KR20150139508A - Yeast culture, and composition for internal application - Google Patents

Abstract

It is an object of the present invention to provide yeast cultures and compositions having high methylthioadenosine content, and to provide novel uses of the yeast cultures and compositions. The present invention relates to a yeast culture comprising methylthioadenosine or a salt thereof and having a methylthioadenosine content of more than 5.5 mass% and yeast and methylthioadenosine or a salt thereof, wherein the content of methylthioadenosine or its salt And the content of methylthioadenosine in relation to the total content of yeast is 1/10000 or more and 1/2 or less. The yeast culture may be prepared by heating or standing a yeast culture containing S-adenosylmethionine or a salt thereof. The yeast cultures and underwear compositions are useful as active ingredients of sleep accelerators.

Description

YEAST CULTURE AND COMPOSITION FOR INTERNAL APPLICATION [0002]

The present invention relates to yeast cultures, underwear compositions and uses thereof.

Methylthioadenosine is known as a biocomponent. Non-Patent Document 1 discloses that S-adenosylmethionine and methylthioadenosine are contained in a yeast culture broth in a sake brewing process, and when Sangju is burned, S- It is described that adenosylmethionine is converted to methylthioadenosine. Patent Document 1 discloses that methylthioadenosine is formed when a microorganism having an S-adenosyl methionine producing function is cultured in a methionine-containing medium (medium), and the maximum value is the amount of methylthioadenosine in the dried bacterial body Amount) is 0.0204% (see Comparative Example of Patent Document 1).

In Non-Patent Document 2, it is described that the addition of methylthioadenosine increases the cAMP concentration in S49 cells, and that an increase in cAMP concentration is involved in growth inhibition.

Patent Document 1: Japanese Patent Application Laid-Open No. 58-146291

Non-Patent Document 1: J. Soc. Brew. Japan 70 (8) 585-587, 1975 Non-Patent Document 2: Biochem Pharmacol. 33 (22): 3639-43., 1984

However, the content of methylthioadenosine in the raw wheat and the content of methylthioadenosine in the culture in Patent Document 1 in the non-patent document 1 were all small. In addition, Non-Patent Document 2 does not describe any effect other than growth inhibition as an effect due to an increase in cAMP concentration.

It is an object of the present invention to provide yeast cultures and compositions having high methylthioadenosine content, and to provide novel uses of the yeast cultures and compositions.

The present invention provides the following [1] to [12].

[1] A yeast culture comprising methylthioadenosine or a salt thereof and having a methylthioadenosine content of 5.5 mass% or more per dry mass of the yeast culture.

[2] Yeast culture containing S-adenosylmethionine degradation product.

[3] The yeast culture according to [2] above, wherein the S-adenosyl methionine degradation product comprises methylthioadenosine.

[4] The yeast culture according to [3], wherein the methyl thioadenosine content per dry mass of the yeast culture is 5.5% by mass or more.

[5] The yeast culture according to any one of [1] to [4] above, wherein the yeast culture containing S-adenosyl methionine or a salt thereof is heated to decompose S-adenosylmethionine or a salt thereof Way.

[6] A pharmaceutical composition comprising a yeast and methylthioadenosine or a salt thereof, wherein A / (A + B) is 1/10000 or more and 1/2 or less, wherein A represents the methylthioadenosine content in the composition, Yeast content, respectively).

[7] The underwear composition according to [6], wherein A / (A + B) is 1/750 or more to 1/5 or less.

[8] The underwear composition according to [6], wherein A / (A + B) is not less than 1/100 and not more than 1/5.

[9] The underwear composition according to the above [6], wherein A / (A + B) is 5.5 / 100 or more and 1/5 or less.

[10] A sleep accelerator comprising the yeast culture according to any one of [1] to [4] and / or the underwear composition according to any one of [6] to [8]

[11] The sleep accelerator according to the above [10], wherein the intake amount of methylthioadenosine per adult is 0.01 to 1000 mg / day.

[12] A food and drink composition containing the sleep accelerator according to the above [10] or [11].

Further, the present invention can provide the following embodiments in other aspects.

(1) A yeast culture according to any one of [1] to [5], or a composition for underwriting according to any one of the above [7] to [10].

(2) The method of (1) above, wherein the yeast culture according to any one of the above [1] to [5] or the underwear composition according to any one of the above [7] to [10] is orally administered.

(3) Use of the yeast culture according to any one of [1] to [5] or the underwear composition according to any one of the above [7] to [10] for producing a sleep accelerator.

According to the present invention, yeast cultures and compositions having a high methylthioadenosine content are provided. The yeast cultures and compositions of the present invention are capable of promoting sleeping and can lead to good natural sleeping.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a chart showing a general pattern of the REM sleep and the NEMEM sleep. FIG.
2 is a graph showing the results of Experimental Example 1. Fig.

[Explanation of common terms]

The yeast in the present invention is not particularly limited as far as it is a fungus in which most of the life circle (ring) passes through a single cell and budding (budding), or cell wall breakdown occurs. Examples of the yeast include yeasts of the genus Saccharomyces, yeasts of the genus Shi osaccharomyces, yeasts such as Saccharomyces cereviciae, Shi osaccharomyces pombe (fission yeast) is preferred.

The yeast culture in the present invention means a mixture obtained by culturing yeast in a medium. The mixture usually contains yeast cells, cell components (crushed pieces of cells), products produced by the yeast metabolism, and the like. The yeast may be either a live cell or a dead cell.

