WO2020067748A1 - Composition having anti-stress, anti-depressant or anxiolytic effect comprising at least one compound selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof as active ingredient - Google Patents

Abstract

The present invention relates to a composition having an anti-stress, anti-depressant or anxiolytic effect, which includes, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof. Since the composition of the present invention has an excellent anti-stress, anti-depressant or anxiolytic effect, the composition may be effectively used as a pharmaceutical composition, a quasi-drug composition, a cosmetic composition, and a health functional food composition.

Description

COMPOSITION HAVING ANTI-STRESS, ANTI-DEPRESSANT OR ANXIOLYTIC EFFECT COMPRISING AT LEAST ONE COMPOUND SELECTED FROM THE GROUP CONSISTING OF UNDECANAL, DODECANAL, AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS ACTIVE INGREDIENT

This application claims priority to and the benefit of Korean Patent Application No. 10-2018-0116497, filed on September 28, 2018, the disclosure of which is incorporated herein by reference in its entirety.

The present invention relates to a composition having an anti-stress, anti-depressant or anxiolytic effect, which includes, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

Stress is an adaptive response of the body to internal/external stressors or triggers, and is medically defined as a harmful stimulus that promotes the secretion of adrenocorticotropic hormone. The term "stress" has been used since 1936, when Canadian physiologist Dr. H. Selye published "Stress Theory" in the magazine Nature.

Stimuli that cause stress are classified into physical, psychological, and physiological stimuli. Physical stimuli refer to temperature, ultraviolet rays, and the like which exist in nature, psychological stimuli refer to mental pain, anger, anxiety, tension, and the like, and physiological stimuli refer to bacteria or viruses, allergens, and the like. In particular, repeated symptoms such as depression, anxiety, insomnia, loss of appetite, and the like, which are caused by psychological stimulation, cause the onset of diseases such as depression, anxiety, and sleep disorders. Depression is a condition that causes a variety of cognitive, mental or physical symptoms, including main symptoms such as decreased motivation and depression, leading to daily dysfunction, makes it difficult to lead a daily life due to overall dysfunction in thinking processes, motivation, desire, behavior, sleep, and the like, and highly associated with a prevalence and a suicide rate. Anxiety is a mental disorder that usually shows persistent, unrecoverable neurological hypersensitivity, tension, anxiety, and the like over six months, with extreme anxiety over every minor event for no particular reason. Sleep disorders include psychotic symptoms such as self-deconstruction, hallucinations, delusions, and the like, and it has been reported that as a result of conducting sleep deprivation experiments on mice, symptoms such as systemic weakness, skin disease, weight loss, increased energy consumption, decreased body temperature, and the like occur, and in severe cases, it leads to death.

Excessive mental stress causes hormones to be secreted into the blood through the circulation system leading to the hypothalamic-pituitary-adrenal axis (HPA axis). In the hypothalamus of the brain, a corticotropin releasing factor (CRF) is produced, which binds to the CRF receptor expressed in the pituitary gland and releases adrenocorticotropic hormone (ACTH). ACTH arrives at the adrenal glands through the blood and lymph nodes to promote the secretion of glucocorticoids such as cortisol and the like, and the glucocorticoids secreted into the blood are delivered to each organ of the body.

Cortisol is a stress hormone among steroid hormones that prepares the human body to cope with mental stress by straining the muscles and making the sensory organs sensitive. Meanwhile, continuous secretion of the cortisol hormone due to repetitive mental stress raises its blood levels, keeps the body constantly tense and disturbs sleep, leading to sleep disorders. This, in turn, causes mental stress, causing a vicious cycle of depressive symptoms. It has been reported that loss of cortisol secretion control by extreme mental stress results in excessive secretion of cortisol, leading to brain atrophy and damage throughout the nervous system, resulting in severe depression symptoms and the possibility of suicide.

In mice in which the CRF gene is overexpressed, anxiety- and depression-like behaviors are increased and investigatory behaviors are reduced. It is reported that it may be involved in emotional disorders and cause Cushing's syndrome. It also shows physical changes such as excessive fat accumulation, muscle atrophy, thin skin, hair loss, and the like, and raises plasma levels of ACTH and cortisol. These symptoms are reported to be alleviated by the administration of CRF antagonists.

Meanwhile, in relation to the development of antistress agents, although the market for early stress recovery dietary supplements has been led by St. John's wort (the effect of alleviating depression and anxiety disorders) and Valerian (sedation and sleep improvement), the rapid expansion of the anti-stress market has recently led to the development of new anti-stress substances. However, only a few counterparts such as GABA, Theanine, phosphatidyl serine, and the like have been proposed, and new products are being developed by combining one or more of the five anti-stress substances.

