KR20220102785A - A composition for preventing or improving circadian rhythm disorders comprising Andrographis paniculata plant extracts or andrographolide - Google Patents

Abstract

The present invention relates to a composition for preventing or alleviating circadian rhythm disorders, comprising an Andrographis paniculata extract or andrographolide as an active ingredient. The Andrographis paniculata extract or andrographolide increases the expression of circadian clock genes and strengthens the circadian rhythm from disturbance of the circadian clock caused by environmental hormones and thus can be usefully used as cosmetic and pharmaceutical compositions for preventing, improving, or treating circadian rhythm disorders.

Description

A composition for preventing or improving circadian rhythm disorders comprising an extract of Cheonsimryeon or andrographolide as an active ingredient {A composition for preventing or improving circadian rhythm disorders comprising Andrographis paniculata plant extracts or andrographolide}

The present invention relates to a composition for preventing and improving circadian rhythm disorder, and a method therefor, comprising an extract of Andrographis paniculata or Andrographolide as an active ingredient, and more specifically, to a circadian rhythm disorder It relates to a composition for preventing, improving or treating circadian rhythm disorder, comprising, as an active ingredient, a cheonsimryeon extract or andrographolide, which has the effect of strengthening and protecting the biological clock gene from environmental hormones that disturb the circadian rhythm, and a method therefor .

Most living things, including mammals, acquire a periodicity of about 24 hours while adapting to the change of day and night, and this is called "biological rhythm". In order to adapt to such repeated changes in the external environment, living things have developed a periodic and intrinsic biological clock. In other words, it is to adjust the physiological process to occur at an appropriate time according to the external environment. The biological clock is synchronized through external signals such as light, temperature, and food intake. Due to the self-sustaining ability of the biological clock, an organism has the advantage of predicting and coping with the external environment in advance, and this has been developed in the course of evolution.

The biological clock can be divided into two major categories: the central clock, which exists in the suprachiasmatic nucleus of the brain hypothalamus, and the peripheral clock, which exists in various peripheral tissues in the body. can be divided into The central circadian clock regulates the peripheral clock through nerve signals, hormones, and body temperature. The peripheral biological clocks present in the liver, kidney, and pancreas are not only regulated through the central biological clock, but also independently respond to external or internal signals.

The biological clock is composed of a transcription-translation feedback loop (TTL) of specific biological clock proteins at the molecular level. Among the main biological clock proteins, clock and droplet 1 (Bmal1) form a form of heterodimer, and include the biological clock-related genes Per, Cry, Ppar, Rev-Erb, etc. having an E-box promoter. induce expression. On the other hand, expression-induced Per and Cry form a heterodimerization form, and by inhibiting the activity of Clark/droplet 1 again, a negative feedback loop is formed. Through the transcription-translational negative feedback loop structure of the biological clock protein, a periodic rhythm phenomenon of biological clock-related gene expression is shown. In addition, through post-translational modification of the protein, it is possible to show an expression rhythm of about 24 hours by controlling an appropriate time delay and pulling phenomenon. The biological clock protein is expressed and activated at a specific time of the day, and regulates the expression and activity of genes and proteins involved in various physiological processes in a cycle of about 24 hours. Through this, the biological clock regulates the activity of physiological responses according to the external environment.

Because the biological clock is a general-purpose regulator that regulates physiology, metabolism, and behavior in general, not only sleep disorders and fatigue syndrome, which are common causes of circadian rhythm disturbances, but also metabolic diseases such as obesity, diabetes, cardiovascular diseases, various tumors, and rheumatism It is widely recognized that it is a risk factor for a wide range of diseases, such as , dementia, and mental disorders. accredited. In this respect, the discovery of molecular biological clock genes and the development of various mutant mice that manipulated them laid a new turning point in the study of the physiological problems caused by circadian rhythm disturbance and the pathogenesis of major circadian rhythm-related diseases (Takahashi et al . ., 2008).

