KR20190023165A - Pharamceutical or food composition containing mono glycerides as active ingradeient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating sleep disorder and/or a functional food composition for increasing sleeping time and improving sleep quality, containing monoglycerides, which are a unsaturated fatty acid ester having two double bonds, as an active component. Monoglycerides used in the present invention are substances produced during a metabolism process in vivo, and safety can be ensured since monoglycerides are not toxic to the living body. Therefore, the composition according to the present invention can be used as the active component of medicine and health functional food and can be utilized in the pharmaceutical industry and the food industry.

Description

[0001] PHARMACEUTICAL OR FOOD COMPOSITION CONTAINING MONO GLYCERIDES AS ACTIVE INGRADEENT [0002]

The present invention relates to a functional composition, and more particularly, to a pharmaceutical composition and / or medicament for treating sleep disorder comprising monoglyceride as an active ingredient and / or a composition for improving sleeping time and / .

Proper sleep is essential to restore body and mind fatigue for normal activities the next day. Recent research has shown that adequate sleep does not only increase concentration and memory, but also prevent obesity and diabetes and prevent accidents such as drowsiness. Therefore, improvement of sleep disorder such as insomnia and improvement of sleep quality are very important factors that can lead to improvement of quality of life.

In modern society, however, many people are unable to sleep adequately due to lack of physical sleeping hours due to extended work or nighttime learning, or due to psychological pressure such as stress, anxiety, and agitation, resulting in sleep disorders. According to statistics, about 15% of people are suffering from insomnia due to anxiety symptoms, so it is known that medication is needed, and it is known that the number of insomnia patients increases with age.

In relation to sleep disturbances, anti-anxiety, etc., the GABA _A receptor acts as a neurotransmitter channel, which is known to regulate physiological activities related to sleep, as well as sedation, anxiety, muscle tension and convulsions in the human body. These drugs are used to treat sleep disorders such as insomnia, such as benzodiazepines and serotonines, and these drugs bind to the GABA _A receptor and cause anxiety, sedation, sleep induction, and improvement . However, long-term use of these drugs has been associated with side effects that are associated with drug resistance and drug dependence, making them unsuitable for use in people who may be experiencing early or transient insomnia.

Therefore, it is necessary to develop a material that has low safety and is safe as a means of substituting conventional sleeping pills for people who need to take a sleeping pesticide for a long time. In developed countries, as side effects of existing sleeping pills are revealed, much efforts have been made to develop sleep enhancement substances that can replace conventional sleeping pills or avoid side effects of sleeping pills. For example, in developed countries, studies have been actively made to reduce side effects or addiction by replacing sleeping pills produced by chemical synthesis, or by using substances derived from natural products. Thus, as interest in the quality of life of individuals increases and the importance of sleep increases, the desire to improve the quality of sleep is increasing. Therefore, not only drugs that can treat or prevent sleep disorders such as insomnia, The demand for health functional foods that can be improved is expected to increase.

On the other hand, in modern medicine, sleep disorders are classified as diseases related to anxiety and nervous irritation, and studies of sleep disorders through a oriental medicine approach are reported in various ways. There are many studies on neuropsychiatric disorders in Oriental medicine. These herbal medicines are known to have anti-anxiety and sleep reporting effects at low-dose, and sedative and anti-depressive effects at high-dose. Other medicinal products with anti-anxiolytic activity include gold, hansam, and horse chestnut.

Research has been actively conducted to treat sleep disorder or to improve sleep by applying natural herbal medicine or herbal medicine used in oriental medicine. For example, Korean Patent Publication No. 2007-0070307 proposes a composition for improving sleep surface comprising various herbal ingredients in an antihistamine drug.

However, there is still a need to develop an active ingredient which has sleep-disordered, anti-anxiety, anti-convulsive and anti-sedative properties and can be safe and harmless to the human body.

Disclosure of the Invention The present invention has been proposed in order to solve the problems of the prior art described above. It is an object of the present invention to provide a pharmaceutical composition for treating sleep disorder containing an effective ingredient which is harmless to the living body and is not toxic, And / or drugs.