Antidepressants are drugs that induce a therapeutic effect through a temporary mood-changing effect by increasing serotonin concentration and activity in the blood through the inhibition of resorption of serotonin secreted from the nerve cell ends into presynaptic cells, and examples thereof include Prozac, Celexa, and the like which are sold under US FDA approval. However, in the case of such serotonin reuptake inhibitors, only about half of patients show symptomatic improvement and a minimum duration of 4 months or longer is required, and depending on patients, there is a problem of continuing to take such a drug for 2 to 3 years. In addition, in the case of these serotonin reuptake inhibitors, it is known that the recurrence of most symptoms was observed within 6 months to 12 months when the drug was stopped, and side effects are also severe. As anti-anxiety drugs, the benzodiazepine series such as diazepam, lorazepam, clonazepam, alprazolam, and the like is mainly used, and drugs of the imidazopyridine family, such as zolpidem, are also used to treat short-term insomnia due to anxiety. However, drugs used for anxiety disorders and mental disorders act directly on the gamma-aminobutyric acid (GABA) receptors of the central nervous system, which inhibits the central nervous system, resulting in excessive sedation and reinforced central suppression such as depression, muscle relaxation, hypnosis, and the like. In addition, drugs used for anxiety disorders and mental disorders cause psychological and physical dependence, leading to risks of drug abuse and the like.

Undecanal is an aldehyde-based compound having a structural formula of C₁₁H₂₂O and a molecular weight of 170.3 g/mol. Undecanal is also called different names such as undecanaldehyde, N-undecanal, undecyl aldehyde, undecylic aldehyde, and the like. Undecanal is a pale yellow transparent liquid component having a melting point of -3 ℃ and a boiling point of 223 ℃.

Undecanal is a fragrance component that is mainly contained in Coriander leaf, cerastium candidissimum, herniaria incana, and the like, and smells and feels soapy, waxy, and aldehydic. Undecanal is mainly used as a fragrance ingredient of a flavoring agent, an air freshener, a cleansing agent, a detergent, and the like, and has been approved to be safe as a flavoring agent and a food additive by the Flavor and Extract Manufacturers Association (FEMA) and the Joint FAO/WHO Expert Committee on Food Additives (JECFA), respectively.

According to studies on the physiological activity of undecanal, effects such as anti-inflammation, antioxidant activity, antimicrobial activity, and the like have been reported. However, there have been no reports of a stress-related effect.

According to a report, an LD₅₀ (lethal dose, 50%) value > 5,000 mg/kg bw/day was exhibited when undecanal was acutely administered orally to rats, and a no observed adverse effect level (NOAEL) was about 1000 mg/kg bw upon chronic oral administration of undecanal, which indicates that it is relatively safe.

[Molecular Structure of Undecanal]

In addition, dodecanal is an aldehyde-based compound having a structural formula of C₁₂H₂₄O and a molecular weight of 184.3 g/mol. Dodecanal is also referred to with different names such as lauraldehyde, dodecyl aldehyde, lauric aldehyde, lauryl aldehyde, and the like. Dodecanal is a pale yellow transparent liquid component with a melting point of 3 ℃ and boiling point of 185 ℃.

Dodecanal is a fragrance component that is mainly contained in Coriandrum sativum (Coriander leaf), Citrus sinensis (Orange), and Piper betle (Betel leaf), and very strongly smells and feels soapy, waky, and aldehydic. Dodecanal is mainly used as a fragrance ingredient of a flavoring agent, an air freshener, a cleansing agent, a detergent, and the like, is listed as a material suitable for use as a flavoring agent in the Food and Drug Administration (FDA) and Korea Food and Drug Administration (KFDA) food additive databases, and is approved to be safe as a flavoring agent and a food additive in the Flavor and Extract Manufacturers Association (FEMA) and the Joint FAO/WHO Expert Committee on Food Additives (JECFA), respectively.

Studies on the physiological activity of dodecanal have been mainly conducted on its role as an arachidonate 5-lipoxygenase inhibitor. Arachidonate 5-lipoxygenase is a non-heme iron-containing enzyme that converts EFA substrates into leukotrienes, and since the overproduction of leukotriene is a cause of asthma and allergic rhinitis, dodecanal is known to play a role in interfering with the production of inflammatory leukotrienes. However, there have been no reports of a stress-related effect.

According to a report, an LD₅₀ (lethal dose, 50%) value was 23,000 mg/kg bw/day when dodecanal was acutely administered orally to rats, and a no observed adverse effect level (NOAEL) was about 1400 mg/kg bw upon chronic oral administration of dodecanal, which indicates that it is relatively safe.

[Molecular Structure of Dodecanal]

References

Korean Patent Publication No. 10-2017-0129194

The present invention has been made to address the above-described problems, and an object of the present invention is to provide a pharmaceutical composition having an anti-stress, anti-depressant or anxiolytic effect, the pharmaceutical composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a quasi-drug composition having an anti-stress, anti-depressant or anxiolytic effect, the quasi-drug composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

Still another object of the present invention is to provide a cosmetic composition having an anti-stress, anti-depressant or anxiolytic effect, the cosmetic composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

Yet another object of the present invention is to provide a health functional food having an anti-stress, anti-depressant or anxiolytic effect, the health functional food including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

However, technical problems to be achieved by the present invention are not limited to the above-described technical problems, and other unmentioned technical problems will become apparent from the following description to those of ordinary skill in the art.