Circadian rhythm sleep disorders are sleep disorders in which sleep-wake rhythms appear abnormal due to genetic or environmental disturbances applied to the biological clock. When the circadian phase of sleep-wake is abnormally late or early, sleep fragmentation due to weakened periodicity and decreased sleep duration, intrinsic circadian rhythm due to environmental factors (jet lag, shift work, etc.) inconsistencies in sleep cycles. In particular, a significant number (10-40%) of patients with insomnia and hypersomnia are estimated to have circadian rhythm sleep disorders, and these three major groups of sleep disorders are commonly associated with circadian rhythm disturbances. classified as a rhythm disorder. Because patients with circadian rhythm sleep disorder have great difficulty falling asleep or waking up at socially necessary times, they tend to complain of symptoms of lack of sleep first. Hereditary circadian rhythm sleep disorders caused by mutations in PERs or CRYs among genes have been identified (Sehgal and Mignot, 2011). The genetic study is consistent with the fact that abnormalities occurred in the sleep-wake rhythm cycle or phase in mutant mice lacking these circadian clock genes. In addition, mutant mice lacking these circadian clock genes tend to have increased non-REM sleep (NREMS) and increased intensity of delta waves compared to normal mice. This suggests that the maintenance of circadian rhythm by the circadian clock gene plays a role in sleep disorders.

Skin cells, such as keratinocytes, melanocytes, and fibroblasts, also have an independent biological clock system. The biological clock protein is expressed not only in cultured human skin cells but also in human skin tissue, affecting skin function. The skin is easily exposed to external environmental factors such as light, temperature, humidity, ultraviolet rays, and pathogens, and these external environmental factors change every day. In order to adapt to this environment, the skin activates the biological clock existing in the skin to regulate various physiological functions. According to the report, it is known that skin cell proliferation and differentiation, hydration and transepidermal water loss (TEWL), capillary blood flow, sebum production, temperature, surface pH, and wrinkle formation change every 24 hours. Specifically, for example, skin cell proliferation and differentiation occur through a series of processes in a daily cycle. Skin cell differentiation mainly occurs between late night and early morning, and during the daytime when exposure to UV rays is easy, the DNA damage protection mechanism is mainly performed, followed by cell division. By temporally separating these series of processes, it is possible to protect skin cells from harmful environments. When the rhythm of this process is broken, the physiological response required at the appropriate time cannot be generated, and the homeostasis of the skin is broken and skin damage is promoted.

The rhythmicity of the biological clock is decreased by external stress or endogenous aging that causes circadian disturbance. Rhythmicity can be defined as the amplitude between the peak and the trough in a sinusoidal pattern, and the decrease in rhythmicity means that the difference in size between the peak and the trough is reduced. The rhythmicity of the circadian clock is weakened with aging or degenerative diseases such as Alzheimer's disease. In general, with aging, the neurological activity of the pituitary gland decreases, the sensitivity to light that can synchronize the circadian rhythm decreases, and as the outside activity decreases during the day, the circadian rhythm weakens. , circadian rhythm, etc.) weakens, causing circadian rhythm sleep disorder. In addition, disturbance of the circadian rhythm occurs due to external environmental stress. For example, the rhythm is weakened by blue light emitted from electronic devices or artificial light, environmental hormones, and oxidative stress.

On the other hand, recently, the search for materials targeting the biological clock has been made in the direction of enhancing the biological clock rhythm. Accordingly, the present inventors have attempted to develop a material that restores the circadian rhythm decreased by environmental hormones while enhancing the circadian rhythm.

Cheonsimryun ( Andrographis paniculata ) belongs to the genus Andrographis of the Acanthaceae family, and uses above-ground parts or outposts for medicinal purposes. It has been used as a traditional medicinal plant in China, Hong Kong, the Philippines, Malaysia, and Thailand. Traditionally, it has been used for antibacterial, antiviral and cholangiectasis, blood sugar lowering, lipid lowering, etc. Recently, it is used for the treatment of colds, anti-thrombotic action has been reported, and efficacy against diseases such as cancer and HIV infection has been studied. have. Andrographolide (andgrographolide) as the main component of cheonsimryeon extract has been studied a lot of pharmacological efficacy, and androg (androg) is known to show a very bitter taste. In addition, it is known that there are components expressing various pharmacological activities, mainly terpenoids, flavonoids, and miscellaneous compounds are abundantly contained.