Another object of the present invention is to provide a functional food composition and / or a health functional food for improving sleeping time and sleep quality by containing an active ingredient harmless to the human body.

According to an aspect of the present invention, there is provided a pharmaceutical composition for treating sleep disorder, comprising a monoglyceride represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient: to provide.

Formula 1

(In the formula (1), any one selected from R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₄ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)

For example, the active ingredient may include a monoglyceride represented by the following formula (2), an isomer thereof, or a pharmaceutically acceptable salt thereof.

(2)

(In Formula 2, any one selected from R ₄ and R ₅ is a C ₁₆ -C ₂₀ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)

In one exemplary embodiment, the active ingredient may be contained in the pharmaceutical composition at a concentration of 0.01 to 1000 mg / ml.

According to another aspect of the present invention, there is provided a method for improving sleep time and improving sleep quality, comprising the monoglyceride represented by Formula 1 or Formula 2, an isomer thereof or a pharmaceutically acceptable salt thereof, To provide a functional food composition.

According to the present invention, a pharmaceutical composition and a functional food composition containing, as an active ingredient, a monoglyceride in which an unsaturated fatty acid having two double bonds are linked via an ester bond is proposed.

When the monoglyceride according to the present invention was administered to an animal, the sleep latency decreased and the sleep duration increased. The monoglyceride, which is an active ingredient, increased in the GABA _A Lt; RTI ID = 0.0 > benzodiazepine < / RTI > binding site of the receptor.

The monoglyceride contained as an active ingredient in the composition according to the present invention is a material that can be produced in a metabolic process in vivo, and is expected to have no toxicity or side effects on the living body. Therefore, it can be applied as an effective active ingredient in pharmaceuticals or foods that can secure human health, and is expected to be utilized in the pharmaceutical industry and the food industry.

FIG. 1 and FIG. 2 are schematic views showing a method of measuring an electroencephalogram (EEG) related to sleep time enhancement in a rat administered monoglyceride according to an exemplary embodiment of the present invention .

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings where necessary.

The compound used as an active ingredient in the pharmaceutical composition and the functional food composition according to the present invention is a glyceride in which an unsaturated fatty acid having two double bonds is linked via an ester bond. Specifically, the compound used as an active ingredient according to the present invention includes monoglycerides / monoacyl glycerols represented by the following formula (1), isomers thereof or pharmaceutically acceptable salts thereof.

Formula 1

(In the formula (1), any one selected from R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₄ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)

As defined in Chemical Formula (1), the monoglyceride is formed by a carboxyl group of an unsaturated fatty acid having two double bonds and a hydroxyl group of one of three hydroxyl groups formed in glycerol via an ester bond. For example, the monoglyceride may be a 1-monoglyceride (R ₁ or R ₃ is an ester bond with a fatty acid) or a 2-monoglyceride (R ₂ is an ester bond with a fatty acid).

In one exemplary embodiment, the unsaturated fatty acid esters having two double bonds are linoleic acid (18: 2 (9, 12), (9Z, 12Z) -octadeca-9,12-dienoic acid) Linolelaidic acid 18: 2 (9,12), (9E, 12E) -octadeca-9,12-dienoic acid, eicosadienoic acid 20: 2 (11,14) , 14Z) -icosa-11,14-dienoic acid, docosadienoic acid 22: 2 (13,16), (13Z, 16Z) -docosa-13,16-dienoic acid) But the present invention is not limited thereto.

In one exemplary embodiment, an isomer (e. G., A stereoisomer) of the monoglyceride represented by Formula 1, which is an active ingredient, may also be used.

The monoglyceride represented by the general formula (1) can be used in the form of a pharmaceutically acceptable salt. For example, as the salt, an acid addition salt or a basic salt formed by a pharmaceutically acceptable free acid is useful .