The present invention provides a pharmaceutical composition having an anti-stress, anti-depressant or anxiolytic effect, the pharmaceutical composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The pharmaceutical composition may be formulated into any one preparation selected from the group consisting of tablets, powders, capsules, pills, granules, suspensions, emulsions, syrups, aerosols, preparations for external application, suppositories, liquids, and injections.

The present invention also provides a quasi-drug composition having an anti-stress, anti-depressant or anxiolytic effect, the quasi-drug composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The present invention also provides a cosmetic composition having an anti-stress, anti-depressant or anxiolytic effect, the cosmetic composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The cosmetic composition may be formulated into any one preparation selected from the group consisting of a skin lotion, a skin softener, a skin toner, an astringent, a lotion, a milk lotion, a moisturizing lotion, a nourishing lotion, a massage cream, a nourishing cream, a moisturizing cream, a hand cream, an essence, a pack, a mask pack, a mask sheet, an exfoliant, a soap, a shampoo, a cleansing foam, a cleansing lotion, a cleansing cream, a body lotion, a body cleanser, an emulsion, a pressed powder, a loose powder, and an eye shadow.

The present invention also provides a health functional food having an anti-stress, anti-depressant or anxiolytic effect, the health functional food including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The present invention also provides a method of preventing or treating stress, depression, or anxiety, including administering a composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof or allowing it to be taken, to a subject.

The present invention also provides a use of a composition for an anti-stress, anti-depressant or anxiolytic effect, the composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The present invention provides a composition having an anti-stress, anti-depressant or anxiolytic effect, the composition including, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The composition of the present invention has an excellent anti-stress, anti-depressant or anxiolytic effect, and thus can be effectively used as a pharmaceutical composition, a quasi-drug composition, a cosmetic composition, and a health functional food composition.

FIG. 1 illustrates the results of analyzing changes in behavioral indicators and plasma corticosterone indicators of undecanal-administered mice (for each value, mean ± standard deviation (n=4), *P < 0.05).

FIG. 2 illustrates the results of analyzing changes in behavioral indicators and plasma corticosterone indicators of dodecanal-administered mice (for each value, mean ± standard deviation (n=4), *P < 0.05).

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

As described above, it has been reported that undecanal or dodecanal has effects, such as anti-inflammation, antioxidant activity, antimicrobial activity, and the like, but there have been no reports of a stress-related effect.

Therefore, the present invention provides a pharmaceutical composition having an anti-stress, anti-depressant or anxiolytic effect, which includes, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The pharmaceutical composition may be formulated into any one preparation selected from the group consisting of tablets, powders, capsules, pills, granules, suspensions, emulsions, syrups, aerosols, preparations for external application, suppositories, liquids, and injections, but the present invention is not limited thereto.

The pharmaceutical composition may be used as a dermatologic composition. Specifically, the pharmaceutical composition may be prepared as a dermatologic agent having an anti-stress, anti-depressant or anxiolytic effect in the form of a cream, a gel, a patch, an aerosol, an ointment, a plaster, a lotion, a liniment, a paste, or a cataplasma, but the present invention is not limited thereto.

The undecanal and/or dodecanal of the present invention may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. The acid addition salt is obtained from: inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid, and phosphorous acid; or nontoxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkandioates, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples of these pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, methaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexane-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitro benzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzene sulfonates, toluene sulfonates, chlorobenzene sulfonates, xylenesulfonates, phenyl acetates, phenylpropionates, phenylbutyrates, citrates, lactates,　β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

Acid addition salts according to the present invention may be prepared using a conventional method, for example, by dissolving undecanal and/or dodecanal in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, e.g., methanol, ethanol, acetone, or acetonitrile. The acid addition salts may also be prepared by heating the same amount of undecanal (or dodecanal) and an acid or alcohol in water, and then evaporating and drying the resulting mixture or suction-filtering the precipitated salt.

In addition, pharmaceutically acceptable metallic salts may be prepared using bases. Alkali metal or alkaline earth metal salts are obtained by, for example, dissolving a compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering a non-soluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically preferable that a sodium salt, a potassium salt, or a calcium salt is prepared as a metal salt. In addition, silver salts corresponding thereto may be obtained by reacting an alkali metal or an alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

In addition, the undecanal and/or dodecanal of the present invention may include not only pharmaceutically acceptable salts thereof, but also all salts, hydrates, and solvates that may be prepared using general methods.

Addition salts according to the present invention may be prepared using general methods, for example, by dissolving undecanal and/or dodecanal in a water-miscible organic solvent, e.g., acetone, methanol, ethanol, acetonitrile, or the like, adding an excess of an organic acid or an aqueous inorganic acid solution thereto, and then precipitating or crystallizing the resulting solution. Subsequently, the solvent or the excess of the acid may be evaporated from the mixture, followed by drying, thereby obtaining an addition salt, or the precipitated salt may be subjected to suction filtration.

In a case in which the composition of the present invention is used as a drug, the pharmaceutical composition including undecanal and/or dodecanal and/or a pharmaceutically acceptable salt(s) thereof as an active ingredient(s) may be formulated into various dosage forms for oral or parenteral administration, which will be described below, when clinically administered, but the present invention is not limited thereto.