Culturing of the yeast may be carried out according to a usual method according to the culture conditions suitable for the species to which the yeast strain to be used belongs. The medium used for the culture is not particularly limited and may include components used in a medium used for culturing ordinary microorganisms such as a carbon source, a nitrogen source, and an inorganic salt. Examples of the carbon source include glucose, sucrose, acetic acid, ethanol, molasses, sulfurous acid pulp, and the like. Examples of the nitrogen source include nitrogen-containing organic substances such as urea, ammonia, ammonium sulfate, ammonium chloride, ammonium chloride and the like, nitrogen-containing inorganic salts such as konsepti- liquor (CSL), casein, yeast extract and peptone . Examples of the inorganic salt include phosphate such as superphosphate lime and ammonium phosphate; Potassium salts such as potassium chloride and potassium hydroxide; Magnesium salts such as magnesium sulfate and magnesium chloride; zinc ; Copper ; Manganese; Iron ions. The medium may also contain components such as vitamins, nucleic acid-related substances, amino acids, and the like. It is preferable that the medium contains at least ethanol and an amino acid (e.g., methionine). When the medium is a solid medium, agar or the like is usually added.

The medium may be solid or liquid. As a culture medium in the case of a liquid medium, for example, batch culture, flow culture, continuous culture and the like may be mentioned, and any of them may be employed.

The incubation temperature may be between 6 캜 and 35 캜, usually between 20 and 35 캜, and preferably between 25 and 32 캜. The incubation time is usually 1 day to several days, preferably 2 days to 10 days.

In the present invention, methylthioadenosine is also referred to as 5'-deoxy-5'-methylthioadenosine. 5'-Dioxy-5'-methylthioadenosine may be in any form of an anti-type or syn (syn) type. Hereinafter, in the present specification, methylthioadenosine or its salt is abbreviated as MTA in some cases.

The salt of methylthioadenosine is not particularly limited as long as it is a pharmacologically acceptable salt, and it may be selected in response to the formulation or the like. Examples of suitable salts of methylthioadenosine include, for example, acid addition salts. The acid addition salt may be any one of inorganic acid addition salts and organic acid addition salts such as hydrochloride, sulfate, nitrate, carbonate, phosphate, formate, oxalate, citrate, ascorbate, methanesulfonate, 1,4 -Butane disulfonic acid salt, 1,5-pentane disulfonic acid salt and p-toluenesulfonic acid salt.

In the present invention, S-adenosylmethionine has a structure in which adenosine and methionine are linked through a methylsulfonyl bond. The optical isomers of methionine include L-isomer, D-isomer and DL-isomer. In the present invention, methionine in the structure of S-adenosylmethionine may be any of the above optical isomers.

The salt of S-adenosylmethionine is not particularly limited as long as it is a pharmacologically acceptable salt, and it can be selected in response to a formulation or the like. Examples of suitable salts of S-adenosylmethionine include acid addition salts and halides, and specific examples thereof include hydrochloride, sulfate, p-toluenesulfonate (tosylate), sulfuric acid-p-toluenesulfonate , Methanesulfonic acid, trifluoromethanesulfonic acid, 1,4-butane disulfonic acid, 1,5-pentanesulfonic acid, phosphates, chlorides, bromides and the like. Of these, a hydrochloride or a tosylate is preferable.

The yeast may contain at least any one of methylthioadenosine and its salt, and may contain both of them.

[First yeast culture of the present invention]

As a preferred embodiment of the yeast culture of the present invention, yeast cultures containing methylthioadenosine or its salt can be mentioned.

The content of methylthioadenosine or its salt in the yeast culture can be expressed as methylthioadenosine content per dry mass of the yeast culture. The content (content) of methylthioadenosine per dry mass means the percentage of the mass of the methylthioadenosine contained in the yeast culture to the total amount of the yeast culture. When the yeast culture contains a methylthioadenosine salt, the mass of the salt portion of the methylthioadenosine salt is not included in the " mass of purity of methylthioadenosine ". The methylthioadenosine content is preferably 5.5% by mass or more, more preferably 7% by mass or more, and further preferably 8% by mass or more. Thus, the yeast culture of the present invention can effectively exert physiological effects of methylthioadenosine or its salts. The upper limit of the methylthioadenosine content is usually 50 mass% or less, preferably 40 mass% or less, more preferably 30 mass% or less, further preferably 20 mass% or less, still more preferably 15 mass% Or less.

In addition, when the lower limit of the methylthioadenosine content per dry mass of the yeast culture is set to 5.5 mass% or more, a high water-inducing effect can be obtained.

The methylthioadenosine content per dry mass in the yeast culture can be defined, for example, by the following equation (1).

Equation (1)

The methylthioadenosine content per dry mass of the yeast culture

= (a / b) x 100

(A) in the formula (1) is the methylthioadenosine content (g) of the methylthioadenosine content (not including the mass of the salt portion of the methylthioadenosine salt) in a certain amount collected from the yeast culture. Quantitative determination as methylthioadenosine can be carried out by liquid chromatography. b is the dry weight (g) after lyophilization (trap cooling temperature-75 ° C) for 24 hours of the yeast culture in an amount the same as that obtained in the measurement of a above.

The yeast culture containing methylthioadenosine or its salt may contain methylthioadenosine or a salt thereof, or may contain methylthioadenosine or a salt thereof in addition to yeast cells.

The yeast culture of the first aspect of the present invention is presumed to include any component that improves the physiological activity of methylthioadenosine or a salt thereof (for example, a cAMP concentration elevation activity, a sleep promoting activity, etc.). Therefore, the first yeast culture of the present invention can be used for various uses exhibiting the aforementioned physiological activity.

[Second yeast culture of the present invention]

Another preferred state of the yeast culture of the present invention is a yeast culture containing a degradation product of S-adenosylmethionine or its salt.