As the free acid, organic acid and inorganic acid can be used. Pharmaceutically acceptable inorganic acids include hydrochloric acid (hydrochloric acid), hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid and / or tartaric acid, but the present invention is not limited thereto. Pharmaceutically acceptable organic acids include, but are not limited to, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, oxalic acid, benzoic acid, citric acid acid, lactic acid and the like may be used, but the present invention is not limited thereto.

Pharmaceutically acceptable bases, on the other hand, include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine and tert-butylamine.

For example, the acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Lt; RTI ID = 0.0 > nonanoic < / RTI > Such pharmaceutically non-toxic salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate.

For example, an acid addition salt can be obtained by a conventional method, for example, by dissolving the monoglyceride represented by the formula (1) in an excess amount of an acid aqueous solution, and then mixing the salt with a water-miscible organic solvent such as methanol, ethanol, Followed by precipitation using nitrile. By heating the same molar amount of monoglyceride represented by the formula (1) and an acid or alcohol (e.g., glycol monomethyl ether) in water, and then evaporating the mixture to dryness, or by precipitating the precipitated salt by filtration You may.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In one exemplary embodiment, the active ingredient according to the present invention may comprise a 2-monoglyceride represented by the following general formula (2), an isomer thereof or a pharmaceutically acceptable salt thereof.

(2)

(In Formula 2, any one selected from R ₄ and R ₅ is a C ₁₆ -C ₂₀ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)

On the other hand, types of sleep include REM (Rapid Eye Movement) sleep and Non-rapid eyes movements (REM) sleep. REM sleep is a state in which beta-waves are released at the time of sleep, and the body turns around at the time of sleep and becomes more and more in the morning. Non-REM sleep, on the other hand, corresponds to deep sleep (sleep) with delta-waves being emitted. When humans take sleep, they generally experience non-REM sleep three or four times, and when the number or time is short, they feel sleep deprivation. Therefore, it is important to extend Non-REM sleep time rather than prolong REM sleep time in the quality of sleep. According to an exemplary embodiment of the present invention, the monoglyceride represented by the formula (1) is administered to an animal model and the electroencephalogram analysis is performed, and the total sleep time and the sleep time (Non-REM time) are greatly increased (See Examples).

In particular, the monoglyceride represented by formula (I) binds to the benzodiazepine binding site in the A receptor (GABA _A receptor) of gamma-aminobutyric acid (GABA) to reduce sleep latency , And increases the sleep duration (see Examples).

GABA _A receptors are receptors involved in neurotransmission and are associated with sleep induction and improvement, as well as receptors associated with anxiety relief, seizure improvement, and sedation. GABA _A receptor binds to a specific substance and opens a channel associated with chloride ion (Cl ^- ). By changing the gradient of the intracellular / extracellular concentration of chloride ion, the GABA _A receptor is associated with relaxation, sleep, anxiety, muscle tension, It functions as a neurotransmitter channel that regulates physiological activity.

Current GABA _A Drugs that act on receptors have been studied and marketed, including benzodiazepine, diazepam, and flumazenil as an antagonist. Drugs currently on the market are known to be effective in improving sleep, but they are dependent and there are reports of side effects that limit the ability to continue taking or taking. On the other hand, the monoglyceride used as an active ingredient according to the present invention is a material produced in a metabolic process in vivo, and safety can be secured since it is expected that there will be no toxicity or side effects on the living body.

In one exemplary embodiment, the monoglyceride as an active ingredient according to the present invention is contained at a concentration of 0.01 to 1000 mg / ml, preferably 0.1 to 1000 mg / ml, more preferably 1 to 500 mg / ml But the present invention is not limited thereto.

Thus, according to one aspect of the present invention, there is provided a pharmaceutical composition for the treatment of sleep disorders, comprising a monoglyceride represented by Chemical Formula 1 or Chemical Formula 2, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, Or medicines.

The pharmaceutical dosage form of the active ingredient according to the present invention may be used not only as the monoglyceride represented by the formula (1) or (2), but also as an isomer thereof or a pharmaceutically acceptable salt thereof, May be used in combination with other pharmaceutically active compounds as well as in suitable aggregates.

