range of content used in conventional formulations.

The pharmaceutical composition is an injectable formulation such as aqueous solution, suspension, emulsion, pill, capsule, granule, tablet, cream, gel, patch, spray, ointment, warning agent, lotion, liniment agent, pasta agent and cataplasma agent. It may be formulated in the form of one or more external agents selected from the group consisting of

The pharmaceutical composition of the present invention may additionally contain a pharmaceutically acceptable carrier and diluent for formulation. The pharmaceutically acceptable carriers and diluents include excipients such as starch, sugar and mannitol, fillers and extenders such as calcium phosphate, cellulose derivatives such as carboxymethylcellulose and hydroxypropylcellulose, gelatin, alginates, and polyvinyl fibres. binders such as rolidone, etc., lubricants such as talc, calcium stearate, hydrogenated castor oil and polyethylene glycol, disintegrants such as povidone, crospovidone, surfactants such as polysorbates, cetyl alcohol, and glycerol; don't The pharmaceutically acceptable carrier and diluent may be biologically and physiologically compatible with the subject. Examples of diluents include, but are not limited to, saline, aqueous buffers, solvents and/or dispersion media.

The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenous, subcutaneous, intraperitoneal or topical application) depending on the desired method. For oral administration, it may be formulated into tablets, troches, lozenges, aqueous suspensions, oily suspensions, powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs. In the case of parenteral administration, it may be formulated as an injection solution, suppository, powder for respiratory inhalation, aerosol for spray, ointment, powder for application, oil, cream, etc.

The dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, age, sex, health condition, dietary constitution specificity, the nature of the preparation, the severity of the disease, the administration time of the composition, the administration method, the administration period or interval, the excretion rate, And the range may vary depending on the type of drug, and may be appropriately selected by a person skilled in the art. For example, it may be in the range of about 0.1 to 10,000 mg/kg, but is not limited thereto, and may be divided and administered once or several times a day.

The pharmaceutical composition may be administered orally or parenterally (eg, intravenous, subcutaneous, intraperitoneal or topical application) depending on the desired method. The pharmaceutically effective amount and effective dose of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time and / or administration route of the pharmaceutical composition, and those skilled in the art can perform the desired treatment An effective dosage can be easily determined and prescribed. Administration of the pharmaceutical composition of the present invention may be administered once a day, or may be divided and administered several times.

In addition, the present invention provides a health functional food composition for preventing or improving sarcopenia comprising reboxetine as an active ingredient.

The present invention can be generally used as a commonly used food.

The food composition of the present invention can be used as a health functional food. The term "health functional food" refers to food manufactured and processed using raw materials or ingredients having useful functionalities for the human body in accordance with the Health Functional Food Act, and "functional" refers to food that is not related to the structure and function of the human body. It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological functions.

The food composition of the present invention may include conventional food additives, and the suitability as the "food additive" is determined according to the general rules of the Food Additive Code and General Test Methods approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the specifications and standards for the item.

Items listed in the "Food Additive Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, goyang pigment, guar gum, and mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations.

The food composition of the present invention can be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills and the like.

For example, among the health functional foods in the form of capsules, hard capsules can be prepared by mixing and filling the composition according to the present invention with additives such as excipients in conventional hard capsules, and soft capsules can be prepared by filling the composition according to the present invention. It can be prepared by mixing with additives such as excipients and filling in a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.

Definitions of terms for the excipients, binders, disintegrants, lubricants, corrigents, flavoring agents, etc. are described in literature known in the art, and include those having the same or similar functions. There is no particular limitation on the type of food, and it includes all health functional foods in the usual sense.

In the present invention, the term prevention refers to all activities that suppress or delay a disease by administering the composition according to the present invention. In the present invention, the term treatment refers to all activities in which the symptoms of a disease are improved or beneficially changed by administration of the composition according to the present invention. In the present invention, "improvement" means any action that improves the bad condition of a disease by administering or ingesting the composition of the present invention to a subject.

In addition, the present invention provides a method for treating sarcopenia comprising administering the pharmaceutical composition to a subject suffering from sarcopenia in a pharmaceutically effective amount.

The pharmaceutically effective amount is an amount effective to treat a disease, such as an amount of a composition administered to a subject to be treated, to prevent recurrence, to relieve symptoms, to inhibit direct or indirect pathological consequences, An amount of the composition that prevents metastasis, reduces the rate of progression, alleviates or palliates the condition, or improves the prognosis.

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Example> Confirmation of the differentiation activity effect of reboxetine on myotubes

Reboxetine was provided from a compound bank and used in the present invention.

In order to confirm the therapeutic effect of reboxetine on sarcopenia, the effect of reboxetine on myoblast myotube formation was evaluated. DMEM (Dulbecco's Modified Eagle's Medium) containing 1% penicillin/streptomycin and 10% FBS (Fetal Bovine Serum) was used as a growth medium, and 1% penicillin/streptomycin streptomycin) and DMEM (Dulbecco's Modified Eagle's Medium) containing 2% NHS (Normal Horse Serum) was used as a differentiation medium. A 96-well plate was coated with a 0.1% gelatin solution. C2C12 cells, a 4-passage mouse myoblast cell line, at a density of 50% to 60% were collected using trypsin, and 5000 cells were plated with a growth medium in a 96-well plate coated with gelatin. After culturing for 24 hours, the medium was replaced with a differentiation medium, and cultured for 48 hours to induce myotube formation. Thereafter, the negative control group and the test group were treated with 150 μM of dexamethasone to induce root canal atrophy. After 24 hours, the test group was treated with 5 µM to 25 µM of reboxetine, and the positive and negative control groups were treated with 0.1% DMSO. After 24 hours, Myosin heavy chain (MYH) and nuclei were stained using Immunocytochemistry (ICC), and the myotube area and fusion index were evaluated.

As shown in FIGS. 1 and 2, in the negative control group, when cells in which myotubes were formed were treated with dexamethasone, the myotubes atrophied and the diameter of the tubes was attenuated, and reboxetine In the case of treatment, it was found that root canal atrophy was improved as the treatment concentration increased. The above results prove that reboxetine improves the sarcopenia phenomenon in the root canal induced by dexamethasone, and that reboxetine has the effect of improving and treating sarcopenia. suggests that

Having described specific parts of the present invention in detail above, it is clear to those skilled in the art that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (7)

A pharmaceutical composition for preventing or treating sarcopenia comprising reboxetine or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 1, wherein the reboxetine improves at least one sarcopenia symptom selected from the group consisting of reduced body weight, skeletal muscle weight, grip strength, and muscle protein-related gene expression levels due to sarcopenia. Or a pharmaceutical composition for treatment. According to claim 2, wherein the muscle protein-related gene is MyoD (MyoD) or Myogenin (Myogenin) coding gene, a gene that produces a muscle protein, or myostatin (Myostatin), artrogin-1 ( Atrogin-1) or MuRF1 (Muscle RING-finger protein-1), a gene encoding a muscle protein, a pharmaceutical composition for preventing or treating sarcopenia, characterized in that. The pharmaceutical composition for preventing or treating sarcopenia according to claim 1, wherein the reboxetine has an effect of improving root canal atrophy. The pharmaceutical composition for preventing or treating sarcopenia according to claim 1, wherein the sarcopenia is degenerative muscle weakness or muscular atrophy. A health functional food composition for preventing or improving sarcopenia, comprising reboxetine as an active ingredient. A method for treating sarcopenia comprising administering the pharmaceutical composition according to any one of claims 1 to 5 in a pharmaceutically effective amount to a subject suffering from sarcopenia.

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