The decomposition product of S-adenosylmethionine or its salt means a component produced by decomposition of S-adenosylmethionine and a component produced by decomposition of a salt of S-adenosylmethionine. Examples of the decomposition products of S-adenosylmethionine or its salts include methylthioadenosine, S-adenosylhomocysteine, S-adenosylmethioniamine, S-aminobutylolactone, adenosine, methionine, adenine, inosine, homoserine , Homocysteine, cystathionine, and the like. The decomposition product of S-adenosyl methionine may be a single component or a combination of two or more components. The decomposition product of S-adenosylmethionine is preferably methylthioadenosine or at least methylthioadenosine, more preferably methylthioadenosine or a salt thereof.

The decomposition product of S-adenosylmethionine or its salt may be a decomposition product of S-adenosylmethionine, a product of decomposition of S-adenosylmethionine salt, a product of decomposition product of S-adenosylmethionine and a product of decomposition product of S-adenosylmethionine salt .

The conditions for the decomposition in the decomposition products of S-adenosylmethionine or its salts are not particularly limited. Examples of the decomposition include decomposition by heating, decomposition by an enzyme, decomposition by an acid, decomposition by an alkali, and decomposition by a chemical reaction. Among them, decomposition by heating is preferable.

The content of the degradation product of S-adenosylmethionine or its salt in the yeast culture can be expressed as the content of methylthioadenosine contained in the degradation product per the dry mass of the yeast culture. The methylthioadenosine content (content ratio) per dry mass means the percentage of the mass of the pithy methylthioadenosine contained in the yeast culture to the total amount of the yeast culture. When the yeast culture contains a methylthioadenosine salt, the mass of the salt portion of the methylthioadenosine salt is not included in the " mass of purity of methylthioadenosine ". The content of methylthioadenosine per dry mass in the yeast culture of the present invention is preferably 5.5% by mass or more, more preferably 7% by mass or more, and further preferably 8% by mass or more. Thus, the yeast culture of the present invention can effectively exert physiological effects of methylthioadenosine or its salts. The upper limit of the methylthioadenosine content is usually 50 mass% or less, preferably 40 mass% or less, more preferably 30 mass% or less, further preferably 20 mass% or less, still more preferably 15 mass% Or less. Measurement of the methylthioadenosine content per dry mass in the yeast culture is as described in the section of the first yeast culture of the present invention.

The yeast culture containing the degradation product of S-adenosylmethionine or its salt may contain the degradation product of S-adenosylmethionine or its salt, the yeast may contain the degradation product of S-adenosylmethionine or its salt There may be.

The second yeast culture of the present invention is characterized in that the physiological activity (for example, the physiological activity of methylthioadenosine in the cell, the intracellular cAMP concentration elevation activity, the sleep-promoting activity, etc.) of the degradation product of S- ≪ / RTI > Therefore, the second yeast culture of the present invention can be used for various uses exhibiting the aforementioned physiological activity.

[Method for producing yeast culture of the present invention]

The method for producing the yeast culture of the present invention is not particularly limited, but the yeast culture containing S-adenosylmethionine or a salt thereof can be easily produced by heating the yeast culture, and the above-mentioned method is preferable. It is preferable that all of the first yeast culture and the second yeast culture of the present invention are produced by the above-mentioned method.

The yeast containing S-adenosylmethionine or its salt may be a yeast originally containing S-adenosylmethionine or a salt thereof, or may be a yeast containing S-adenosylmethionine or a salt thereof and a yeast containing S- The obtained yeast may be obtained by producing methionine. Examples of a method of producing S-adenosylmethionine or a salt thereof in yeast include a method in which yeast is cultured to produce S-adenosylmethionine or a salt thereof in yeast (intracellularly). In this method, the obtained culture solution may be used as a yeast culture containing S-adenosylmethionine or a salt thereof as it is, and the yeast recovered after cultivation may be used as a yeast containing S-adenosylmethionine or a salt thereof . The yeast culture in a dry state obtained by allowing the culture medium after the culture to be cultured or collected (collected) and then dried may be used. In the present invention, it is preferable to use a yeast culture containing S-adenosylmethionine or a salt thereof in a dry state.

Further, components such as a stabilizer and an excipient may be added to the yeast culture after weighing with the formula (1), and then the following heating operation may be carried out.

Conditions for heating yeast cultures containing S-adenosylmethionine or salts thereof are not particularly limited. The temperature is usually 40 占 폚 or higher, preferably 50 占 폚 or higher, more preferably 60 占 폚 or higher, and even more preferably 80 占 폚 or higher. The upper limit is usually 200 占 폚 or lower, preferably 180 占 폚 or lower, more preferably 160 占 폚 or lower, and even more preferably 120 占 폚 or lower. But it is usually 40 to 200 ° C, preferably 50 to 180 ° C, more preferably 60 to 160 ° C, and even more preferably 80 to 120 ° C. The treatment time may be controlled by the degree of production of methylthioadenosine or a salt thereof.

The heating method is not particularly limited. Examples of the heating method in the case of a liquid yeast culture include a method in which a container containing a yeast culture is heated with a heating device such as a direct heating or an electric heating heater while being stirred, A method of placing the yeast culture in a container with a water jacket and heating the same through a bath or steam in a water jacket, a method in which the yeast culture is heated in a hot water jacket, A method in which a container filled with water is heated by a heat exchange type plate heater, a method in which a container containing a yeast culture is sealed, a container is heated with hot water, a method in which heating is performed using electromagnetic waves (microwave) A heating method, a method of heating by an autoclave, a method of heating by a dryer such as a fluidized bed dryer, a shelf dryer and the like. Examples of the heating method in the case of a solid yeast culture such as a powder include a method of heating with an autoclave, a method of heating a sealed container by applying hot water, a fluidized bed dryer, a rotary ventilation dryer, a shelf dryer , A method of heating with a dryer of an electric furnace, and a method of heating with a distributor (roasting machine).