That is, the pharmaceutical composition for the treatment of sleep disorders comprises a monoglyceride represented by the formula (1) or (2), an isomer thereof or a pharmaceutically acceptable salt thereof (hereinafter referred to as the active ingredient in the pharmaceutical composition or the functional food composition according to the present invention Monoglyceride, etc.) as its active ingredient, and may contain other ingredients such as a formulation, a method of use, and the like. Depending on the intended use, it may further comprise additional components, that is, pharmaceutically acceptable or nutritionally acceptable carriers, excipients, diluents or subcomponents.

For example, the pharmaceutical composition containing monoglyceride according to the present invention may be formulated into oral compositions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories and sterilized May be formulated in the form of injection solutions. In addition, the formulation of the pharmaceutical composition of the present invention may be in a preferred form depending on the method of use.

For example, the monoglyceride of the present invention may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of formulation, a filler, an extender, a binder, a wetting agent, a surfactant, A lubricant, a wetting agent, a flavoring agent, an emulsifying agent or a diluent such as an antiseptic agent or an excipient, and may be used either orally or parenterally.

Examples of the carrier, excipient and diluent which can be contained in a pharmaceutical composition containing an active ingredient such as monoglyceride include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, Alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, but is not limited thereto, and any conventional carrier, excipient or diluent may be used.

The solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like. These solid preparations can be prepared by adding to the monoglyceride as an active ingredient according to the present invention at least one excipient such as starch, calcium carbonate calcium carbonate, sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. Various excipients such as wetting agents, sweeteners, fragrances and preservatives may be included in addition to water and liquid paraffin, which are commonly used simple diluents. have.

For example, formulations for oral administration may be provided with an enhancer. Orally acceptable absorption enhancers include surfactants such as sodium lauryl sulfate and derivatives thereof; Bile salts such as sodium deoxycholate and sodium taurocholate; Chelating agents such as EDTA, citric acid and salicylate; And fatty acids (e.g., oleic acid, lauric acid, acylcarnitines, mono and diglycerides). Other oral absorption enhancers include benzalkonium chloride, benzethonium chloride, benzyl alcohol, phenols, cresols, and alkyl alcohols.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. As a suppository base, witepsol, macrogol, tween 61 and the like can be used. The pharmaceutical composition of the present invention can be administered parenterally, subcutaneously, intravenously or intramuscularly.

Examples of the form for parenteral administration include toothpastes, mouthwashes, topical administration agents (creams, ointments, dressing solutions, sprays, and other coating agents). An example of the formulations of the topical administration agent may be a monoglyceride or the like as an active ingredient impregnated with a carrier such as gauze made of natural fibers or synthetic fibers.

The pharmaceutical composition may further contain, in addition to the active ingredient, a nutritional supplement, a vitamin, an electrolyte, a flavoring agent, a coloring agent, a stabilizer, a pectic acid and a salt thereof, an alginic acid and a salt thereof, an organic acid, a protective colloid thickening agent, Preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages, and the like.

Although the preferable dosage of the pharmaceutical composition for treating sleep disorder including monoglyceride of the present invention varies depending on the condition and body weight of the patient, the degree of disease, the drug form, the administration route and the period of time, And can be appropriately selected by a person having ordinary knowledge (hereinafter, ordinary skill in the art). However, for the desired effect, the monoglyceride, etc., which is an effective ingredient according to the present invention, is preferably administered in an amount of 0.01 to 1000 mg / kg, preferably 0.1 to 1000 mg / kg per day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.

For example, monoglycerides and the like, which are active ingredients according to the present invention, can be used as an active ingredient of a pharmaceutical composition for treating sleep disorders by activating GABA _A receptors, particularly GABA _A benzodiazepine receptors.

According to another aspect of the present invention, there is provided a composition for improving sleep time and improving sleep quality, which comprises monoglyceride represented by Chemical Formula 1 or Chemical Formula 2, an isomer thereof or a food engineerally acceptable salt thereof as an active ingredient Functional food composition or health functional food.