Korean Patent Registration No. 10-1065608 (published on Sept. 9, 2011) on Cheonsimryeon extract is a method for alleviating itchiness caused by sensitive skin diseases including Cheonsimryeon extract and/or andrographolide, scalp itchiness, and itchiness caused by allergies. Disclosed are compositions such as scalp cleaning compositions, hypoallergenic cosmetics, skin protectants, and whole body cleansers, and Korean Patent Registration No. 10-1843065 (2018.03.22. Announcement) discloses an anti-aging cosmetic composition containing cheonsimryeon extract, In addition, Korean Patent Registration No. 10-1694958 (2017.01.04. Announcement) discloses a composition for stem cell or skin cell proliferation containing chrysanthemum extract, and a composition for improving skin condition including the composition. .

However, there have been few studies on the prevention, improvement or treatment effect of circadian rhythm disruption of cheonsimryeon extract or andrographolide so far.

Therefore, the present inventors were studying to find a substance that strengthens circadian rhythm and protects circadian rhythm from environmental hormones that disturb circadian rhythm in order to solve the above problems The present invention was completed by confirming the enhancement of circadian rhythmicity of grapholide.

One object of the present invention is to provide a pharmaceutical composition for preventing, improving or treating circadian rhythm disorder, which comprises a cheonsimryeon extract or andrographolide as an active ingredient.

It is an object of the present invention to provide a cosmetic composition for preventing or improving circadian rhythm disorder, comprising a cheonsimnyeon extract or andrographolide as an active ingredient.

Another object of the present invention is to provide a composition for topical application for skin for preventing or improving circadian rhythm disorder, comprising a cheonsimryeon extract or andrographolide as an active ingredient.

Another object of the present invention is to provide a quasi-drug composition for preventing or improving circadian rhythm disorder, comprising a cheonsimnyeon extract or andrographolide as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or improving circadian rhythm disorder, comprising a cheonsimryeon extract or andrographolide as an active ingredient.

Another object of the present invention is to provide a method for preventing, improving, or treating a circadian rhythm disorder in an individual by administering a composition comprising the cheonsimryeon extract or andrographolide as an active ingredient to the individual.

In order to solve the above technical problem, the present invention provides a composition for preventing, improving or treating circadian rhythm disorder comprising a cheonsimnyeon extract as an active ingredient, and a method for preventing, improving or treating a circadian rhythm disorder by administering the composition to an individual provides

In the present invention, "Cheonsimnyeon (穿心蓮, Andrographis paniculata )" is an annual plant of the family Acanthaceae, and is a plant that grows mainly in shady and moist places throughout India, especially in fields or forests in the south. The height is 0.3 to 1.0 m, the stem is dark green, 2 to 6 mm thick, the leaves are 8 cm long and 2.5 cm wide, pointed in the shape of a willow leaf, and the flowers have purple spots on white or pale pink petals. Cheonsimryeon is known as 'Maha-tita' (King of bitters) because the taste of all plant parts is extremely bitter, and although much smaller in size than neem, it is also called 'bhui-neem' because of its similar shape and bitter taste.

In the present invention, "extract" refers to a liquid component obtained by immersing a target substance in various solvents, and then extracting and fractionating it for a certain time at room temperature or heated condition, a solid obtained by removing the solvent from the liquid component, etc. means the result of In addition, in addition to the result, it can be comprehensively interpreted as including all of the dilutions of the results, their concentrates, their preparations, and their purified products.

The Cheonsimryeon extract may be extracted using a conventional solvent known in the art, and the extracted liquid may be used in a liquid form or may be used after concentration and/or drying. In this case, the solvent is, for example, (a) water, (b) an anhydrous or hydrous lower alcohol having 1-4 carbon atoms (methanol, ethanol, propanol, butanol, etc.), (c) a mixed solvent of the lower alcohol and water , (d) acetone, (e) ethyl acetate, (f) chloroform or (g) 1,3-butylene glycol as the extraction solvent. Preferably, extraction is performed using methanol, ethanol or butane. Depending on the organic solvent to be extracted, the degree of extraction and loss of the active ingredient of the extract may be different, so an appropriate organic solvent should be selected and used. The extraction method is not particularly limited, and examples thereof include cold extraction, ultrasonic extraction, and reflux cooling extraction.

