WO2014163150A1 - Composition for internal use - Google Patents
Composition for internal use Download PDFInfo
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- WO2014163150A1 WO2014163150A1 PCT/JP2014/059867 JP2014059867W WO2014163150A1 WO 2014163150 A1 WO2014163150 A1 WO 2014163150A1 JP 2014059867 W JP2014059867 W JP 2014059867W WO 2014163150 A1 WO2014163150 A1 WO 2014163150A1
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- WIPO (PCT)
- Prior art keywords
- component
- sleep
- salt
- methylthioadenosine
- adenosylmethionine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/86—Addition of bitterness inhibitors
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Definitions
- the present invention relates to an internal use composition.
- the oral composition is taken orally, it is desirable that it does not have an unpleasant taste such as bitterness or astringency when taken.
- a method of suppressing unpleasant taste such as bitterness As a method of suppressing unpleasant taste such as bitterness, a method of masking bitterness and the like by combining a sweetener such as sucrose with an internal use composition has been conventionally known. However, in such a method, the composition for internal use becomes sweeter than necessary, and the feeling of taking may be worsened, and the effect of suppressing bitterness is not sufficient.
- Patent Document 1 reports a technique using a bitterness suppressing component such as 5'-adenylic acid (AMP). In such a technique, it has been confirmed that the bitterness of the internal use composition can be suppressed even when it contains a component exhibiting a strong bitter taste such as potassium chloride.
- a bitterness suppressing component such as 5'-adenylic acid (AMP).
- AMP 5'-adenylic acid
- the present inventors have found that methylthioadenosine has an excellent sleep promoting effect.
- methylthioadenosine has bitterness, and it may be difficult to take an effective amount orally.
- the present inventors have found that it is difficult to suppress the bitterness caused by methylthioadenosine even with the technique described in Patent Document 1 capable of suppressing the strong bitterness of potassium chloride.
- An object of the present invention is to provide an internal use composition containing methylthioadenosine with reduced bitterness.
- the present invention provides the following [1] to [5].
- component S-adenosylmethionine or a salt thereof
- the mass ratio of component (A) (as methylthioadenosine) / component (B) (as S-adenosylmethionine) is 0.05 to 1000
- (A) The internal use composition whose content of a component is 0.1 mass% or more as methylthio adenosine.
- an object of the present invention is to provide an oral composition containing methylthioadenosine with reduced bitterness.
- FIG. 1 is a sleep progress diagram showing a general pattern of REM sleep and non-REM sleep.
- the internal use composition of the present invention comprises (A) component: methylthioadenosine or a salt thereof and (B) component: S-adenosylmethionine or a salt thereof, and the mass ratio of (A) component / (B) component Is 0.05 to 1000, and the content of the component (A) is 0.1% by mass or more.
- the bitterness when taken orally tends to become remarkable.
- the present inventors specify that the ratio of the component (A) and the component (B) is a specific ratio even when the content of the component (A) is 0.1% by mass or more. It was found that the bitterness at the time of oral intake can be suppressed by using in combination.
- the component (A) contained in the internal use composition of the present invention is methylthioadenosine or a salt thereof.
- methylthioadenosine means 5'-deoxy-5'-methylthioadenosine.
- 5'-deoxy-5'-methylthioadenosine may be in either the anti-type or the syn-type.
- the salt of methylthioadenosine is not particularly limited as long as it is a pharmacologically acceptable salt, and can be selected according to the dosage form and the like.
- Suitable salts of methylthioadenosine include, for example, acid addition salts.
- the acid addition salt may be either an inorganic acid addition salt or an organic acid addition salt.
- hydrochloride, sulfate, nitrate, carbonate, phosphate, formate, oxalate, citrate , Ascorbate, methanesulfonate, 1,4-butanedisulfonate, 1,5-pentanesulfonate and p-toluenesulfonate for example, hydrochloride, sulfate, nitrate, carbonate, phosphate, formate, oxalate, citrate , Ascorbate, methanesulfonate, 1,4-butanedisulfonate, 1,5-pentanes
- the present inventors have found that such methylthioadenosine or a salt thereof has an excellent sleep promoting effect.
