WO2025206783A1 - Composition for preventing, alleviating, or treating emotional disturbance comprising rilmenidine - Google Patents

Abstract

The present disclosure relates to a composition for preventing, alleviating, or treating emotional disturbance comprising rilmenidine. In the present invention, administration of rilmenidine to an animal model of depression was found to alleviate symptoms of depression and anxiety. In addition, behavioral improvements were confirmed in an animal model with impaired cognitive function following rilmenidine administration. Accordingly, rilmenidine can be utilized as a composition for preventing or treating emotional disturbance.

Description

Composition for preventing, improving or treating emotional disorders containing rilmenidine

This application claims the benefit of Republic of Korea Patent Application No. 10-2024-0042524, filed March 28, 2024, the entire disclosure of which is incorporated herein by reference.

The present invention relates to a composition for preventing, improving or treating emotional disorders, including rilmenidine, and more specifically, to a pharmaceutical composition for preventing or treating emotional disorders, including rilmenidine or a pharmaceutically acceptable salt thereof as an active ingredient, and a composition for a health functional food for preventing or improving emotional disorders.

Emotional disorder refers to cases where a person has inappropriate behavior or feelings in a normal environment, has depression or anxiety, cannot maintain good interpersonal relationships with peers, and has learning disabilities in perception, cognition, or movement.

Among them, depression, or depressive disorder, is a common mental illness, sometimes called the common cold of the mind. It can lead to dysfunctional interpersonal relationships and, in severe cases, even suicide. Fortunately, depression is a medical condition that can be effectively treated, with a 70-80% initial recovery rate within two months. Counseling and psychiatric treatment are essential for depression, and antidepressant medication is also essential for moderate to severe depression.

Anxiety disorders are a collective term for mental illnesses characterized by abnormal, pathological anxiety and fear, which interfere with daily life. While anxiety and fear are normal emotional responses, when they exceed the normal range, they can lead to mental distress and physical symptoms. Anxiety can be diagnosed when the sympathetic nervous system is stimulated by anxiety, resulting in physical symptoms such as headaches, increased heart rate, increased breathing, and gastrointestinal symptoms, which can be uncomfortable and interfere with daily activities such as home, work, and school.

Most current antidepressants work by increasing the concentration of neurotransmitters at central serotonin or noradrenergic synapses. Depending on the mechanism by which they increase neurotransmitter concentrations, antidepressants are broadly classified into tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs). While these existing antidepressants are relatively effective, some can exhibit severe side effects and suboptimal efficacy.

The present invention, based on extensive efforts to develop a substance with more effective efficacy in preventing, improving, or treating emotional disorders, confirmed that administering rilmenidine to an animal model of depression improved symptoms of depression and anxiety. Furthermore, the present invention was completed by confirming that administration of rilmenidine improved behavior in an animal model with impaired cognitive function.

Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating emotional disorders, and a composition for health functional foods for preventing or improving emotional disorders, comprising relmenidine or a pharmaceutically acceptable salt thereof as an active ingredient.

To achieve the above-mentioned purpose,

The present invention provides a pharmaceutical composition for preventing or treating emotional disorders, comprising rilmenidine or a pharmaceutically acceptable salt thereof represented by the following chemical formula 1 as an active ingredient.

In addition, the present invention provides a composition for a health functional food for preventing or improving emotional disorders, which comprises rilmenidine represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

According to a preferred embodiment of the present invention, the emotional disorder may be depression, bipolar disorder, seasonal affective disorder, or panic disorder.

According to another preferred embodiment of the present invention, the daily dosage of the relmenidine or a pharmaceutically acceptable salt thereof may be 0.01 mg/kg (body weight) to 10 mg/kg (body weight).

In addition, the present invention provides a method for preventing or treating emotional disorders, comprising a step of administering or ingesting to a subject a pharmaceutical composition comprising rilmenidine represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a pharmaceutical composition comprising rilmenidine represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating emotional disorders.

In the present invention, administration of rilmenidine to an animal model of depression confirmed improvement in depressive and anxiety symptoms. Furthermore, administration of rilmenidine also improved behavior in an animal model with impaired cognitive function. Therefore, rilmenidine can be utilized as a composition for the prevention or treatment of affective disorders.

Figure 1 shows data confirming the improvement of depressive and anxiety symptoms when rilmenidine was administered to an animal model induced by restraint stress (RS). In a forced swimming test, it was confirmed that rilmenidine administration reduced immobility time (#, p < 0.05).

Figure 2 shows data confirming the improvement in cognitive function when rilmenidine was administered to an animal model induced by restraint stress (RS). In the object recognition memory test, it was confirmed that the discrimination index was improved by rilmenidine administration (###, p < 0.001; ****, p < 0.0001).

Hereinafter, the present invention will be described in detail.