In one specific aspect of the present invention, the cheonsimnyeon extract can be obtained through a conventional purification process in addition to the method of extraction with the extraction solvent. For example, separation using an ultrafiltration membrane having a constant molecular weight cut-off value, separation by various chromatography (prepared for separation according to size, charge, hydrophobicity, or affinity), etc. obtained through various additional purification methods Cheonsimryun extract can be obtained even by using the fraction.

In the present invention, "andrographolide (andrographolide)" refers to a C ₂₀ H ₃₀ O ₅ compound that has a very bitter taste as a major component of Cheonsimryeon.

In the present invention, the andrographolide may be in the form of a pharmaceutically, cosmetic, and/or food-acceptable salt or in a form that becomes andrographolide in the body (eg, a prodrug). Examples of the salt include an acid addition salt formed by a free acid or a metal salt formed by a base that is pharmaceutically, cosmetically and/or food acceptable. The free acid may be an inorganic acid or an organic acid. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, sulfurous acid or phosphoric acid. Examples of the organic acid may include citric acid, acetic acid, maleic acid, humic acid, gluconic acid, methanesulfonic acid, and the like. The metal salt includes an alkali metal salt or an alkaline earth metal salt, and sodium, potassium or calcium salts may be usefully used.

The andrographolide or a salt thereof may be extracted, isolated and purified from a natural source, biotransformation, synthesized, or a commercially available material may be used. The natural source is not necessarily limited thereto, but includes Cheonsimryun ( Andrographis Paniculata ) and the like.

The composition of the present invention, using the extract or andrographolide as an active ingredient, enhances the circadian rhythm and protects the circadian rhythm from environmental hormones that disturb the circadian rhythm, thereby preventing, improving or treating circadian rhythm disorders. .

As used herein, the term "biological clock rhythm" refers to a periodicity of about 24 hours acquired while living things, including mammals, adapt to the day and night changes formed due to the rotation of the earth, and the "biological clock rhythm strengthening" ” means that it occurs as the expression of the circadian clock gene increases.

In the present invention, the term “circadian rhythm disorders” means caused by a circadian rhythm disturbance, and the circadian rhythm disturbance is caused by a decrease in the expression of a circadian rhythm gene. The circadian rhythm disorder is the cause of a wide range of diseases or disorders such as sleep disorders, fatigue syndrome, obesity, metabolic diseases such as diabetes, cardiovascular diseases, various tumors, rheumatism, dementia, mental disorders, disruption of skin homeostasis, and skin damage. do.

In the present invention, the term “prevention” refers to inhibiting the occurrence of a circadian rhythm disorder in an individual who has never been diagnosed with the circadian rhythm disorder, but is prone to such circadian rhythm disorder.

As used herein, the term “improvement” or “treatment” refers to (a) suppression of a circadian rhythm disorder, or (b) alleviation of a circadian rhythm disorder in a subject.

In the present invention, the term “individual” refers to mammals, including humans, that can achieve the above object by administering a composition comprising the extract of cheonsimryeon or andrographolide as an active ingredient of the present invention, for example, monkey, means cattle, horses, pigs, sheep, dogs, cats, rats, mice, chimpanzees, and the like.

In the present invention, the term “administration” means introducing a predetermined substance to an individual by any suitable method, and the administration route of the composition of the present invention is oral or parenteral through any general route as long as it can reach the target tissue. may be administered. In addition, the compositions of the present invention may be administered by any device capable of transporting an active substance to a target subject, eg, a cell.

A suitable dosage of the composition of the present invention varies depending on the individual's condition and body weight, the degree of disease, drug form, and time, but may be appropriately selected by those skilled in the art. The daily dose of the Cheonsimryeon extract is 1.0 ㎖ to 3.0 ㎖ based on an adult, and may be administered by applying one to five times a day if necessary.

The composition comprising the extract or andrographolide as an active ingredient is 0.00001 to 15.0% by weight, preferably 0.0001 to 10% by weight, more preferably 0.0001 to 5% by weight, based on the total weight of the total composition. may be included. If, if the extract and andrographolide is less than 0.0001% by weight, there is a disadvantage in that the efficacy is weak. In addition, when it exceeds 15% by weight, the increase in the effect according to the increase in the content is insignificant, and there may be a problem in that the stability of the formulation is not secured.

In one specific aspect, the present invention provides a cosmetic composition for preventing or improving circadian rhythm disorder, comprising the cheonsimryeon extract or andrographolide as an active ingredient.