As the pharmacologically acceptable salt of the monoglyceride represented by the formula (1) or (2), the above-mentioned pharmaceutically acceptable salts may be mentioned. Examples of the functional food composition of the present invention include food, food additive, beverage or beverage additive.

For example, the food which can contain the monoglyceride according to the present invention includes various foods, beverages, gums, candies, tea, vitamin complex, functional foods and the like. Specifically, examples of the food to which monoglyceride and the like can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gourd, ice cream, Drinks, tea, drinks, alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.

In addition, in the present invention, the food may contain special nutritional foods (eg, crude oil, infant formula, etc.), meat products, fish products, tofu, mackerel, noodles (eg, (Such as soy sauce, soybean paste, hot pepper paste, mixed sauce), sauces, confectionery (eg snacks), dairy products (eg fermented milk, cheese), other processed foods, kimchi, pickled foods But are not limited to, natural flavors (eg, ramen soup, etc.), vitamin complexes, alcoholic beverages, alcoholic beverages and other health supplement foods. The food, beverage or food additive may be prepared by a conventional production method.

Functional foods may include food-grade acceptable food-aid additives and may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of functional foods. When the monoglyceride or the like of the present invention is used as a food additive, the monoglyceride or the like may be added as it is or may be used together with other food or food ingredients, and may be suitably used according to a conventional method. The functional food composition containing the monoglyceride or the like as an active ingredient may further contain an appropriate carrier, excipient and diluent conventionally used in the production thereof. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment).

Alternatively, the amount of the monoglyceride and the like in the functional food composition for improving sleeping time and / or sleep quality may be 0.01 to 50% by weight of the total food, and in the case of the beverage composition, , Preferably 0.01 g to 10 g, based on the total weight of the composition. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, the amount may be less than the above-mentioned range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

The functional food composition includes forms such as tablets, capsules, pills, liquids and the like. The functional food composition or the health functional food is not particularly limited to the other ingredients other than the monoglyceride and the like as essential ingredients in the indicated ratios, and the food supplementary ingredients such as various flavors or natural carbohydrates such as ordinary beverages are added As a component.

Examples of natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose and the like; Sugar alcohols such as xylitol, sorbitol and erythritol, as well as conventional sugars such as polysaccharides such as dextrin and cyclodextrin. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 mL of the functional food composition of the present invention. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition according to the present invention.

In addition to the above, the functional food composition of the present invention may contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and heavies (cheese, chocolate etc.), pectic acid and its salts, And salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, carbonating agents used in alcoholic carbonated beverages, and the like. In addition, the functional food composition according to the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such an additive is not so important, but is generally selected in the range of 0 to about 20 parts by weight, preferably 0.01 to 1.0 part by weight per 100 parts by weight of the monoglyceride and the like of the present invention.

For example, the active ingredient monoglyceride and the like according to the present invention may have an effect such as improving sleep time by activating a GABA _A receptor, particularly a GABA _A benzodiazepine receptor.

Hereinafter, the present invention will be described with reference to exemplary embodiments. The following examples are intended to further illustrate the present invention and are not to be construed as limitations of the present invention.

Example  1: radioisotope [ ³ H] marking Glyceryl Monolinolate  GABA _A - Measurement of benzodiazepine receptor binding activity

[ ³ H] labeling, a radioactive isotope, was used to confirm the binding ability of GABA _A benzodiazepine receptor of glyceryl monolinolate. _A GABA _A benzodiazepine receptor sample was prepared from brain cortical tissue of the brains of Rat cut from the head and glyceryl monolinolate was treated with [ ³ H] flumazenil containing radioisotope by concentration and glyceryl monolinoleate The concentration of benzodiazepine (BDZ) and its binding site were analyzed by measuring the IC ₅₀ ([ ³ H] flumazenil half bound to the receptor). Specific experimental methods are as follows.