After the heating or standing treatment, the yeast culture is subjected to a drying treatment to obtain a yeast culture having a high methylthioadenosine or its salt content. The method of drying the culture is not particularly limited, and any of the preparation methods usually used in the preparation of the dry yeast strain may be used. For example, the freeze-drying method, the spray drying method, the drum drying method . Further, by culturing the obtained dry yeast culture in powder form, a yeast culture having a high content of methylthioadenosine or its salt having excellent handling properties can be obtained.

[Underwear composition of the present invention]

The underwear composition of the present invention comprises yeast and methylthioadenosine or a salt thereof.

Methylthioadenosine or a salt thereof may be obtained by a known method or may be a commercially available product. Commercially available products of methylthioadenosine or its salts include, for example, a commercially available product of Sigma-Aldrich, a commercially available product of Santa Cruz, and the like. In addition, some or all of methylthioadenosine may be contained in the yeast.

The yeast may be any of live cells, dead cells, and cell components. Yeast may be commercially available.

The yeast may be a single species, or may be a combination of two or more species of different kinds, forms, and the like. Methylthioadenosine and its salts may be used alone or in combination of two or more such as chemical structure, salt type and form. The underwear composition may contain at least any one of methylthioadenosine and its salt, and may contain both of them.

In the underwear composition of the present invention, the mass ratio represented by the following formula (2) is preferably 1/10000 or more and 1/2 or less, more preferably 1/750 or more or 1/5 or less, More preferably not less than 5.5 / 100 nor more than 1/5. Thereby, an excellent sleep promoting effect can be obtained. The bitterness (bitterness) of methylthioadenosine and the yeast remaining in the mouth can be reduced at the same time when A / (A + B) is 5.5 / 100 or more and 50/100 or less:

Equation (2)

A / (A + B)

In the formula (2), A is the methylthioadenosine content in the composition. The methylthioadenosine content in the composition means the amount of the purity of methylthioadenosine contained in the composition. When the underwear composition contains a methylthioadenosine salt, the methylthioadenosine content does not include the mass of the salt portion of the methylthioadenosine salt. When the yeast contains methylthioadenosine or its salt, the amount of methylthioadenosine in methylthioadenosine or its salt contained in the yeast is also reflected in methylthioadenosine content. In the formula (2), B is the yeast content in the composition.

In the production of the underwear composition of the present invention, the yeast may be mixed with methylthioadenosine or a salt thereof, and the production conditions are not particularly limited. When mixing, a solvent (such as a methyl cellulose aqueous solution) may be used.

The form of the presence of yeast and methylthioadenosine or a salt thereof in the underwear composition of the present invention is not particularly limited. Normally, the yeast may contain a part or all of methylthioadenosine or a salt thereof.

The underwear composition of the present invention can be prepared by combining a yeast with methylthioadenosine or a salt thereof to improve the physiological activity of methylthioadenosine or a salt thereof (for example, an activity of increasing intracellular cAMP concentration, . Therefore, the underwear composition of the present invention can be used for various uses exhibiting the aforementioned physiological activity.

[Sleep accelerator]

Since the yeast culture and the underwear composition of the present invention exert a natural sleep promoting effect, each of them or a combination of the two is preferably used as a sleep accelerator (sleep accelerating composition), especially a Nemem sleep accelerator, more preferably deep Sleep) accelerators (deep sleep accelerating compositions).

The sleep-promoting effect means an effect of extending the ratio of the time of the sleeping time to the sleeping time in the sleeping time. Nomplex sleep can be judged by polygramming analysis (brain waves, eye diagrams, electromyograms, etc.). As the brain wave, the nominal sleep surface can be judged by the decrease of the alpha wave (for example, 8 to 3 Hz as human) and the increase of the delta wave (for example, 0.5 to 4.5 Hz for human). The measured EEG can also be determined by using automatic analysis software such as SleepSign (registered trademark). It is preferable that the ratio of the time of the deep water surface in the time of the Nemem water surface is high.

Means that the state of the Nemem sleep surface is observed for a longer period of time, 2) the depth of the Nemem sleep surface is shorter than the depth of the Nemem sleep surface (i.e., Or 3) the transition to the Nemem surface is performed more smoothly.

The term " deep water surface " refers to a water surface in which the depth of the water surface is a certain level or more in the case of humans, and the water surface state in the depth of the third or higher layer It says. It is known that the occupancy rate of the delta wave (0.5 to 4.5 Hz) against the entire EEG (0.5 to 20 Hz) is higher than a certain level, and the higher the occupancy rate is, the higher the delta power value is in the sleep of the III and IV layers. Therefore, a deep surface can be defined as a surface with a high delta power value. The delta power value can be measured using, for example, a polysomnography testing apparatus, and the depth of the water surface and the sum of the time, the size of the deep water surface, and the delta power value are defined as times multiplied by the delta power value.

The term " accelerating the deep water surface " means that the condition of the deep water surface is observed for a longer period of time, 2) the depth of the deep water surface is deeper than that of the state of contrast (for example, Or 3) the transition to the deep water surface proceeds more smoothly. That is, in an experimental system using a mouse or a guinea pig, the value obtained by multiplying the delta power value by the time can be increased.

"Natural water surface" refers to water surface that does not cause disappearance of cliff reflex (direct reflection). The term " cling reflection " is a reflection movement that causes the head to return to its normal position with respect to the direction of gravity, and is also referred to as righting reflex.