The cosmetic composition according to one specific aspect of the present invention may additionally include components commonly used in cosmetic compositions in addition to the composition containing the cheonsimryeon extract or andrographolide as an active ingredient. For example, it may contain conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, and carriers.

The cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing agent , oil, powder foundation, emulsion foundation, wax foundation, spray, etc., but is not limited thereto. More specifically, it may be prepared in the form of a nourishing cream, astringent lotion, softening lotion, lotion, essence, nutrition gel or massage cream.

When the formulation of the cosmetic composition is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide is used as a carrier component. can be

When the formulation of the cosmetic composition is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydrocarbon, propellants such as propane/butane or dimethyl ether.

When the formulation of the cosmetic composition is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil, glycerol fatty esters, fatty acid esters of polyethylene glycol or sorbitan.

When the formulation of the cosmetic composition is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester; Crystalline cellulose, aluminum metahydroxide, bentonite, agar, or tracanth may be used.

When the formulation of the cosmetic composition is surfactant-containing cleansing, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid as carrier components Amide ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters can be used.

In another specific aspect, the present invention provides a pharmaceutical composition for preventing or treating circadian rhythm disorder comprising the cheonsimnyeon extract or andrographolide as an active ingredient.

The pharmaceutical composition may include a pharmaceutically acceptable carrier in addition to containing the cheonsimnyeon extract or andrographolide.

Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvininpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. it's not going to be The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention may be administered by various routes, such as oral or parenteral, preferably parenteral administration, more preferably topical application by application.

A suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity of the patient. can be The oral dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg/kg (body weight) for adults. In addition, in the case of an external preparation, it is recommended to apply it once to 5 times a day in an amount of 1.0 to 3.0 ml based on an adult and continue it for at least 1 month. However, the dosage does not limit the scope of the present invention.

The pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. or may be prepared by incorporation into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, syrup, or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.

As another specific aspect, the present invention provides a composition for external application for skin for preventing or improving circadian rhythm disorder, comprising the cheonsimryeon extract or andrographolide as an active ingredient.

The composition for external application for skin according to the present invention may be formulated containing a cosmetically or dermatologically acceptable medium or base. These are all formulations suitable for topical application, for example, solutions, gels, solids, kneaded dry products, emulsions obtained by dispersing an oily phase in an aqueous phase, suspensions, microemulsions, microcapsules, microgranules or, ionic (liposomes) and It may be provided in the form of a non-ionic vesicular dispersant, or in the form of a cream, skin, lotion, powder, ointment, spray, pack or cone stick. It can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant. These compositions can be prepared according to conventional methods in the art.

In addition, the composition for external application for skin according to the present invention is a fatty substance, an organic solvent, a solubilizer, a thickener, a gelling agent, an emollient, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, water, an ionic type. or nonionic emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic actives, lipid vesicles or any other commonly used in cosmetics. It may contain adjuvants commonly used in the field of cosmetics or dermatology, such as ingredients. The adjuvant is introduced in an amount generally used in the field of cosmetology or dermatology.

As another specific aspect, the present invention provides a quasi-drug composition for preventing or improving circadian rhythm disorder comprising the cheonsimryeon extract or andrographolide as an active ingredient.

As used herein, the term "quasi-drug" refers to articles with a milder action than pharmaceuticals among articles used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases of humans or animals. For example, quasi-drugs according to the Pharmaceutical Affairs Act exclude products used for pharmaceutical purposes, and include products used for the treatment or prevention of diseases of humans/animals, and products with minor or no direct action on the human body.

Specifically, the quasi-drugs may include external preparations for skin and personal care products. More specifically, it may be a disinfectant cleaner, shower foam, gargrin, wet tissue, detergent soap, hand wash, or ointment, but is not limited thereto.

When the composition according to the present invention is used as a quasi-drug additive, the composition may be added as it is or used together with other quasi-drugs or quasi-drug ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be suitably determined according to the purpose of use.

As another specific aspect, the present invention provides a food composition for preventing or improving circadian rhythm disorder, comprising the cheonsimryeon extract or andrographolide as an active ingredient.