Two cerebellar cortices of SD rats (200-250 g) were placed in 10 mL Tris-HCl buffer (30 mM, pH 7.4) and homogenized for 10 seconds in a bead using a tissue syringe. The supernatant was discarded, and 10 mL of Tris-HCl buffer was added to the pellet, followed by washing (centrifugation at 48,000 rpm, 15 minutes) for 3 times. The supernatant was centrifuged at 48,000 rpm for 15 min. 37 water bath for 30 min to remove endogenous GABA. The supernatant was centrifuged (48,000 rpm, 10 min, 4) in a new centrifuge tube, and the supernatant was discarded. 10 mL of Tris-HCl buffer was added to the pellet and centrifuged at 48,000 rpm for 15 min. The supernatant was discarded and 15 mL of Tris-HCl buffer (50 mM, pH 7.4) was added to the pellet and stored at -80 ° C until binding. After dissolving it, 10 mL of 5 samples (5 mL total) was subdivided into 1 mL of tis-citrate buffer (50 mM, pH 7.1, 0-4) and centrifuged at 48,000 rpm for 10 min. And repeated twice. BCA (bicinchoninic acid) was measured and used in accordance with 100 μg of protein.

1) CON (total binding = receptor 329 l + tris-HCl buffer 150 l + radio-ligand 21 l); 2) NSB (non-specific binding = receptor 329 μl + BDZ (10 mg / ml) 100 μl + tris-HCl buffer 125 μl + radio-ligand 21 μl); 3) H10 (25 μl of receptor 329 μl + H (10 mg / ml) + 125 μl of tris-HCl buffer + 21 μl of radio-ligand); 4) H50 (25 μl of receptor 329 μl + H (50 mg / ml) + 125 μl of tris-HCl buffer + 21 μl of radio-ligand); Total concentration of 500 μL, final concentration of 3H of 0.84 nM), glyceryl monolinoleate sample and other substances were measured at a concentration of 1 mg / ml. Incubation was carried out in 0-4 (refrigerator) for 40 minutes, and filtration was performed with a GF / B glass fiber filter. After overnight at 0-4 (refrigerator), the degree of binding was measured according to the following equation (1) using LSC (liquid scintillation counter).

x 100 ( 1) [ ³ H] Binding ( % ) =

x 100 ( 1)

In equation (1), GM means glyceryl monolinoleate sample, and DPM means disintegration per minute. Total binding DPM is the value measured when all isotopes are bound to the binding site with only the isotope at the receptor. Non-specific binding DPM is the result of binding of benzodiazepine to the binding site of the receptor when an isotope is treated with an excess of benzodiazepine and measuring the value of binding of the isotope to another unspecified part of the receptor, do. According to Eq. (1), finally [ ³ H] Binding (%) in which the isotope binds to the receptor can be obtained. Subsequently, the relative value of the binding of the sample to the receptor in place of the isotope according to the following formula (2) was measured and calculated.

According to the method described above, ^[3 H] -flumazenil the method was conducted for GABA _A -benzodiazepine receptor binding assay, are shown in Table 1. The measurement results. Glyceryl monolinoleate, 1-monoglyceride used in the experiment, Sigma; Purity 97%) was 1 ㎎ / ㎖, and the inhibitory activity of the radioactive isotope [ ³ H] -flumazeni 1 (Ro15-1788) was analyzed.

Example  2: radioisotope [ ³ H] < / RTI > Monolinolein GABA _A - Benzodiazepine  Measurement of receptor binding activity

The procedure of Example 1 was repeated except that 1 mg / ml of 2-monolinolein (2-monolinolein, Santa Cruz), which is an isomer of 2-monoglyceride, was used instead of glyceryl monorinolate used in Example 1 And repeated. The measurement results are shown in Table 1 below.