- Non-REM sleep can be determined by polysomnograph analysis (electroencephalogram, electrooculogram, electromyogram). As an electroencephalogram, non-REM sleep can be determined by a decrease in alpha waves (8-13 Hz in humans) and an increase in delta waves (0.5-4.5 Hz in humans). The measured electroencephalogram can also be determined using automatic analysis software such as SleepSign.
- Non-REM sleep is divided into four stages of layer I, layer II, layer III, and layer IV in the order of shallow sleep according to the depth of sleep.
- the sleep in which the depth of sleep is in the III layer and the IV layer among the I layer to the IV layer is particularly referred to as “deep sleep”.
- Methylthioadenosine or a salt thereof has an effect of promoting non-REM sleep, particularly deep sleep, in natural sleep.
- natural sleep refers to sleep that does not cause loss of direct reflex.
- Direct reflection is a reflection motion that restores the head to a normal position with respect to the direction of gravity, and is also referred to as bounce reflection.
- the disappearance of the direct reflex in the mouse or rat can be confirmed, for example, as a state where the mouse or rat placed in the supine position or the dorsal position does not return to the abdominal position within 30 seconds. If a sleeping mouse or rat is placed in a supine or dorsal position and immediately wakes up from sleep or quickly returns to the prone position, the sleep disappears from the positive reflex. There is no sleep. In humans, there is no equivalent of “direct reflection” as defined by animals. However, in humans, a state in which the “direct reflex does not disappear” corresponds to sleep that can be easily awakened, such as waking up immediately when the shoulder is hit, and can be defined as natural sleep.
- Anesthesia causes the loss of right-angle reflexes against natural sleep. Loss of direct reflex in mice or rats is known as an evaluation index of anesthetic effect. The effect of anesthesia with anesthetics such as pentobarbital or other agents can be assessed by the increase in the number of animals that have lost the right reflex.
- the origin of the EEG in the frequency band that cannot be seen during sleep without anesthesia or conventional hypnotics is not clear at present, but there is a relationship with the poor awakening of anesthesia or conventional hypnotics Inferred.
- “Promoting non-REM sleep” means that 1) the state of non-REM sleep is observed for a longer period of time compared to the state to be compared (for example, the state before ingestion of the internal use composition of the present invention), 2) It means that the effect of either deeper non-REM sleep or 3) the smooth transition to non-REM sleep is observed.
- methylthioadenosine or a salt thereof has an effect of promoting deep sleep in natural sleep.
- “Deep sleep” means sleep in which the depth of sleep is more than a certain level in humans, and sleep state at a depth of layer III or higher when non-REM sleep is classified into four stages of I to IV layers I mean.
- the occupancy of the delta wave (0.5-4.5 Hz) to the entire electroencephalogram (0.5-20 Hz) is above a certain level. It is known that the power value is high. Therefore, deep sleep can also be defined as sleep with a high delta power value.
- the delta power value can be measured using, for example, a polysomnography inspection apparatus, and the “depth of sleep”, which is the sum of sleep depth and time, is obtained by multiplying the delta power value by time. Defined.
- the delta power value itself is used for mouse and guinea pig sleep, and the time is added to the delta power value.
- the multiplied value may be the size of deep sleep. “Promoting deep sleep” means that 1) the state of deep sleep is observed for a longer time than the state to be compared (for example, the state before ingestion of the internal use composition of the present invention), 2) It means that the effect of either deeper deep sleep or 3) the smooth transition to deep sleep is observed. That is, in an experimental system using a mouse or guinea pig, the value obtained by multiplying the delta power value by time increases.
- the origin of the component (A) and the production method thereof are not particularly limited.
- the component (A) may be methylthioadenosine obtained by chemical synthesis or a salt thereof.
- the method of chemical synthesis is not particularly limited as long as methylthioadenosine or a salt thereof can be synthesized, and any method may be used.
- the component (A) may be methylthioadenosine derived from an organism or a salt thereof.
- methylthioadenosine or a salt thereof can be obtained from S-adenosylmethionine derived from an organism or a salt thereof described later via an intramolecular cyclization reaction of a methionine moiety.
- one type obtained by a specific origin and production method may be used alone, or two or more types having different origins and production methods may be used in combination.