The present invention relates to a pharmaceutical composition for preventing or treating emotional disorders, comprising rilmenidine or a pharmaceutically acceptable salt thereof represented by the following chemical formula 1 as an active ingredient.

In another aspect of the present invention, the present invention relates to a composition for a health functional food for preventing or improving emotional disorders, comprising rilmenidine represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

In the present invention, the emotional disorder may be depression, bipolar disorder, seasonal affective disorder or panic disorder, and is more preferably characterized as an emotional disorder caused by stress.

In the present invention, the daily dosage of the rilmenidine or a pharmaceutically acceptable salt thereof may be 0.01 mg/kg (body weight) to 10 mg/kg (body weight), preferably 0.01 mg/kg (body weight) to 1 mg/kg (body weight). If rilmenidine is administered at a concentration of less than 0.01 mg/kg (body weight), the therapeutic effect of emotional disorder may be minimal, and if rilmenidine is administered at a concentration exceeding 10 mg/kg (body weight), side effects such as toxicity may occur.

In the present invention, the above-mentioned rilmenidine may be a rilmenidine metabolite, and the rilmenidine metabolite refers to a product that appears after being metabolized in the body of a subject to which rilmenidine is administered.

In the present invention, "prevention" refers to any action that inhibits or delays the onset of a disease by administering a composition. In the present invention, "improvement" or "treatment" refers to any action that improves or beneficially alters the symptoms of a disease by administering a composition.

The pharmaceutical composition of the present invention can be formulated and used in various forms according to conventional methods. For example, it can be formulated in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and can be formulated and used in the forms of topical preparations, suppositories, and sterile injectable solutions. Depending on each dosage form, pharmaceutically acceptable carriers, excipients, and diluents may be further included. In addition, it can be formulated and used in the forms of topical preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and sterile injectable solutions according to conventional methods.

The carrier, excipient and diluent include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, etc. When formulating or formulating the pharmaceutical composition, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants that are commonly used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. with the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin, and glycerogelatin.

The term "administration" as used herein means providing the pharmaceutical composition of the present invention to a subject by any suitable method. The pharmaceutical composition of the present invention may be administered in a therapeutically effective amount, which is an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue, animal, or human as contemplated by a researcher, veterinarian, physician, or other clinician, i.e., an amount that induces alleviation of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dosage and frequency of administration of the pharmaceutical composition of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be readily determined by those skilled in the art and can be adjusted according to various factors, including 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 formulation, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, the excretion rate of the composition, the treatment period, and concurrently used drugs. The pharmaceutical composition of the present invention may be administered to a subject by various routes. For example, it can be administered intravenously, intraperitoneally, intramuscularly, intraarterially, orally, intracardiacly, intramedullary, intrathecally, transdermally, enterally, subcutaneously, sublingually, or topically, but is not limited thereto. The pharmaceutical composition of the present invention can be administered in an amount of 1 to 10,000 mg/kg/day, and can be administered once a day or divided into several doses.

The health functional food composition of the present invention can be used as a health functional food, food additive, or dietary supplement. When the composition of the present invention is used as a food additive, it can be appropriately used according to conventional methods, such as by adding it as is or mixing it with other foods or food ingredients.

In addition, the mixing amount of the health functional food composition may be appropriately changed depending on the intended use (prevention, health, or therapeutic treatment). For example, when manufacturing food or beverages, the composition of the present invention is added in an amount of 15 wt% or less, preferably 10 wt% or less, based on the raw material. However, when consumed for long-term purposes such as health and hygiene or health control, the composition may be added in an amount below the above range, and since there are no safety issues, the active ingredient may be used in an amount exceeding the above range.

There is no particular limitation on the type of the above food, but examples of foods to which the composition of the present invention can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, etc., and include all health foods in the conventional sense.

When the health functional food composition of the present invention is manufactured into a beverage, it may contain additional ingredients such as various flavoring agents or natural carbohydrates, as in conventional beverages. As the natural carbohydrates, monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; natural sweeteners such as dextrin and cyclodextrin; and synthetic sweeteners such as saccharin and aspartame may be used. The natural carbohydrates are contained in an amount of 0.01 to 10 wt%, preferably 0.01 to 0.1 wt%, based on the total weight of the food composition of the present invention.

The health functional food composition of the present invention may include various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc., and may include fruit pulp for the production of natural fruit juice, fruit juice beverages, and vegetable beverages, but is not limited thereto. These components may be used independently or in combination. The proportion of the above additives is not particularly limited, but is preferably included within the range of 0.01 to 0.1 wt% with respect to the total weight of the food composition of the present invention.

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

These examples are intended solely to illustrate the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

[Example 1]

Manufacturing of animal models of depression

Before stress induction for the production of an animal model of depression (RS), male C57BL/6 7-week-old mice were acclimatized to the breeding space for 1 week and then randomly divided into 4 groups of 10 mice each as follows.