Comparative Example  1 to 8: radioisotope [ ³ H] marking GABA _A - Benzodiazepine  Measurement of receptor binding activity

1 mg / ml of glyceryl stearate as a saturated fatty acid di-glyceride (Comparative Example 1), 1 unsaturated fatty acid mono-unsaturated fatty acid having one double bond as a substitute for the glyceryl monorinolate used in Example 1 1 mg / ml of glyceryl monooleate (Glyceryl monooleate, manufactured by Sigma) (1 mg / ml) (Comparative Example 2), and saturated fatty acid monoglyceride glyceryl monostearate (Sigma) (Comparative Example 5), 1 mg / ml of glyceryl monocaprylate (Sigma) (Comparative Example 4), 1 mg / ml of glyceryl monolaurate (Tokyo Chemical Industry Co., Ltd.) 1 mg / ml of glyceryl monocaprate (Sigma) (comparative example 6), 1 mg / ml of glyceryl monomyristate (Sigma) (comparative example 7), sorbitan monooleate 1 mg / ml (Comparative Example 8) of sorbitan monooleage, Sigma) The procedure of Example 1 was repeated. The measurement results are shown in Table 1.

GABA _A - benzodiazepine receptor binding inhibitory activity of glyceride
Example Sample Inhibitory activity (%)
(Displacement of [< 3 > H] Flumazenil bond) One Glyceryl monolinoleate 50.3 2 2-monolinoleine 40.2 Comparative Example 1 Glyceryl distearate 3.4 Comparative Example 2 Glyceryl monooleate 15.8 Comparative Example 3 Glyceryl monostearate 2.3 Comparative Example 4 Glyceryl monocaprylate 3.4 Comparative Example 5 Glyceryl monolaurate 5.1 Comparative Example 6 Glyceryl monocaprate 2.5 Comparative Example 7 Glyceryl monomyristate 2.6 Comparative Example 8 Sorbitan monolinoleate 10.2

As shown in Table 1, glyceryl monolinoleate, which is an unsaturated fatty acid monoglyceride having two double bonds, exhibited a 50.3% inhibition of receptor binding of [ ³ H] -flumazenil, which is an antagonist of central benzodiazepine receptor 2-monolinolein, which is an isomer of glyceryl monorinolate, also showed an inhibitory activity of 40.2%. In addition, the glyceryl monooleate having one double bond showed a inhibitory activity of 15.8%, and the remaining saturated mono - glycerides showed a very low inhibitory activity and a suppressive activity of about 10.2% or less.

Example  3: Analysis of sleep time and sleep quality by electroencephalogram (EEG) using SD-rat

The glyceryl monorinolate prepared in Example 1 was administered to an animal model, and an electroencephalogram test was conducted (see FIGS. 1 and 2). Animals used in the experiments were Sprague-Dawley (SD rats) with an average weight of 250 g supplied from BioLink (DBL). Experimental animals were adapted to the environment for 5 days and then randomly assigned to 8 animals per treatment group. Experimental animals were maintained at ambient temperature of 20 ~ 22 and relative humidity of 50 ~ 55%. The darkness was controlled by 12 - hour cycle and water and feed were fed free.

Surgery was performed by isoflurane anesthesia, fixed to a stereotaxic device, and an electroencephalogram (EEG) electrode was inserted according to the Paxinos and Watson anatomy. After the operation, the animals were allowed to recover for one week, and then the EEG transmitter was attached and the EEG was measured at 15 mm / sec from 10 am to 6 pm based on the oral administration of the test substance.

Total sleep and sleep quality were analyzed by baseline recording, control recording, and experimental recording of electroencephalogram (EEG) analysis. Types of sleep include Rapid Eye Movement (REM) sleep and Non-rapid eyes movements (REM) sleep. Since the duration of non-rapid eye movements (REM) is more important than the rapid eye movements (REM) sleep time in the quality of sleep, these times were measured separately.

Each of the prepared SD-rats was orally administered with salt water, and the positive control group was 80 ㎍ / kg (corresponding to 160 mg / kg of long root extract) of valerenic acid, which is a main component of the common herbal extract, And 40 ㎍ / kg of glyceryl monolinolate prepared in Example 1 was orally administered to the experimental group. Using these EEGs, a total of 8 hours of EEG was measured from 10:00 to 18:00 for 8 days. The measured EEG was divided into total sleep time, REM sleep time and non-REM sleep time.