For example, a mouse or a rat placed in a supine position or a dorsal position returns to the abdominal position within 30 seconds in a rodent animal such as a mouse or a rat, It can be confirmed as a non-coming state. When the animal in a sleeping state is put in a supine position or a coordinate, it is instantly wakened from the water surface, or when it returns to the rapid return rapidly, the sleep surface is a sleep surface that does not lose the clitoral reflection. As human beings, there is no term equivalent to "cliff reflex" defined in animals. However, in the human condition, the state in which the cliff reflex is not lost can be defined as a natural sleep surface, for example, a sleeping surface that can be awakened easily, for example, when the shoulder is struck and wakes up immediately.

For natural sleep, anesthesia causes closure loss. The disappearance of the cling reflection in a mouse or a rat is known as an evaluation index of the anesthetic effect. The anesthetic effect by an anesthetic such as pentobarbital or other drugs can be evaluated by an increase in the number of animals with the above-mentioned disappearance of the cystic reflex. Further, by analyzing the frequency distribution by the Fourier transform analysis with respect to EEG at the time of sleep by sleeping medicine as an anesthesia or a conventional medicine, and sleeping without using an anesthesia or a conventional sleeping medicine, (0.5 to 4.5 Hz) increases in brain waves, but in anesthesia or hypnosis by conventional sleeping medication, 15 to 20 Hz fh, anesthesia or conventional sleeping pills are used When not sleeping, an increase in EEG frequency is observed. It is not known at the present time what the EEG frequency of the unseen frequency is derived from when sleeping without anesthesia or conventional sleeping medication, but it is not known yet, but the anxiety due to anesthesia or conventional sleeping medication is poor And so on.

The content of the yeast culture in the water surface-promoting agent of the present invention is not particularly limited and can be suitably adjusted in accordance with various conditions such as an effective amount capable of exerting the effect. The content of the underwear composition in the sleep accelerator of the present invention is not particularly limited and can be suitably adjusted in accordance with various conditions such as an effective amount capable of exerting the effect.

The sleep accelerator of the present invention may be mixed with or used in combination with a component capable of accelerating the water surface (including sleeping pills) other than the yeast culture and the underwear composition of the present invention. Herein, the sleeping medicines may include, for example, those referred to as sleeping agents, sleeping agents, and the like. However, any form of mixing with an anesthetic agent of the kind or amount that causes a loss of clenching is excluded.

The sleeping accelerator of the present invention can be prepared from only the yeast culture and / or the underwear composition of the present invention, or the yeast culture and / or the underwear composition of the present invention, the yeast culture, (Composition) containing one or more of the other ingredients.

The other components included in the sleep accelerator of the present invention are not particularly limited so long as they do not substantially impair the effect of the present invention. Examples of the other components include an excipient, a disintegrant, a binder, a lubricant, a coating agent, a colorant, a colorant, a mating agent, a flavoring agent, an antioxidant, an antiseptic, Thickeners, surfactants, and other pharmacologically acceptable additives. Among them, it is preferable to use a composition which does not deteriorate the effect of accelerating the water surface and various properties (for example, formulation stability) necessary for the preparation, and also the quality of the final product (such as food and drink, medicines, ), Etc.) can be selected from one or more kinds of additives. The other components included in the sleeping accelerator of the present invention may be one kind or a combination of two or more kinds.

The formulation of the sleeping accelerator of the present invention is not particularly limited as long as it is a form capable of using the yeast culture and / or the underwear composition of the present invention as an active ingredient. Examples of formulations for oral administration include liquid (liquid), syrup (syrup), solid (tablets), capsules (capsules), powder (granules, Soft capsules), semi-liquid, cream, and paste. Examples of formulations in the case of parenteral administration include liquid preparations (injecting agents, point nasal preparations), aerosols (spray preparations, inhalants) and the like. Such formulations may be prepared by mixing the yeast cultures of the present invention with a pharmaceutically acceptable medium.

The dosage of the sleeping accelerator of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately adjusted depending on factors such as the age and condition of the body to be administered. A preferable dosage for achieving the desired effect is the dose (mg / day) of methylthioadenosine or its salt per day for an adult, the lower limit thereof is preferably 0.01 mg or more, more preferably 0.1 mg or more Preferably 1 mg or more, and even more preferably 10 mg or more. The upper limit thereof is preferably 1000 mg or less, more preferably 500 mg or less, and still more preferably 100 mg or less.

The dosage form of the sleeping accelerator of the present invention is not particularly limited and may be any of oral administration and parenteral administration, but oral administration is preferable because it is less invasive (invasive). Examples of the oral administration include intraoral administration, sublingual administration, and the like. Examples of the parenteral administration include intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, transdermal administration, and parenteral administration.

Although the time for administration of the sleep accelerator of the present invention is not particularly limited, it is usually administered before bedtime, preferably between 3 hours before going to bed and going to bed, more preferably from 2 hours before bedtime to bedtime , It is more preferable to be administered between one hour before bedtime and bedtime, and it is more preferable to be administered one hour before bedtime.

The subject to be ingested by the sleeping accelerator of the present invention is not particularly limited. Examples of the subject to be ingested include subjects who are shallow to sleep, sleepy at the time of the weather, have a bad sleep, lack sleepiness (can not sleep deeply), dream dreams are bad, A person who is dissatisfied with the subject, a person who is feeling fatigue and wants to improve the subjective sleep feeling, and the like. In addition, subjects who do not have a particular problem can be taken on a daily basis for the purpose of maintaining a good sleep, preventing sleeping disorder, and accelerating natural sleep.

The sleep accelerator of the present invention may be used as an additive for food and drink, an additive for medicine, and an additive for quasi-drug. As a result, the effect of promoting natural sleep can be imparted to the food, medicine, and quasi-drugs.