- a commercial item may be used for a component.
- Methylthioadenosine or a salt thereof can be obtained from a supplier such as Sigma-Aldrich.
- the content of the component (A) is 0.1% by mass or more as methylthioadenosine.
- the content of the component (A) is 0.1% by mass or more. Even if it exists, the bitterness at the time of oral ingestion can be suppressed.
- the content of the component (A) is further increased without causing a problem of bitterness when taken orally. be able to.
- the content of the component (A) in the internal use composition is 0.5% by mass or more, 1% by mass or more, 2% by mass or more, 3% by mass or more, 4% by mass or more, 5% by mass or more as methylthioadenosine, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 11% or more, 12% or more, 13% or more, 14% or more, or 15% or more It may be increased to.
- the upper limit of the content of the component (A) in the internal use composition is not particularly limited, but is usually 50% by mass or less, preferably 20% by mass or less.
- content of (A) component in an internal use composition is the conversion amount as methylthio adenosine regardless of the origin of (A) component, a manufacturing method, and the kind of methylthio adenosine or its salt. is there.
- content of (A) component can be measured in a well-known procedure by the liquid chromatography method, for example.
- the oral composition of the present invention can contain the component (A) at a high content as described above without causing the problem of bitterness when taken orally. Therefore, the internal use composition of this invention can enjoy the effect which (A) component show
- the content of the component (A) in the internal use composition is preferably 2% by mass or more, more preferably 3% by mass or more, and still more preferably Is 5% by mass or more, and more preferably 10% by mass or more.
- the component (B) contained in the internal use composition of the present invention is S-adenosylmethionine or a salt thereof.
- S-adenosylmethionine has a structure in which adenosine and methionine are linked via a methylsulfonyl bond.
- the optical isomers of methionine include L-form, D-form, and DL-form.
- methionine in the structure of S-adenosylmethionine may be any of the optical isomers, but is preferably L-form.
- the salt of S-adenosylmethionine is not particularly limited as long as it is a pharmacologically acceptable salt, and can be selected according to the dosage form and the like.
- Suitable salts of S-adenosylmethionine include, for example, acid addition salts and halides, and specifically include hydrochloride, sulfate, p-toluenesulfonate (tosylate), sulfuric acid ⁇ p -Toluenesulfonate, methanesulfonic acid, trifluoromethanesulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentanesulfonic acid, phosphate, chloride, bromide and the like. Of these, hydrochloride or tosylate is preferred.
- the origin of the component (B) and the production method thereof are not particularly limited.
- the component (B) may be S-adenosylmethionine obtained by chemical synthesis or a salt thereof.
- the method of chemical synthesis is not particularly limited as long as S-adenosylmethionine or a salt thereof can be synthesized, and any method may be used.
- the component (B) may be S-adenosylmethionine derived from an organism or a salt thereof.
- the organism include cells containing S-adenosylmethionine or a salt thereof.
- the cell containing S-adenosylmethionine or a salt thereof may be a cell originally containing S-adenosylmethionine or a salt thereof.
- a microbial cell containing S-adenosylmethionine or a salt thereof may be used as the component (B) as it is, or a dry microbial cell obtained by drying the microbial cell may be used as the component (B).
- S-adenosylmethionine or a salt thereof isolated and purified from the bacterial cells containing S-adenosylmethionine or a salt thereof may be used as component (B).
- the microbial cells containing S-adenosylmethionine or a salt thereof originally do not contain S-adenosylmethionine or a salt thereof, or contain only a trace amount, but S-adenosylmethionine or It may be a microbial cell that contains S-adenosylmethionine or a salt thereof by producing the salt.
- Such cells can be obtained, for example, by culturing cells and producing S-adenosylmethionine or a salt thereof in the cells (intracellular).
- the resulting culture, the culture solution, the cells recovered after the culture, and the dried cells obtained by drying the cells Any of the purified bacterial cells obtained by purifying the body, culture or culture solution, and dried purified bacterial cells obtained by drying the purified bacterial cells may be used as the component (B).
- the type of microbial cells is not particularly limited, but yeast is preferred.
- the type of yeast is not particularly limited as long as it produces S-adenosylmethionine or a salt thereof and can be taken orally.