Examples of preparations for oral administration include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, and the like. These preparations include, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine), and a lubricant (e.g., silica, talc, stearic acid and magnesium or calcium salts thereof, and/or polyethylene glycol). Tablets may include a binder such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone, and in some cases, may include a disintegrating agent such as starch, agar, alginic acid or sodium salts thereof, or a boiling mixture and/or an absorbent, a coloring agent, a flavoring agent, and a sweetening agent.

The pharmaceutical composition including undecanal and/or dodecanal and/or a pharmaceutically acceptable salt(s) thereof as an active ingredient(s) may be administered parenterally, and parenteral administration is performed via subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this regard, to formulate preparations for parenteral administration, the pharmaceutical composition including undecanal and/or dodecanal and/or a pharmaceutically acceptable salt(s) thereof may be mixed with a stabilizer or a buffer in water to prepare a solution or a suspension, followed by preparation into an ampoule or vial unit dosage form. The composition may be sterilized and/or include an adjuvant such as a preservative, a stabilizer, wettable powder, an emulsifying agent, a salt for the control of osmotic pressure, and/or a buffer, and other therapeutically effective materials, and may be formulated using a conventional method, such as mixing, granulation, or coating.

In addition, a dose of the composition of the present invention, which is to be administered to the human body, may vary depending on the age, body weight, and gender of patients, administration forms, health conditions, and the severity of diseases, and may generally range from 0.001 mg/day to 1,000 mg/day, preferably 0.01 mg/day to 500 mg/day, with respect to an adult patient with a body weight of 60 kg, and the composition of the present invention may also be administered once a day or in multiple doses at regular intervals in accordance with the prescription of a doctor or a pharmacist.

The present invention also provides a quasi-drug composition having an anti-stress, anti-depressant or anxiolytic effect, which includes, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

When the undecanal and/or dodecanal of the present invention are/is used as an active ingredient(s) of the quasi-drug composition, undecanal and/or dodecanal may be directly added, or may be used in combination with other quasi-drugs or quasi-drug ingredients, and may be appropriately used according to a general method. Mixing amounts of the active ingredients may be appropriately determined according to the purpose of use.

The quasi-drug composition having an anti-stress, anti-depressant or anxiolytic effect of the present invention is not particularly limited in terms of a preparation thereof, and may be variously formulated into the form of quasi-drugs known in the art.

The quasi-drug composition may be formulated into a preparation such as granules, powder, a solution, a cream, an ointment, an aerosol, a paste, a gel, a wax, or the like, and the solution may include not only a solution state in which the active ingredient is dissolved in a solvent, but also include a suspension or emulsion state.

Examples of the formulated quasi-drugs include a hair tonic, a hair lotion, a hair cream, a hair spray, a hair mousse, a hair gel, a hair conditioner, a hair shampoo, a hair rinse, a hair pack, a hair treatment, a hand cleaner, a detergent soap, a soap, a disinfectant cleaner, wet tissue, a mask, an ointment, a patch, a filter filler, and the like, and include all quasi-drugs in a general sense.

In addition, for each preparation, the quasi-drug composition having an anti-stress, anti-depressant or anxiolytic effect may be mixed with other ingredients arbitrarily selected according to the preparations of other quasi-drugs, the purpose of use, or the like. Mixing amounts of the active ingredients may be appropriately determined according to the purpose of use, and the composition may include, for example, general adjuvants such as a thickener, a stabilizer, a solubilizing agent, vitamins, a pigment, and a flavor, a carrier, and the like.

The amount of the active ingredient may range from 0.0001 wt % to 10 wt % with respect to a total weight of the composition. When the amount of the active ingredient is greater than 10 wt %, stability deteriorates in preparation of the composition, and when the amount of the active ingredient is less than 0.0001 wt %, effects thereof are insignificant. The quasi-drug composition including undecanal and/or dodecanal as an active ingredient(s) of the present invention has little cytotoxicity and almost no side effects on cells, and thus may be effectively used as a quasi-drug material.

The present invention also provides a cosmetic composition having an anti-stress, anti-depressant or anxiolytic effect, which includes, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

In addition to undecanal and/or dodecanal and/or a pharmaceutically acceptable salt(s) thereof, the cosmetic composition of the present invention includes, as active ingredients, ingredients commonly used in cosmetic compositions, such as general adjuvants such as antioxidant, a stabilizer, a solubilizing agent, vitamins, a pigment, and a flavor, and a carrier.

The cosmetic composition of the present invention may be prepared into any formulation commonly prepared in the art, and may be formulated into, for example, a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, powder, a soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, spray, and the like, but the present invention is not limited thereto.

For paste, cream, or gel preparations of the present invention, as a carrier ingredient, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, or the like may be used.

For powder or spray preparations of the present disclosure, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier ingredient. In particular, in the case of spray preparations, the composition may further include a propellant such as a chlorofluorohydrocarbon, propane/butane, or dimethyl ether.