[Food and drink of the present invention]

The food or drink containing the water-swelling agent of the present invention can be used as a food or drink that is expected to have the sleeping-promoting effect as described above and the accompanying effect. Examples of such food and drink include health food, functional food, nutritional supplement (supplement), specific health food, medical food, patient food, infant food, nursing food, and food for the elderly.

The sleeping accelerator of the present invention can increase the sleeping time of the non-sleeping water during sleep as compared with the case where the sleeping accelerator of the present invention is not administered, as shown in the following examples. Therefore, it is expected to be applied to the prevention and treatment of diseases which are associated with shortening of the sleeping time of the Nemem or reduction of the depth of the water surface, or both of which are associated with a deterioration of the sleep quality.

The sleep accelerator of the present invention can be used as a natural sleep inducer because it can accelerate natural sleep. The term " inducing natural sleep " refers to a phenomenon that causes sleep that does not cause disappearance of the cliff reflex. The natural sleeping inducer of the present invention can promote natural sleeping, so that a good sleeping pattern can be eliminated or a disrupted sleeping pattern can be restored to a good sleeping pattern. When the sleep-promoting agent of the present invention is used as a natural sleep inducing agent, the embodiment of the sleep-promoting agent of the present invention may be applied to embodiments such as the dosage.

[Food and drink of the present invention]

The form of the food or drink of the present invention is not particularly limited and includes, for example, beverages (soft drinks, carbonated drinks, nutritional drinks, powder drinks, fruit drinks, milk drinks, jelly drinks, (Hamburger, ham, sausage, shrimp, sherbet, etc.), processed fish products (fish paste, fish skewers, hanpen, etc.), livestock products (hamburger, ham, sausage, (Mayonnaise, shortening, dressing, sauces, etc.), soups (powdered soups, liquid soups, etc.), stocks (such as butter, yogurt, cream, margarine, and fermented milk) Dense broth, soy sauce, etc.). Further, the food or drink of the present invention is useful as a health food, a functional food, a health supplement food, a nutritional supplement food, a specific health food, a medical food, a patient food, a baby food, a nursing food, . Of these, health supplements are preferred, and health supplements on tablets are more preferred.

Example

Hereinafter, the present invention will be described concretely with examples, but the present invention is not limited to the following examples.

Examples 1 to 13 and Comparative Examples 1 to 3

<Preparation of sample>

In Examples 1 to 2, 8 to 13 and Comparative Examples 2 to 3, yeast (manufactured by Nissei Food Co., Ltd., trade name: Nissei Supercarriya Dryest) and methylthioadenosine or its salt (hereinafter referred to as MTA) Deoxy-5 '- (methylthio) adenosine) manufactured by Sigma-Aldrich Co., Ltd. was mixed so that the mass ratio of MTA to the whole mixture was as shown in Table 1. The resulting composition was used as a sample.

In Examples 3 to 7, yeast cultures containing MTA (hereinafter referred to as MTA-containing yeast cultures) were used, respectively. The preparation method of the MTA-containing yeast culture was carried out as follows. Yeast culture powder containing S-adenosylmethionine or its salt (manufactured by Iwata Chemical Co., Ltd., trade name: Ami) was heated at 120 DEG C for 20 minutes using a drier to obtain an MTA-containing yeast culture. bracket

The mass ratio of MTA in the examples is shown in Table 1.

[Table 1]

Footnotes in Table 1

*: The &quot; mass ratio &quot; is the ratio of the methylthioadenosine content to the sum of the methylthioadenosine content and the yeast content when the sample is a composition. If the sample is an MTA-containing yeast culture, it is the mass ratio of the MTA in the yeast culture.

The content of methylthioadenosine in the yeast culture of the sample is defined by the above-mentioned formula (1). For example, the sample of Example 1 was measured by a high-performance liquid chromatography method by a known method in which S-adenosylmethionine and MTA can be separated. The methylthioadenosine content when the sample is a composition is defined by the above-described formula (2).

<Experimental Example 1>

For each of the samples of Examples 1 to 13 and Comparative Examples 1 to 5, HEK cells (cAMPZen (cAMP assayed cultured cells)) were allowed to act for 30 minutes. Subsequently, Eu-cAMP tracer and ULight-anti-cAMP (all reagents in LANCE Ultra cAMP Kit, manufactured by Perkin-Elmer) were added to measure intracellular cAMP concentration by FRET (fluorescence resonance energy transfer) &Lt; / RTI &gt; Then, the signal value was measured under the following conditions. The intracellular cAMP concentration elevating activity was calculated by the following formula (3).

<Measurement Conditions>

Excitation wavelength: 320nm

Emission wavelength: 665nm

Integration time: 100 ㎲

Lag time: 50 μs

<Formula>

Equation (3):

Intracellular cAMP concentration elevation activity% =

 {(Fluorescence signal value when no sample is added - fluorescence signal value of sample) /

 (Fluorescence signal value at the time of no sample addition-fluorescence signal value at the time of single administration of MTA)}

 × 100

The results of intracellular cAMP concentration-uptake activity of the respective examples are shown in Fig. 2, the following is evident.

In Examples 1, 2, and 8 to 13, the activity was higher than that of Comparative Examples 1 to 5. This indicates that the composition of the present invention has an effect of increasing intracellular cAMP concentration.

In Examples 3 to 7, activity was higher than in Comparative Examples 1 to 5. This indicates that the yeast culture of the present invention has an effect of increasing intracellular cAMP concentration.

In Examples 7 and 8, although the mass ratio of MTA was the same, Example 7 was more active than Example 8. This indicates that when the MTA is contained in the yeast, the effect of increasing the intracellular cAMP concentration is more remarkable than when the yeast is added to the MTA.