- yeasts include yeasts of the genus Saccharomyces (Saccharomyces) and yeasts of the genus Shizosaccharomyces (Saccharomyces cerevisiae; budding yeast), Yeast) is preferred.
- (B) component may be used individually by 1 type obtained by specific origin and a manufacturing method, and may be used in combination of 2 or more types from which an origin and a manufacturing method differ.
- the component (B) includes chemically synthesized S-adenosylmethionine or a salt thereof, S- A cell containing adenosylmethionine or a salt thereof, a dried product thereof, or a culture thereof is preferable, and chemically synthesized S-adenosylmethionine or a salt thereof, yeast containing S-adenosylmethionine or a salt thereof, a dried product thereof Or a culture thereof.
- S-adenosylmethionine or a salt thereof can be obtained from a supplier such as Sigma-Aldrich.
- Commercially available yeast containing S-adenosylmethionine or a salt thereof includes, for example, “SAMe-rich dry yeast (trade name)” manufactured by Mitsubishi Gas Chemical Co., Ltd., “Super Essé ( Product name) ",” Amy (trade name) "manufactured by Iwata Chemical Industry Co., Ltd., and the like.
- the content of the component (B) is such that the mass ratio of the component (A) to the component (B) (component (A) / component (B)) is in the range of 0.05 to 1000. There is no particular limitation.
- the content of the component (B) in the oral composition is S-adenosyl regardless of the origin of the component (B), the production method, and the type of S-adenosylmethionine or a salt thereof. It is a conversion amount as methionine.
- content of (B) component can be measured in a well-known procedure by the liquid chromatography method, for example.
- the lower limit of the mass ratio of the (A) component and the (B) component promotes sleep while suppressing the bitterness attributed to the (A) component.
- it is 0.05 or more, preferably 0.1 or more, more preferably 0.2 or more, still more preferably 0.5 or more, and even more preferably.
- the upper limit of the mass ratio of the component (A) to the component (B) is 1000 or less, preferably 800 or less, from the viewpoint of suppressing the bitterness caused by the component (A). More preferably, it is 600 or less, More preferably, it is 400 or less, More preferably, it is 200 or less.
- the mass ratio of the component (A) to the component (B) is the mass ratio of the component (A) (as methylthioadenosine) / (B) component (as S-adenosylmethionine).
- the internal use composition of this invention may further contain components (henceforth "optional component") other than (A) component and (B) component, unless the effect of this invention is impaired essentially.
- optional components include excipients, disintegrants, binders, lubricants, coating agents, colorants, color formers, flavoring agents, flavoring agents, antioxidants, preservatives, flavoring agents, Pharmacologically acceptable additives such as sour agents, sweeteners, fortifiers, vitamin agents, swelling agents, thickeners, surfactants, solvents and the like can be mentioned.
- the effects of the present invention and various properties necessary for the preparation are not impaired, and the final product (for example, food and drink, pharmaceuticals, quasi drugs, nutritional supplement products (supplements)) Etc.) can be selected depending on the dosage form.
- the final product for example, food and drink, pharmaceuticals, quasi drugs, nutritional supplement products (supplements)) Etc.
- Such pharmacologically acceptable additives may be used alone or in combination of two or more.
- the internal use composition of the present invention comprises (A) component, (B) component, and a pharmacologically acceptable salt, and the mass of (A) component / (B) component.
- the ratio is 0.05 to 1000, and the content of the component (A) is 0.1% by mass or more.
- the internal composition of the present invention may also contain other components that can promote non-REM sleep.
- other components that can promote non-REM sleep for example, what is called a sleep improving agent, a sleep inducing agent, and the like can be included.
- a sleep improving agent for example, what is called a sleep improving agent, a sleep inducing agent, and the like can be included.
- the mixed form with the component of the kind or quantity which produces the loss of specular reflection is excluded.
- the internal use composition of this invention contains (A) component which has a sleep promotion effect as an active ingredient.
- the internal use composition of the present invention is preferably an internal use composition for promoting sleep, more preferably an internal use composition for promoting non-REM sleep in natural sleep, and promotion of deep sleep in natural sleep. It is more preferable that the composition is for internal use.