For solution or emulsion preparations of the present disclosure, a solvent, a solubilizing agent, or an emulsifying agent may be used as a carrier ingredient, and the carrier ingredient may be, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, a glycerol aliphatic ester, polyethylene glycol, or a sorbitan fatty acid ester.

For suspension preparations of the present invention, as a carrier ingredient, a liquid diluent such as water, ethanol, or propylene glycol, a suspension agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, or polyoxyethylene sorbitan ester, micro-crystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, or the like may be used.

For surfactant-containing cleansing preparations of the present disclosure, as a carrier ingredient, an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinate monoester, isethionate, imidazolinium derivatives, methyltaurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, an aliphatic alcohol, a fatty acid glyceride, a fatty acid diethanol amide, vegetable oil, a lanolin derivative, an ethoxylated glycerol fatty acid ester, or the like may be used.

The present invention also provides a health functional food composition having an anti-stress, anti-depressant or anxiolytic effect, which includes, as an active ingredient, at least one selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

The food composition according to the present invention may be prepared into various forms according to a general method known in the art. The food composition may be prepared by adding the undecanal and/or dodecanal of the present invention to general foods which include, but are not limited to, beverages (including alcoholic beverages), fruits and processed foods thereof (e.g., canned fruits, bottled foods, jam, marmalade, and the like), fish, meat and processed foods thereof (e.g., ham, sausage, corn, beef, and the like), bread and noodles (e.g., Japanese-style noodles, buckwheat noodles, ramen, spaghetti, macaroni, and the like), fruit juices, various drinks, cookies, taffy, dairy products (e.g., butter, cheese, and the like), edible vegetable oils, margarine, vegetable proteins, retort foods, frozen foods, various seasonings (e.g., soybean paste, soy sauce, other sauces, and the like), and the like. In addition, the food composition may be prepared by adding the undecanal and/or dodecanal of the present invention to nutritional supplements, which include, but are not limited to, capsules, tablets, pills, and the like. In addition, the health functional foods may include, but are not limited to, for example, the undecanal and/or dodecanal of the present invention itself which is prepared in the form of tea, juice, and drink and is liquefied, granulated, capsulated, and powdered for drinking (health beverages). In addition, the undecanal and/or dodecanal of the present invention may be prepared in the form of powder or a concentrated liquid to be used as a food additive. In addition, the food composition may be prepared in the form of a composition by mixing the undecanal and/or dodecanal of the present invention with a known active ingredient known to have an anti-stress, anti-depressant or anxiolytic effect.

When the undecanal and/or dodecanal of the present invention is used as a health beverage, the health beverage composition may include, as additional ingredients, various flavoring agents, natural carbohydrates, and the like as in general beverages. Examples of the above-described natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugar alcohols such as xylitol, sorbitol, erythritol, and the like. As sweeteners, natural sweeteners such as thaumatin and stevia extracts; synthetic sweeteners such as saccharin and aspartame; and the like may be used. The proportion of the natural carbohydrates may generally range from about 0.01 g to about 0.04 g, preferably about 0.02 g to about 0.03 g, with respect to 100 mL of the composition of the present invention.

In addition, the undecanal and/or dodecanal of the present invention may be included as an active ingredient of a health functional food having an anti-stress, anti-depressant or anxiolytic effect, and a dose thereof is an effective amount for achieving an anti-stress, anti-depressant or anxiolytic effect and may range, but is not particularly limited, from 0.01 wt% to 100 wt% with respect to a total weight of the composition. The food composition of the present invention may be prepared by mixing undecanal and/or dodecanal with other active ingredients known to have an anti-stress, anti-depressant or anxiolytic effect.

In addition to the above ingredients, the health food of the present invention may include various nutrients, vitamins, electrolytes, a flavoring agent, a colorant, pectic acid and a salt thereof, alginic acid and a salt thereof, organic acids, a protective colloidal thickening agent, a pH adjusting agent, a stabilizer, a preservative, glycerin, alcohols, carbonating agents, or the like. In addition, the health food of the present invention may include pulp for preparing natural fruit juices, fruit beverages, or vegetable beverages. These ingredients may be used alone or a mixture of these ingredients may be used. The proportion of such additives is not very important, but is generally selected from the range of 0.01 part by weight to 0.1 part by weight with respect to 100 parts by weight of the composition of the present invention.

Hereinafter, the present invention will be described in further detail with reference to the following examples. The objects, features, and advantages of the present invention will be readily understood with reference to the following examples. The present invention is not limited to the examples described herein and may be embodied in other forms. The examples introduced herein are provided to fully convey the spirit of the present invention to those of ordinary skill in the art to which the present invention pertains. Therefore, the following examples should not be intended to limit the present invention.