The increase in intracellular cAMP levels in the sleep apnea is thought to lead to the promotion of sleep. From this, it is presumed that the composition of the present invention and the culture of yeast exert a sleep-promoting effect.

Example 14 and Comparative Examples 6 to 8

&Lt; Evaluation sample and dose >

As a sample (control solution) of Comparative Example 6, a 0.5 mass% methyl cellulose aqueous solution was used. The dose was 10 ml / body weight (kg).

The sample of Comparative Example 7 was prepared by suspending MTA (Sigma-Aldrich, trade name: 5'-Deoxy-5 '- (methylthio) adenosine) in an aqueous solution of 0.5% by mass methyl cellulose (Sigma-Aldrich, Respectively. The dose was 15 mg / body weight (kg) (10 ml / body weight (kg) as suspension) as the amount of MTA.

The sample of Example 14 was prepared as follows. A commercially available S-adenosylmethionine-containing yeast culture powder (trade name: Iwata Chemical Co., Ltd., trade name: Ami) was heat-treated at 120 ° C for 20 minutes. The methyl thioadenosine content in the obtained yeast culture was 275 mg, the dry weight of the yeast culture (including MTA) was 5000 mg, and the dry weight of the yeast culture other than MTA was 4725 mg. That is, the mass ratio of the methylthioadenosine content to the yeast culture (expressed by the above formula (1)) is 5.5% by mass and the ratio represented by the above formula (2) is 275 / (275 + 4725) , And 5.5 / 100 (about 6/100). The resultant was suspended in a 0.5 mass% aqueous solution of methylcellulose, and the suspension was used as a sample. The dosage was 275 mg / body weight (kg) (10 ml / body weight (kg) as suspension and 15 mg / body weight (kg) as MTA amount) as yeast culture.

The sample of Comparative Example 8 was a sample containing S-adenosylmethionine-containing yeast and was prepared as follows. A commercial commercially available S-adenosylmethionine-containing yeast culture powder as used in Example 14 was suspended in a 0.5 mass% methyl cellulose aqueous solution, and the suspension was used as a sample. The dosage was 275 mg / kg body weight (as a suspension, 10 ml / kg body weight, and 0 mg / body weight (kg) as the amount of MTA) as S-adenosylmethionine-containing yeast.

<Experimental Example 2>

Eight weeks old male C57BL / 6 mice purchased from Japan SLC were equipped with electrodes for EEG and muscles. After the electrodes were attached, they were allowed to recover in the recovery chamber for 10 days. Thereafter, the film was transferred to a recording chamber and a cable was connected. EEG discrimination was confirmed by SleepSign (registered trademark) Ver 3.0 (Kisei Comtec Co., Ltd.), which was an EEG analysis software, and then refined for 3 days. Thereafter, EEG was measured for 24 hours, and it was confirmed whether or not the sleep arousal rhythm was maintained, and the administration group was divided into each of the examples and the comparative examples. Each treatment group consisted of 8 follicles (n = 8).

Immediately before the dark phase, samples were orally administered to each dose group and 24 hour brain waves were recorded. In addition, all the mice that had been orally administered with 275 mg / kg body weight (as a yeast culture) on the day different from the day on which the EEG measurement was performed showed awakening when they came into contact with each other to make supine. It was confirmed that the water surface was in a state "the cliff reflex is not lost".

After the recording, the brain waves were automatically analyzed by SleepSign (registered trademark) Ver 3.0, and the evaluator confirmed the results of the automatic analysis and classified them into the respective sleep stages of arousal, REM sleep, and Nemem sleep. The total accumulated amount (unit: sec) of the non-sleep time from the EEG measurement time to the 4-hour later is calculated, and the percentage of the normal sleeping amount of the same subject in the baseline is obtained. The amount of sleep ".

[Table 2]

As is apparent from the results of Table 2, in Example 14, compared to Comparative Examples 6 to 8, the ratio of the Nomal sleeping amount to the Nominal sleeping amount at the time of administration was very high. This indicates that the yeast culture of the present invention has an excellent sleep improving effect.

Examples 15 to 19

<Preparation of Evaluation Sample>

Each sample was a yeast culture containing MTA as shown in Table 3, and was prepared as follows. (Trade name: 5'-Deoxy-5 '- ((trade name) manufactured by Sigma-Aldrich Co., methylthio) adenosine, and the mass ratio of the MTA to the total mixture was as shown in Table 3. The resulting composition was used as a sample.

<Experimental Example 3>

Ten test subjects were each administered 50 mg of a sample orally, and the degree of bitter taste and the remaining feeling in the mouth were evaluated based on the criteria, and the average value of the scores of the respective panelists was obtained. In the evaluation of the bitter taste, the bitter taste of the MTA itself was used as a criterion, and this was evaluated as one point. In the evaluation of the remaining feeling in the mouth, the remaining feeling of the yeast alone was used as a reference, and this was evaluated as one point.

Bitter taste evaluation standard

[Rating criteria]

5 points: I do not feel a bitter taste

4 points: I feel a little bitter bitterness.

3 points: I feel a bitter taste.

2 points: I feel a bitter taste.

1 point: Bitter taste is hard to bear

[Evaluation standard]

◎: Average of 3.5 points or more

○: Average value 2.5 points or more and less than 3.5 points

?: Average value 1.5 or more and less than 2.5 points

X: Average value of 1.0 or more to less than 1.5

· Criteria for evaluating the residual in mouth

5 points: I do not feel the rest in the mouth

4 points: I feel a little bit of staying in my mouth

3 points: I feel the remaining in my mouth

2 points: I feel strong in the mouth.