Group 1: Control group (unstressed group)

Group 2: Stress + no drug administration group

Group 3: Stress + rilmenidine 0.03 mg/kg

Group 4: Stress + rilmenidine 0.3 mg/kg

For the following 10 days, the experimental animals were placed in 50-mL conical tubes (polypropylene conical tubes) and subjected to restraint stress for 2 hours per day. Stress was administered for 10 days, and rilmenidine was administered intraperitoneally 1 hour before stress once a day for 6 to 10 days. Rilmenidine was administered intraperitoneally at a dose of 0.03 mg/kg or 0.3 mg/kg, and 0.25% DMS0 was administered intraperitoneally to Groups 1 and 2.

Next, a behavioral experiment was conducted to confirm the onset of depression from the 11th to the 13th day after stress was administered.

[Example 2]

Confirmation of the effect of relmenitine on improving depression

2-1: Forced swimming experiment

The forced swim test is the most widely performed experimental method for evaluating despair symptoms among depressive behaviors in rodents. A cylinder with a diameter of 15 cm and a height of 25 cm is filled with water at 25±1℃ to a depth of 16 cm, and the experimental animal is placed one by one for the 6-minute experiment. The first 2 minutes of the total 6 minutes are considered an adaptation period and are excluded from the measurement method. The immobility time of the experimental rats is measured for the remaining 4 minutes to evaluate despair symptoms.

As a result, as shown in Fig. 1, immobility time was reduced by rilmenidine administration, indicating the antidepressant effect of rilmenidine.

2-2: Object recognition memory experiment

The object recognition memory experiment is an experiment conducted to evaluate the cognitive ability of rodents and is conducted in three stages.

1) Habituation (spatial adaptation stage)

① One hour before conducting the experiment, acclimatize the experimental animals in the behavioral laboratory.

② Place the experimental animal in the OFT box and allow it to adapt to the space for 10 minutes.

2) Familiarization (object adaptation stage, performed 24 hours after performing the first test - time can be adjusted)

① One hour before conducting the experiment, acclimatize the experimental animals in the behavioral laboratory.

② Place the same object in the OFT box.

③ Place the experimental animal in the OFT box and acclimate it to the object for 10 minutes.

3) Test (This experimental stage, conducted 4 hours after performing step 2 - time can be adjusted)

① One hour before conducting the experiment, acclimatize the experimental animals in the behavioral laboratory.

② Place another object in the OFT box.

③ Place the experimental animal in the OFT box and conduct the experiment for 10 minutes.

The cognitive and discrimination indices of rodents were evaluated as the ratio of the time spent exploring a novel object (T _n ) to the time spent exploring a familiar object (T _f ): [(T n - T f)/(T n + T f)]

As a result, as shown in Fig. 2, it was confirmed that the discrimination index was improved by rilmenidine administration, indicating the cognitive function and memory improvement effect of rilmenidine.

Claims (8)

A pharmaceutical composition for preventing or treating emotional disorders, comprising rilmenidine or a pharmaceutically acceptable salt thereof represented by the following chemical formula 1 as an active ingredient: [Chemical Formula 1] . In the first paragraph, A pharmaceutical composition for preventing or treating emotional disorders, characterized in that the emotional disorders are depression, bipolar disorder, seasonal affective disorder, or panic disorder. In the first paragraph, A pharmaceutical composition for preventing or treating emotional disorders, characterized in that the daily dosage of the above-mentioned rilmenidine or a pharmaceutically acceptable salt thereof is 0.01 mg/kg (body weight) to 10 mg/kg (body weight). A composition for a health functional food for preventing or improving emotional disorders, comprising rilmenidine or a pharmaceutically acceptable salt thereof represented by the following chemical formula 1 as an active ingredient: [Chemical Formula 1] . In paragraph 4, A composition for health functional food for preventing or improving emotional disorders, characterized in that the emotional disorders are depression, bipolar disorder, seasonal affective disorder, or panic disorder. In paragraph 4, A composition for a health functional food for preventing or improving emotional disorders, characterized in that the daily dosage of the above-mentioned rilmenidine or a pharmaceutically acceptable salt thereof is 0.01 mg/kg (body weight) to 10 mg/kg (body weight). A method for preventing or treating emotional disorders, comprising administering or ingesting to a subject a pharmaceutical composition comprising rilmenidine or a pharmaceutically acceptable salt thereof represented by the following chemical formula 1 as an active ingredient: [Chemical Formula 1] . Use of a pharmaceutical composition comprising rilmenidine or a pharmaceutically acceptable salt thereof represented by the following chemical formula 1 as an active ingredient for preventing or treating emotional disorders: [Chemical Formula 1] .