- the dosage form of the internal use composition of the present invention is, for example, liquid (liquid), syrup (syrup), solid (tablet), capsule (capsule), powder (granule, fine granule), soft capsule (Soft capsule), semi-liquid, cream, and paste.
- the internal use composition of this invention for food / beverage products, as a dosage form of this food / beverage products, for example, beverages (soft drinks, carbonated drinks, nutrition drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks, etc.) Confectionery (cookies, cakes, gums, candy, tablets, gummies, buns, sheepskins, pudding, jelly, ice cream, sherbet, etc.), processed fishery products (kamaboko, chikuwa, hanpen, etc.), processed livestock products (hamburger, ham, Sausages, winners, cheese, butter, yogurt, fresh cream, margarine, fermented milk, etc.), soups (powdered soup, liquid soup, etc.), staple foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.) , Seasonings (mayonnaise, shortening, dressing, sauce, sauce, soy sauce, etc.). Furthermore, the internal use composition of the present invention comprises health food, functional food, health supplement (supplement), nutrition supplement
- chewable tablets can be mentioned.
- bitterness is more easily perceived at the time of ingestion, but according to the present invention, bitterness caused by component (A) can be remarkably suppressed, and an effective amount of component (A) A chewable tablet that contains no bitterness when ingested.
- the internal use composition of the present invention is preferably taken before going to bed.
- the intake amount of the internal composition 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 living body ingesting the internal composition of the present invention.
- the lower limit of the intake amount of the internal use composition of the present invention as the intake amount of methylthioadenosine per day (mg / day) is preferably 0.01 mg or more, more preferably 0.1 mg or more, even more preferably.
- Is 1 mg, and 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 subject of ingestion of the internal composition of the present invention is not particularly limited.
- people who are ingested may feel sleepy, sleepy when waking up, poor sleep, lack of deep sleep (cannot sleep deeply), bad dreams, and fatigue after sleep.
- Examples include subjects who are dissatisfied and subjects who feel fatigue and want to improve their subjective sleep feeling.
- the subject who does not have a special problem can be ingested on a daily basis for the purpose of maintaining good sleep, preventing sleep disorders, and promoting non-REM sleep (particularly deep sleep) in natural sleep.
- the internal use composition of the present invention can be used as a sleep promoter, preferably a non-REM sleep promoter under natural sleep, more preferably a deep sleep promoter under natural sleep.
- the time of administration of the sleep promoting agent is not particularly limited, but it is usually administered before going to bed and may be administered between 3 hours before going to bed and before going to bed. More preferably, it is administered between 2 hours before bedtime and during bedtime, more preferably administered between 1 hour before bedtime and during bedtime, and particularly preferably administered 1 hour before bedtime.
- this sleep promoter can increase the non-REM sleep time during sleep compared with the case where the sleep promoter of this invention is not administered. Specifically, it can be used for the prevention and treatment of sleep quality deterioration due to shortening of non-REM sleep time and / or reduction of depth of non-REM sleep.
- the internal use composition of the present invention can promote non-REM sleep (especially deep sleep) under natural sleep, and therefore can also be used as a natural sleep inducer. “Inducing natural sleep” refers to inducing sleep without loss of direct reflex. When the internal use composition of the present invention is used as a natural sleep inducer, non-REM sleep (especially deep sleep) can be promoted under natural sleep, so a good sleep pattern is maintained or a disturbed sleep pattern is good It can contribute to recovering to a proper sleep pattern.
- the present invention also provides a method for suppressing the bitter taste of methylthioadenosine or a salt thereof.
- bitterness caused by methylthioadenosine or a salt thereof can be suppressed by mixing methylthioadenosine or a salt thereof and S-adenosylmethionine or a salt thereof at a specific mass ratio.
- the method for suppressing the bitter taste of methylthioadenosine or a salt thereof comprises: (A) component: methylthioadenosine or a salt thereof; (B) component: S-adenosylmethionine or a salt thereof; And a step of mixing so that the mass ratio of (as methylthioadenosine) / (B) component (as S-adenosylmethionine) is 0.05 to 1000.