<Examples>

Confirmation of Anti-stress, Anti-depressant or Anxiolytic Effect through Single Administration of Undecanal or Dodecanal in Wild-type Mice

Experimental Methods

1) Experimental Animals and Experimental Diets

① Regarding Undecanal

8-week-old male C57BL/6 mice used as experimental animals were purchased from OrientBio Inc., (143-1, Sangdaewon-dong, Jungwon-gu, Seongnam-city, Gyeonggi-do). The experimental animals were subjected to an adaptation period of 1 week in a rearing room, and then divided into a control (CON, n=4) and an undecanal-administered group (n=4). For the control and the undecanal-administered group, olive oil and undecanal (8 mg/kg body weight) dissolved in olive oil were respectively intraperitoneally administered once 30 minutes before an experiment for stress behavioral indicators. The used olive oil and undecanal were purchased from Sigma-Aldrich (Missouri, USA). The experimental animals were raised in a space where a temperature of 23±1℃, a humidity of about 50±10%, and 12 hour light/dark cycles were constantly maintained, and were allowed to freely eat Chow (OrientBio) and drink drinking water.

② Regarding Dodecanal

8-week-old male C57BL/6 mice used as experimental animals were purchased from OrientBio Inc., (143-1, Sangdaewon-dong, Jungwon-gu, Seongnam-city, Gyeonggi-do). The experimental animals were subjected to an adaptation period of 1 week in a rearing room, and then divided into a control (CON, n=4) and a dodecanal-administered group (n=4). For the control and the dodecanal-administered group, olive oil and dodecanal (8 mg/kg body weight) dissolved in olive oil were respectively intraperitoneally administered once 30 minutes before an experiment for stress behavioral indicators. The used olive oil and dodecanal were purchased from Sigma-Aldrich (Missouri, USA). The experimental animals were raised in a space where a temperature of 23±1℃, a humidity of about 50±10%, and 12 hour light/dark cycles were constantly maintained, and were allowed to freely eat Chow (OrientBio) and drink drinking water.

2) Measurement of Behavioral Indicators of Anti-stress, Anti-depressant or Anxiolytic Effect of Undecanal or Dodecanal

2-1) Tail Suspension Test (TST)

A tail suspension test was conducted using a method of Steru et al., (1985). After attaching a fixing device to about 1 cm from the tail end of each laboratory mouse, each mouse was hung at a position 50 cm away from the ground, and for behavioral patterns, the immobility time of each experimental animal was measured using a video tracking system (smart v.2.5.21). A case in which the mice were completely stopped without any movement in the suspended state was regarded as an immobility state, and after an adaptation period of 2 minutes, the state of each mouse was measured for 4 minutes. Generally, when a mouse gets stress, the mouse is more likely to have anxiety and depression and is less likely to move, and therefore, a shorter immobility time of mice was regarded as having an anti-stress, anti-depressant or anxiolytic effect.

2-2) Forced Swimming Test (FST)

For a forced swimming test, a method of Porsolt et al., (1997) was used. A water tank having a height of 40 cm and a diameter of 20 cm was filled with water at a temperature of 25 ± 1 ℃ up to a height of 30 cm, and then each laboratory mouse was placed in the water tank and the immobility time of each laboratory mouse was measured using a video tracking system (smart v.2.5.21). A case where the mouse floated without any movement, standing upright with only its face above the surface of the water was regarded as an immobility state, and after an adaptation period of 2 minutes, the state of each mouse was measured for 4 minutes. Generally, when a mouse gets stress, the mouse is more likely to have anxiety and depression and is less likely to move, and therefore, a shorter immobility time of mice was regarded as having an anti-stress, anti-depressant or anxiolytic effect.

2-3) Open Field Test (OFT)

For an open field test, a method of Noldus et al., (2001) was used. Mice with stress having been induced through the forced swimming test were placed in a white acrylic box with a size of 50 cm x 50 cm x 50 cm. Subsequently, an area with a size of 30 cm x 30 cm at the center of a field was set as a central zone, and after an adaptation period of 2 minutes, the time each laboratory mouse stayed in the central zone was measured for 8 minutes using a video tracking system (smart v.2.5.21). Generally, when a mouse gets stress, the mouse is more likely to have anxiety, and thus the time each mouse stays in the central zone inside the open field decreases and the time each mouse stays on the edge side thereof increases, and therefore, a longer period of time each mouse stayed in the central zone was regarded as having an anti-stress, anti-depressant or anxiolytic effect.

3) Measurement of Plasma Corticosterone Concentration

After the tests for stress behavioral indicators were completed, each mouse was anesthetized with avertin and blood was collected from each mouse. Blood having been collected from the abdominal aorta was centrifuged at 2000 xg for 15 minutes to separate plasma. The plasma corticosterone concentration was measured using an EIA kit, which is generally used (Corticosterone EIA kit, Enzo Life Sciences, NY, USA). Basic experimental methods were performed in accordance with the manufacturer's instructions. Since an increase in the secretion of corticosterone is a typical symptom of stress, a lower plasma corticosterone concentration was regarded as having an anti-stress, anti-depressant or anxiolytic effect.

4) Statistical Processing

Statistical analysis of all data was carried out using a SPSS (Statistical Package for the Social Sciences version 21.0, IBM, Armonk, NY, USA) PC package, and analysis values were expressed as mean ± SEM. An independent sample t-test was conducted to verify a significant difference between groups (*P < 0.05).