When the food composition of the present invention is used as a food additive, the extract or andrographolide may be added as it is, or it may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be suitably determined according to the purpose of use (prophylactic, health or therapeutic treatment), and may further include a food pharmaceutically acceptable food supplement additive. The composition of the present invention is not only a material derived from a natural product, but also has confirmed its stability from a human safety test, so there is no great limitation on the mixing amount.

The food composition of the present invention may include all foods in a conventional sense, and may be used interchangeably with terms known in the art, such as functional food and health functional food.

As used herein, the term “functional food” refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Health Functional Food Act No. 6727, and “functionality” refers to the structure of the human body. And it means ingestion for the purpose of obtaining useful effects for health purposes such as regulating nutrients for function or physiological action.

In addition, the term "health functional food" of the present invention refers to a food manufactured and processed by methods such as extraction, concentration, purification, mixing, etc. of a specific ingredient as a raw material or a specific ingredient in a food raw material for the purpose of health supplementation, It refers to a food designed and processed to sufficiently exert biological control functions, such as biological defense, regulation of biological rhythm, prevention and recovery of disease, etc. with respect to the living body by the above ingredients. It can perform functions related to recovery, etc.

There is no limitation on the kind of food in which the composition of the present invention can be used for the prevention or improvement of circadian rhythm disorders. In addition, the composition comprising the cheonsimryeon extract or andrographolide of the present invention as an active ingredient can be prepared by mixing other suitable auxiliary ingredients that may be contained in food and known additives according to the selection of those skilled in the art. Examples of foods that can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and There are vitamin complexes and the like, and it can be prepared by adding the extract or andrographolide according to the present invention to juice, tea, jelly, juice, etc.

In addition, foods that can be applied to the present invention include, for example, special nutritional foods (eg, formula milk, infant food, etc.), processed meat products, fish meat products, tofu, jelly, noodles (eg, ramen, noodles, etc.), health supplements , Seasoned foods (eg soy sauce, soybean paste, red pepper paste, mixed soy sauce, etc.), sauces, sweets (eg snacks), dairy products (eg fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi, pickles, etc.) ), beverages (eg, fruit, vegetable beverages, soy milk, fermented beverages, etc.), and natural seasonings (eg, ramen soup, etc.).

When the food composition of the present invention is used in the form of a beverage, it may contain various sweetening agents, flavoring agents, natural carbohydrates, etc. as an additional component like a conventional beverage. In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol , a carbonation agent used in carbonated beverages, and the like. In addition, it may contain the pulp for the production of natural fruit juice, fruit juice beverage and vegetable beverage.

In another aspect, the present invention provides a circadian rhythm disorder comprising administering a composition for preventing, improving, or treating circadian rhythm disorder comprising the Cheonsimnyeon extract or andrographolide as an active ingredient Methods for preventing, treating, or ameliorating are provided.

The prevention, treatment, and improvement effects of the cheonsimryeon extract and andrographolide on circadian rhythm disorders are as described above. In addition, the "subject", "prevention", "treatment", and "improvement" are the same as described above.

The prevention, treatment, or improvement method of the present invention is specifically, pharmaceutically, cosmetically, or food-effectively administering the composition to an individual who has or is likely to develop a circadian rhythm disorder caused by circadian rhythm disturbance. It may include the step of administering in an amount. The method of administration is the same as described above.

A suitable dosage of the composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the drug form, and time, but may be appropriately selected by those skilled in the art.

The composition comprising the extract or andrographolide of the present invention as an active ingredient enhances circadian rhythm and prevents circadian rhythm disorders by protecting the rhythmicity of circadian clock genes from environmental hormones that disturb the circadian clock. , it can be usefully used as an active ingredient in cosmetic compositions, pharmaceutical compositions, and compositions for external application for skin for improvement or treatment.

1 is a graph showing the effect of strengthening the circadian rhythm of the extract of the present invention cheonsimnyeon.
2 is a graph showing that the circadian rhythm is strengthened by andrographolide, which is a major component of the cheonsimryeon extract of the present invention.
Figure 3 is a graph showing the effect of protecting the rhythmicity of the circadian rhythm disturbed by TCDD stimulation of the environmental hormone TCDD by the extract and andrographolide of the present invention.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention.