- the (A) component and the (B) component are as described above, and the preferable range of the mass ratio of the (A) component / (B) component is also as described above.
- the component (A) and the component (B) can be mixed so that the mass ratio of the component (A) / the component (B) is 0.05 to 1000.
- the method is not particularly limited, and a conventionally known mixing method may be used.
- the bitterness of oral compositions containing methylthioadenosine or a salt thereof when ingested can be remarkably suppressed.
- the method for suppressing the bitter taste of methylthioadenosine or a salt thereof comprises (A) component: methylthioadenosine or a salt thereof, and (A) component: methylthioadenosine or a salt thereof.
- the composition of internal use and the component (B): S-adenosylmethionine or a salt thereof, the mass ratio of component (A) (as methylthioadenosine) / component (B) (as S-adenosylmethionine) is 0 And a step of mixing so as to be 05 to 1000.
- the preferred range of the content of the component (A) in the internal use composition is as described above. According to the present invention, the bitterness attributed to methylthioadenosine or a salt thereof can be remarkably suppressed even in an internal composition in which the content of component (A) is 0.1% by mass or more as methylthioadenosine.
- Examples 1 to 7 and Comparative Examples 1 to 4 (A) component, (B) component ((B ') component about the comparative example 1), and crystalline cellulose were powder-mixed with the compounding quantity shown in following Table 1, and the composition was obtained. About the obtained composition, the bitterness at the time of oral ingestion and the sleep promoting effect were evaluated according to the following procedure. The results are shown in Table 1.
- Electroencephalogram and myoelectric electrodes were attached to 8-week-old male C57BL / 6 mice purchased from Japan SLC. After the electrodes were mounted, they were recovered for 10 days in a recovery chamber. Then, it moved to the recording chamber and the cable was connected. Mice that could be discriminated by electroencephalogram using SleepSign (registered trademark) Ver 3.0 (Kissei Comtech Co., Ltd.), an electroencephalogram analysis software, were acclimated for 3 days. Furthermore, the brain waves were then measured for 24 hours, and the administration groups were divided into mice in which sleep / wake rhythm was maintained.
- As the control solution a 0.5 mass% methylcellulose aqueous solution was used.
- the above suspension or control solution was forcibly orally administered to each mouse, and the electroencephalogram was recorded for 24 hours.
- the electroencephalogram was automatically analyzed by SleepSign (registered trademark) Ver 3.0, and the evaluator confirmed the result of the automatic analysis and classified it into sleep stages of wakefulness, REM sleep and non-REM sleep.
- the total integrated amount (unit: sec) of non-REM sleep time from the start of electroencephalogram measurement to 4 hours later was calculated, and the percentage of non-REM sleep amount at the time of non-administration (baseline) of the same individual was obtained.
- the average value of percentage was calculated for each administration group, and the sleep promoting effect was evaluated from the average value based on the following evaluation criteria.
- Methylthioadenosine (MTA) -containing yeast was prepared as follows.
- Commercially available S-adenosylmethionine-containing yeast culture powder (manufacturer name: Mitsubishi Gas Chemical Co., Ltd., trade name: SAMe-containing dry yeast) was heat-treated at 120 ° C. for 20 minutes.
- the methylthioadenosine content in the obtained yeast culture was 320 mg
- the dry weight of the yeast culture (including MTA) was 5000 mg
- the dry weight of the yeast cultures other than MTA was 4680 mg. That is, the mass ratio of the methylthioadenosine content to the yeast culture was 6.4% by mass.
- Example 8 a tablet (methylthioadenosine content in 4 tablets: 21 mg) containing the above MTA-containing yeast was prepared. As a sample of Comparative Example 5, a placebo tablet not containing MTA-containing yeast was prepared. Details of each composition are as shown in Table 2.
- each sample was orally ingested by the same six subjects, and after the subject went to bed, the subject's shoulder was beaten. As a result, it was confirmed for each subject that the subject woke up easily, that is, the sleep after each sample (the sample of Example 8 and Comparative Example 5) was orally ingested by each subject was natural sleep. .
- the electroencephalogram was analyzed by requesting Sleepwell.
- the depth of sleep can be known from the delta power value of the electroencephalogram during sleep. The greater the delta power value, the deeper the sleep depth.