Example 1: Behavioral Test Results of Anti-stress, Anti-depressant or Anxiolytic Effect of Undecanal

1) Measurement of Behavioral Indicators of Anti-stress, Anti-depressant or Anxiolytic Effect

1-1) Tail Suspension Test (TST)

It could be confirmed that a significant reduction (-34%) in immobility time was exhibited in the undecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of undecanal (see FIG. 1A).

1-2) Forced Swimming Test (FST)

It could be confirmed that a significant reduction (-34%) in immobility time was exhibited in the undecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of undecanal (see FIG. 1B).

1-3) Open Field Test (OFT)

It could be confirmed that a significant increase (+42%) in the time each mouse spent in the central zone was exhibited in the undecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of undecanal (see FIG. 1C).

2) Plasma Corticosterone Concentration Results

It could be confirmed that a significant decrease (-32%) in plasma corticosterone concentration was exhibited in the undecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of undecanal (see FIG. 1D).

Example 2: Behavioral Test Results of Anti-stress, Anti-depressant or Anxiolytic Effect of Dodecanal

1) Measurement of Behavioral Indicators of Anti-stress, Anti-depressant or Anxiolytic Effect

1-1) Tail Suspension Test (TST)

It could be confirmed that a significant reduction (-25%) in immobility time was exhibited in the dodecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of dodecanal (see FIG. 2A).

1-2) Forced Swimming Test (FST)

It could be confirmed that a significant reduction (-21%) in immobility time was exhibited in the dodecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of dodecanal (see FIG. 2B).

1-3) Open Field Test (OFT)

It could be confirmed that a significant increase (+31%) in the time each mouse spent in the central zone was exhibited in the dodecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of dodecanal (see FIG. 2C).

2) Plasma Corticosterone Concentration Results

It could be confirmed that a significant decrease (-21%) in plasma corticosterone concentration was exhibited in the dodecanal group compared to the control (CON), from which it was confirmed that an anti-stress, anti-depressant or anxiolytic effect was exhibited via the administration of dodecanal (see FIG. 2D).

Hereinafter, preparation examples of medicines, foods, or cosmetics including undecanal or dodecanal according to the present invention as an active ingredient will be described, but these examples are provided for illustrative purposes only and are not intended to limit the present invention. Pharmaceutical preparations, foods, or cosmetic compositions of Preparation Examples 1 to 4 were prepared according to a general method using the ingredients having an excellent anti-stress, anti-depressant or anxiolytic effect, in accordance with the ingredients and composition ratios as described below.

Preparation Example 1. Preparation of Pharmaceutical Preparations

1-1. Preparation of Powder

Undecanal or dodecanal of the present invention 0.1 g

Lactose 1.5 g

Talc 0.5 g

The above ingredients were mixed and put into an airtight bag, thereby completing the preparation of powder.

1-2. Preparation of Tablets

Undecanal or dodecanal of the present invention 0.1 g

Lactose 7.9 g

Crystalline cellulose 1.5 g

The above ingredients were mixed and then tablets were prepared using a direct tableting method.

1-3. Preparation of Capsules

Undecanal or dodecanal of the present invention 0.1 g

Corn starch 5 g

Carboxycellulose 4.9 g

The above ingredients were mixed to prepare powder, and then a hard capsule was filled with the powder according to a general capsule preparation method, thereby completing the preparation of capsules.

1-4. Preparation of Injections

Undecanal or dodecanal of the present invention 0.1 g

Sterile distilled water for injection appropriate amount

pH adjusting agent appropriate amount

An injection was prepared in the above-described content per 1 ampoule (2 ml) according to a general injection preparation method.

1-5. Preparation of Liquids

Undecanal or dodecanal of the present invention 0.1 g

Isomerized sugar 10 g

Mannitol 5 g

Purified water appropriate amount

The above ingredients were added to purified water and dissolved therein according to a general liquid preparation method, and an appropriate amount of a lemon flavor was added thereto, and then the ingredients were mixed. Thereafter, purified water was added to the mixture to adjust a total amount to 100 wt%, and then a brown vial was filled with the resulting mixture and sterilized, thereby completing the preparation of a liquid.

Preparation Example 2. Preparation of Health Food

2-1. Preparation of Wheat Flour Foods

0.5 part by weight to 5.0 parts by weight of undecanal or dodecanal of the present invention was added to wheat flour and mixed, and bread, cakes, cookies, crackers, and noodles were prepared using the mixture.

2-2. Preparation of Soups and Gravies

0.1 part by weight to 5.0 parts by weight of undecanal or dodecanal of the present invention was added to soup or gravy and used to prepare processed meat products for health promotion, and soups and gravies of noodles.

2-3. Preparation of Ground Beef

10 parts by weight of undecanal or dodecanal of the present invention was added to ground beef to prepare ground beef for health promotion.

2-4. Preparation of Dairy Products

5 parts by weight to 10 parts by weight of undecanal or dodecanal of the present invention was added to milk, and the milk was used to prepare various dairy products such as butter and ice cream.