Table 2 shows the analysis results according to this embodiment. In the control group Gilchoung extract extract group, the awakening time was significantly decreased and the sleeping time was significantly increased compared to the control group. The non-REM time increased significantly and the REM time decreased significantly, indicating that the increase in sleep time was due to the increase in Non-REM time.

When glyceryl monolinolate was administered, a significant decrease in awakening time was observed compared with the normal control group. As a result, sleep time was significantly increased in the glyceryl monolinoleate-treated group, and a significant increase in non-REM time and a significant decrease in REM time were observed compared with the normal control group.

The non-REM was 4.9 hours compared with valerenic acid, which is a functional ingredient of the extract, and the sleep time of the rat treated with glyceryl monorinolate was about 15% longer than 5.5 hours . Therefore, glyceryl monolinoleate was found to have the same sleeping time and NREM sleeping effect as those of general medicine.

Sleeping Effect of Monoglyceride Total sleep time Sleep time (Non-REM sleep) Hour % hour % Negative control 6.09 100 4.14 100 Valerenic acid 6.33 103 4.91 118 Glyceryl momolinoleate 6.52 107 5.51 133

Manufacturing example  One: Sanje  Produce

Glyceryl monorinolate 10 mg

Lactose 100 mg

Talc 35 mg

The above components are mixed and filled in airtight bags to prepare powders.

Production Example 2: Preparation of tablets

Glyceryl monorinolate 10 mg

Amorphous cellulose 400 mg

150 mg of maltodextrin

Magnesium stearate 2 mg

After mixing the above components, they are prepared by tableting according to a conventional preparation method of tablets.

Preparation Example 3: Preparation of a knife preparation

Glyceryl monorinolate 10 mg

Crystalline cellulose 5 mg

Lactose 25 mg

Magnesium stearate 2 mg

1 mg of hydroxypropylmethylcellulose

Glycerin fatty acid ester 0.5 mg

Manufacturing example  4: Manufacture of functional beverage

Glyceryl monorinolate 100 mg

Citric acid 300 mg

Oligosaccharide 20 g

Barley extract concentrate 3 g

Brown Rice Extract Concentrate 2.5 g

0.5 g of pure white sugar

Purified water 300 ml

The ingredients were mixed according to a conventional beverage manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour, and the resulting solution was filtered to obtain a sterilized container. The resulting solution was sealed and sterilized, It is used to make beverage composition.

Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.

Although the present invention has been described based on the exemplary embodiments and examples of the present invention, the present invention is not limited to the technical ideas described in the above embodiments and examples. Those skilled in the art will appreciate that various modifications and changes may be made without departing from the spirit and scope of the present invention as defined by the appended claims. It is apparent, however, that the appended claims are intended to cover all such modifications and changes as fall within the true scope of the invention.

Claims (6)

1. A pharmaceutical composition for treating a sleep disorder comprising monoglyceride represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
Formula 1

(In the formula (1), any one selected from R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₄ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)
The method according to claim 1,
Wherein the active ingredient is a monoglyceride represented by the following formula (2), an isomer thereof, or a pharmaceutically acceptable salt thereof.
(2)

(In Formula 2, any one selected from R ₄ and R ₅ is a C ₁₆ -C ₂₀ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)
3. The method according to claim 1 or 2,
Wherein the effective ingredient is contained in the pharmaceutical composition at a concentration of 0.01 to 1000 mg / ml.
A functional food composition for improving sleeping time and improving sleep quality, comprising monoglyceride represented by the following formula (1), an isomer thereof or a bioengineered salt thereof as an active ingredient.
Formula 1

(In the formula (1), any one selected from R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₄ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)
5. The method of claim 4,
Wherein the active ingredient is a monoglyceride represented by the following general formula (2), an isomer thereof or a food engineerally acceptable salt thereof.
(2)

(In Formula 2, any one selected from R ₄ and R ₅ is a C ₁₆ -C ₂₀ unsaturated fatty acid ester having two double bonds, and the remainder is a hydroxyl group (-OH)
The method according to claim 4 or 5,
Wherein the active ingredient is contained in the functional food composition at a concentration of 0.01 to 1000 mg / ml.

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