Example 1: Preparation of Cheonsimryun extract

After thoroughly washing the leaves and branches of Cheonshimryeon, they were dried in the shade at 20°C to 35°C, and then pulverized to a particle size of 1 mm or less. After that, 1 liter of purified water was added to 100 g of the pulverized cheonsimnyeon leaf and eggplant powder and reacted at 121° C. for 30 minutes, and the obtained extract was filtered using filter paper (Advantec, No. Concentrated to prepare a Cheonsimryun extract.

Example 2: Measurement of the effect of increasing biological clock gene expression by the cheonsimnyeon extract

In order to measure the effect of increasing skin circadian clock expression by the cheonsimryeon extract, the promoter activity of Per2, a circadian clock representative gene, was measured. HaCaT containing Per2pro-LUC was inoculated into a 96-well plate containing 200 μg/ml of Hygromycine B and DMEM medium containing 10% FBS (1.4 × 10 ⁴ cells/ml). well), in a 5% concentration of CO ₂ incubator at 37° C. for 48 hours. After 48 hours, the cells were treated with the cheonsimryeon extract 1 and 10 ug/ml of Example 1. After 24 hours, after treatment with dexamethasone for 1 hour for clock synchronization, medium for luciferase measurement (HEPES 10 mM, luciferin 1 mM, hygromycin B 200 ug/ml, 10 DMEM with % FBS). Thereafter, the degree of luminescence was measured in real time for 4 days every hour with a luminometer (F200 Pro, Tecan, Switzerland), and the results are shown in FIG. 1 .

As shown in FIG. 1 , it was confirmed that the expression of Per2pro-LUC in cells treated with cheonsimryeon extract was increased in a concentration-dependent manner compared to the control treated with DMSO (dimethyl sulfoxide).

Example 3: Measurement of the effect of increasing expression of biological clock genes by andrographolide

In order to measure the effect of increasing skin circadian clock expression by andrographolide, the main active ingredient of Cheonsimnyeon extract, HaCaT containing Per2pro-LUC was added with 200 μg/ml of Hygromycine B and 10% FBS. A 96-well plate containing DMEM medium was inoculated at the number of 1.4 × 10 ⁴ cells per well, and incubated at 37° C. in a 5% concentration CO ₂ incubator for 48 hours. After 48 hours, the cells were treated with 1 and 10 uM andrographolide. After 24 hours, after treatment with dexamethasone for 1 hour for clock synchronization, medium for luciferase measurement (HEPES 10 mM, luciferin 1 mM, hygromycin B 200 ug/ml, 10 DMEM with % FBS). Thereafter, the luminescence degree was measured in real time for 4 days every 1 hour with a luminometer (F200 Pro, Tecan, Switzerland), and the results are shown in FIG. 2 .

As shown in FIG. 2 , it was confirmed that the expression of Per2pro-LUC in the cells treated with andrographolide was increased compared to the control treated with dimethyl sulfoxide (DMSO).

Example 4: Protective effect of circadian clock gene damaged due to environmental hormones by cheonsimryeon extract and andrographolide

The skin circadian clock activity was measured after the co-treatment of the extract according to the present invention or andrographolide, which is a major component thereof, with TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin), which is an environmental hormone dioxin. did. HaCaT containing Per2pro-LUC was inoculated into a 96-well plate containing 200 ug/ml of hygromycin B and 10% FBS in DMEM medium (1.4 × 10 ⁴ cells/well), and 5% Concentration of CO ₂ Incubated in an incubator at 37° C. for 48 hours. After 48 hours, 1, 10, and 50 ug/ml cheonsimnyeon extract or 10 uM andrographolide and 1.5 nM TCDD were co-treated for 4 hours, and then the medium for luciferase measurement (HEPES 10 mM, Luciferin 1 mM) , hygromycin B 200 ug/ml, DMEM with 10% FBS). The results are shown in FIG. 3 below.

As shown in FIG. 3 , the absolute value of Per2pro-LUC rhythm was reduced by about 28% in the cells treated with TCDD compared to cells not treated with only toluene, a solvent. On the other hand, it was confirmed that the inhibitory effect of Per2pro-LUC by TCDD decreased as the concentration increased in the cells treated with Chunsimnyeon extract. In addition, it was confirmed that the cells co-treated with 10uM andrographolide decreased the Per2pro-LUC inhibitory effect by TCDD.