2-5. Preparation of Health Supplement Foods

Undecanal or dodecanal of the present invention 100 mg

Vitamin mixture appropriate amount

Vitamin A acetate 70 μg

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

Vitamin B12 0.2 μg

Vitamin C 10 mg

Biotin 10 μg

Nicotinic acid amide 1.7 mg

Folic acid 50 μg

Calcium pantothenate 0.5 mg

Mineral mixture appropriate amount

Ferrous sulfate 1.75 mg

Zinc oxide 0.82 mg

Magnesium carbonate 25.3 mg

Monobasic potassium phosphate 15 mg

Dibasic Calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although ingredients relatively suitable for use in health foods are mixed in the above-described composition ratio of the vitamin and mineral mixture as an exemplary embodiment, the mixing ratio may be arbitrarily varied. In addition, the above-listed ingredients may be mixed according to a general method of preparing a health functional food, and then prepared into granules, which may then be used for the preparation of a health functional food composition according to a general method.

Preparation Example 3. Preparation of Health Drinks

Undecanal or dodecanal of the present invention 100 mg

Citric acid 100 mg

Oligosaccharide 100 mg

Green plum concentrate 2 mg

Taurine 100 mg

Purified water to total 500 ml

The above-listed ingredients are mixed according to a general method of preparing a health drink, the mixture is heated and stirred at 85 ℃ for 1 hour to prepare a solution, the solution is filtered, the filtrate is collected in a 1 L sterilized container and then sealed and sterilized, followed by refrigerated storage, which is then used for the preparation of a heath drink composition according to the present prevention.

Although ingredients relatively suitable for use in favorite beverages are mixed in the above-described composition ratio as an exemplary example, the mixing ratio may be arbitrarily varied depending on local and national preferences such as demand classes, demand countries, purposes of use, and the like.

Preparation Example 4. Preparation of Cosmetic Compositions

4-1. Face lotion (milk lotion)

A face lotion (milk lotion) including undecanal or dodecanal of the present invention may be prepared according to a general preparation method used in the cosmetic field by mixing the ingredients described below.

Ingredients to be mixed (wt%)

Undecanal or dodecanal of the present invention 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

Carboxyvinyl polymer 0.1

Triethanolamine 0.2

Preservative, pigment, fragrance appropriate amounts

Purified water to 100

4-2. Skin softener

A skin softener (skin lotion) including undecanal or dodecanal of the present invention may be prepared according to a general preparation method used in the cosmetic field by mixing the ingredients described below.

Ingredients to be mixed (wt%)

Undecanal or dodecanal of the present invention 2.0

Glycerin 3.0

Butylene glycol 2.0

Propylene glycol 2.0

Carboxyvinyl polymer 0.1

PEG12 nonylphenyl ether 0.2

Polysorbate 80 0.4

Ethanol 10.0

Triethanolamine 0.1

Preservative, pigment, fragrance appropriate amounts

Purified water to 100

4-3. Nourishing cream

A nourishing cream including undecanal or dodecanal of the present invention may be prepared according to a general preparation method used in the cosmetic field by mixing the ingredients described below.

Ingredients to be mixed (wt%)

Undecanal or dodecanal of the present invention 2.0

Polysorbate 60 1.5

Sorbitan sesquioleate 0.5

PEG60 hydrogenated castor oil 2.0

Squalane 5.0

Caprylic/capric triglyceride 5.0

Glycerin 5.0

Butylene glycol 3.0

Propylene glycol 3.0

Preservative, pigment, fragrance appropriate amounts

Purified water to 100

Claims (8)

1. A pharmaceutical composition having an anti-stress, anti-depressant or anxiolytic effect, the pharmaceutical composition comprising, as an active ingredient, one or more selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated into any one preparation selected from the group consisting of tablets, powders, capsules, pills, granules, suspensions, emulsions, syrups, aerosols, preparations for external application, suppositories, liquids, and injections.
3. A quasi-drug composition having an anti-stress, anti-depressant or anxiolytic effect, the quasi-drug composition comprising, as an active ingredient, one or more selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.
4. A cosmetic composition having an anti-stress, anti-depressant or anxiolytic effect, the cosmetic composition comprising, as an active ingredient, one or more selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.
5. The cosmetic composition of claim 4, wherein the cosmetic composition is formulated into any one preparation selected from the group consisting of a skin lotion, a skin softener, a skin toner, an astringent, a lotion, a milk lotion, a moisturizing lotion, a nourishing lotion, a massage cream, a nourishing cream, a moisturizing cream, a hand cream, an essence, a pack, a mask pack, a mask sheet, an exfoliant, a soap, a shampoo, a cleansing foam, a cleansing lotion, a cleansing cream, a body lotion, a body cleanser, an emulsion, a pressed powder, a loose powder, and an eye shadow.
6. A health functional food composition having an anti-stress, anti-depressant or anxiolytic effect, the health functional food composition comprising, as an active ingredient, one or more selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.
7. A method of preventing or treating depression or anxiety, the method comprising administering a composition comprising, as an active ingredient, one or more selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof, or allowing it to be taken, to a subject.
8. A use of a composition for anti-stress, anti-depression, or antianxiety, the composition comprising, as an active ingredient, one or more selected from the group consisting of undecanal, dodecanal, and pharmaceutically acceptable salts thereof.

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