1 point: It feels hard to survive in the mouth

An average value of 10 persons of the average score of the remaining sensation in the mouth rate calculated by the above-mentioned evaluation standard was calculated, and the mouth-filling remaining feeling was judged based on the obtained value. The results are shown in Table 3. In Table 3, the mass ratio of MTA is the mass ratio of MTA to yeast culture.

[Table 3]

From the results in Table 3, in Examples 16 to 18, the bitter taste and the remaining mouth feel derived from the MTA were all reduced. This indicates that the yeast culture of the present invention has a good flavor due to the MTA content of 0.06 to 0.5 mass%.

Practical Example 20

<Preparation of Evaluation Sample>

MTA-containing yeast cultures were prepared as follows. A commercially available S-adenosylmethionine-containing yeast culture powder (manufactured by Mitsubishi Gas Chemical Company, trade name: SAMe-containing dry yeast) was subjected to heat treatment at 120 ° C for 20 minutes. The content of methylthioadenosine in the obtained yeast culture was 320 mg, the dry weight of the yeast culture (including MTA) was 5000 mg, and the dry weight of the yeast culture other than MTA was 4680 mg. That is, the mass ratio of the methylthioadenosine content to the yeast culture (expressed by the above formula (1)) is 6.4 mass% and the ratio represented by the above formula (2) is 320 / (4680 + 320) , 6.4 / 100.

As a sample of Example 20, tablets (methylthioadenosine content in 4 tablets: 21 mg) containing the aforementioned MTA-containing yeast culture were prepared. Further, as a sample of Comparative Example 9, purification of a placebo containing no MTA-containing yeast was prepared. The details of each composition are as shown in Table 4.

[Table 4]

&Lt; Experimental Example 4 > (Evaluation in human)

Six subjects were orally ingested one tablet of tablets of Example 20 above one hour before bed, and a 2-electrode type portable electroencephalograph ("brain wave system slip scope" manufactured by Slipwell Co., Ltd.) Of the brain was measured. Likewise, six tablets of the sample of Comparative Example 9 were orally ingested one hour before going to bed in six subjects of the same kind, and a two-electrode type portable electroencephalograph ("Electroencephalograph Slip Scope" manufactured by Slipwell Co., ), And the brain waves in the subject's sleep surface were measured. For each subject, the sample of Example 20 and the sample of Comparative Example 9 were administered and EEG was performed four times.

In addition to the above administration and EEG measurement, each sample was taken orally to six identical subjects, and the subject knocked the subject's shoulder after going to bed. As a result, it was confirmed with respect to each subject that the subject easily wakes up, that is, the sleep surface after oral intake of each sample (sample of Example 20 and Comparative Example 9) to each subject.

(Brain wave analysis)

The EEG was interpreted with reference to Slipwell. The depth of the water surface is known by the delta power value of the EEG during sleep. The larger the delta power value, the deeper the depth of the water surface. In general, immediately after sleeping, the Nemem sleep surface appears, and then the REM sleep surface appears. In this experiment, the delta power value (ie, the delta power value until the occurrence of the REM sleeping surface once entered in the Nemem sleeping surface after sleeping) appeared as the delta power value at the beginning of the sleep.

The delta power value varies from person to person. Thus, the delta power value at the initial stage of the water surface after oral administration of the sample of Example 20 or Comparative Example 9 was measured four times for each subject, and the average value of the four measurements was calculated. (%) Of the delta power value after ingesting the MTA-containing yeast (sample of Example 20) to the delta power value after taking the placebo (sample of Comparative Example 9) for each subject was calculated by the following formula Respectively.

[Expression (2)]

 Change rate (%) of delta power value =

 {(Average value of delta power value after sample intake of Example 20) / (average value of delta power value after sample intake of Comparative Example 9)} x 100

Table 5 shows the rate of change of the delta power value. The rate of change of the delta power value is an average value of six subjects.

[Table 5]

From Table 5, it can be seen that: In Example 20 in which the tablets of MTA-containing yeast were taken orally as a sample, the delta power value at the initial stage of sleep was larger than that of Comparative Example 9 in which the placebo tablets were ingested orally. This indicates that the yeast culture and the underwear composition of the present invention can sufficiently deepen the surface of the Notre-Mam in the early stage of the sleeping, thereby promoting the sleeping and inducing a good natural sleeping.

Claims (12)

Methylthioadenosine or a salt thereof,
A yeast culture characterized in that the methylthioadenosine content per dry mass of the yeast culture is 5.5% by mass or more. S-adenosylmethionine degradation product. 3. The method of claim 2,
A yeast culture characterized in that the S-adenosylmethionine degradation product comprises methylthioadenosine. The method of claim 3,
A yeast culture characterized in that the methylthioadenosine content per dry mass of the yeast culture is 5.5% by mass or more. 5. The method according to any one of claims 1 to 4,
Adenosylmethionine or a salt thereof to heat a yeast culture containing S-adenosylmethionine or a salt thereof to decompose S-adenosylmethionine or a salt thereof. Yeast and methylthioadenosine or a salt thereof,
A / (A + B) is 1/10000 or more and 1/2 or less, wherein A represents a methylthioadenosine content in the composition and B represents a yeast content in the composition. The method according to claim 6,
A / (A + B) is 1/750 or more or 1/5 or less. The method according to claim 6,
A / (A + B) is 1/100 or more or 1/5 or less. The method according to claim 6,
A / (A + B) is not less than 5.5 / 100 and not more than 1/5. A sleep promoter characterized by comprising the yeast culture according to any one of claims 1 to 4 and / or the underwear composition according to any one of claims 6 to 8 as an active ingredient. 11. The method of claim 10,
Wherein the amount of methylthioadenosine ingested per adult is 0.01 to 1000 mg / day. 11. A food and drink composition comprising the water-swelling promoter according to claim 10 or 11.

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