Formulation examples for the composition of the present invention are exemplified below.

Formulation Example 1: Cosmetic formulation

1-1. soft lotion

ingredient weight% Cinnamon extract or andrographolide 0.05 glycerin 3.0 butylene glycol 2.0 propylene glycol 2.0 carboxyvinyl polymer 0.1 ethanol 10.0 triethanolamine 0.1 Preservatives, micro pigments, micro fragrances and micro-purified water 82.74 sum 100.0

1-2. nourishing lotion

ingredient weight% Cinnamon extract or andrographolide 0.05 beeswax 4.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 liquid paraffin 5.0 squalane 5.0 Caprylic/Capric Triglycerides 5.0 glycerin 3.0 butylene glycol 3.0 propylene glycol 3.0 carboxyvinyl polymer 0.1 triethanolamine 0.2 Preservatives, micro pigments, micro fragrances and micro-purified water 69.64 sum 100.0

1-3. nourishing cream

ingredient weight% Cinnamon extract or andrographolide 0.05 beeswax 10.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 liquid paraffin 10.0 squalane 5.0 Caprylic/Capric Triglycerides 5.0 glycerin 5.0 butylene glycol 3.0 propylene glycol 3.0 triethanolamine 0.2 Preservatives, micro pigments, micro fragrances and micro-purified water 56.74 sum 100.0

1-4. massage cream

ingredient weight% Cinnamon extract or andrographolide 0.05 beeswax 10.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.8 liquid paraffin 40.0 squalane 5.0 Caprylic/Capric Triglycerides 4.0 glycerin 5.0 butylene glycol 3.0 propylene glycol 3.0 triethanolamine 0.2 Preservatives, micro pigments, micro fragrances and micro-purified water 27.45 sum 100.0

1-5. pack

ingredient weight% Cinnamon extract or andrographolide 0.05 polyvinyl alcohol 13.0 Sodium Carboxymethylcellulose 0.2 allantoin 0.1 ethanol 5.0 nonylphenyl ether 0.3 Preservatives, micro pigments, micro fragrances and micro-purified water 81.34 sum 100.0

Formulation Example 2: Pharmaceutical Formulation

2-1. Preparation of powders

ingredient Weight (g) Cinnamon extract or andrographolide 2 lactose One

The above ingredients were mixed and filled in an airtight cloth to prepare a powder.

2-2. manufacture of tablets

ingredient Weight (mg) Cinnamon extract or andrographolide 100 corn starch 100 lactose 100 magnesium stearate 2

After mixing the above ingredients, tablets were prepared by tableting according to a conventional manufacturing method of tablets.

2-3. manufacture of capsules

ingredient Weight (mg) Cinnamon extract or andrographolide 100 corn starch 100 lactose 100 magnesium stearate 2

After mixing the above ingredients, the capsules were prepared by filling in gelatin capsules according to a conventional manufacturing method of capsules.

Claims (8)

A cosmetic composition for preventing or improving circadian rhythm disorder, comprising an extract of Andrographis paniculata or andrographolide as an active ingredient. The cosmetic composition for preventing or improving circadian rhythm disorder according to claim 1, wherein the circadian rhythm disorder is caused by circadian rhythm disturbance. The cosmetic composition for preventing or improving circadian rhythm disorder according to claim 1, wherein the circadian rhythm disorder occurs due to a decrease in the expression of a circadian clock gene. Cheonsimnyeon ( Andrographis paniculata ) A pharmaceutical composition for preventing or treating circadian rhythm disorder comprising an extract or andrographolide as an active ingredient. The pharmaceutical composition for preventing or treating circadian rhythm disorder according to claim 4, wherein the circadian rhythm disorder is caused by circadian rhythm disturbance. The pharmaceutical composition for preventing or treating circadian rhythm disorder according to claim 4, wherein the circadian rhythm disorder occurs due to a decrease in the expression of a circadian clock gene. A composition for external application for skin for preventing or improving circadian rhythm disorder, comprising an extract of Andrographis paniculata or andrographolide as an active ingredient. Cheonsimryun ( Andrographis paniculata ) A food composition for preventing or improving circadian rhythm disorder comprising an extract or andrographolide as an active ingredient.

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