- non-REM sleep appears immediately after going to bed, and REM sleep appears thereafter.
- the delta power value during non-REM sleep that appeared immediately after going to sleep was taken as the delta power value in the early stage of sleep. .
- Delta power value varies depending on the individual. Therefore, after ingesting the sample of Example 8 or the sample of Comparative Example 5, the delta power value in the early stage of sleep was measured four times for each subject, and the average value of the four measured values was calculated. For each subject, the change rate (%) of the delta power value after ingestion of the MTA-containing yeast (sample of Example 8) relative to the delta power value after ingestion of the placebo (sample of Comparative Example 5) is calculated by the following equation (1). did.
- Delta power value change rate (%) ⁇ (Average value of delta power value after sample intake of Example 8) / (Average value of delta power value after sample intake of Comparative Example 5) ⁇ ⁇ 100
- Table 3 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.
- Example 3 shows the following.
- Example 8 in which a tablet containing methylthioadenosine and S-adenosylmethionine at a specific ratio was orally ingested as a sample, the delta power value at the initial stage of sleep was higher than that in Comparative Example 5 in which a placebo tablet was orally ingested. large.
- the internal use composition of the present invention can sufficiently deepen the non-REM sleep in the early stage of sleep, thereby promoting sleep and inducing good natural sleep.
Abstract
Description
〔1〕 (A)成分:メチルチオアデノシンまたはその塩と、
(B)成分:S-アデノシルメチオニンまたはその塩と
を含有し、
(A)成分(メチルチオアデノシンとして)/(B)成分(S-アデノシルメチオニンとして)の質量比が0.05~1000であり、
(A)成分の含有量がメチルチオアデノシンとして0.1質量%以上である内服組成物。
〔2〕 (A)成分(メチルチオアデノシンとして)/(B)成分(S-アデノシルメチオニンとして)の質量比が1~1000である、〔1〕に記載の内服組成物。
〔3〕 (A)成分の摂取量がメチルチオアデノシンとして0.01mg/日~1000mg/日である、〔1〕又は〔2〕に記載の内服組成物。
〔4〕 睡眠促進用である、〔1〕~〔3〕のいずれかに記載の内服組成物。
〔5〕 (A)成分:メチルチオアデノシンまたはその塩と、(B)成分:S-アデノシルメチオニンまたはその塩とを、(A)成分(メチルチオアデノシンとして)/(B)成分(S-アデノシルメチオニンとして)の質量比が0.05~1000となるように混合する、メチルチオアデノシンまたはその塩の苦味を抑制する方法。 The present invention provides the following [1] to [5].
[1] Component (A): methylthioadenosine or a salt thereof,
(B) component: S-adenosylmethionine or a salt thereof,
The mass ratio of component (A) (as methylthioadenosine) / component (B) (as S-adenosylmethionine) is 0.05 to 1000,
(A) The internal use composition whose content of a component is 0.1 mass% or more as methylthio adenosine.
[2] The internal use composition according to [1], wherein the mass ratio of the component (A) (as methylthioadenosine) / (B) component (as S-adenosylmethionine) is 1-1000.
[3] The internal use composition according to [1] or [2], wherein the intake of component (A) is 0.01 mg / day to 1000 mg / day as methylthioadenosine.
[4] The internal use composition according to any one of [1] to [3], which is for sleep promotion.
[5] Component (A): methylthioadenosine or a salt thereof, and component (B): S-adenosylmethionine or a salt thereof, (A) component (as methylthioadenosine) / (B) component (S-adenosyl) A method for suppressing the bitter taste of methylthioadenosine or a salt thereof, which is mixed so that the mass ratio of (as methionine) is 0.05 to 1000.
本発明の内服組成物は、(A)成分:メチルチオアデノシンまたはその塩と、(B)成分:S-アデノシルメチオニンまたはその塩とを含有し、(A)成分/(B)成分の質量比が0.05~1000であり、(A)成分の含有量が0.1質量%以上であることを特徴とする。 [Internal composition]
The internal use composition of the present invention comprises (A) component: methylthioadenosine or a salt thereof and (B) component: S-adenosylmethionine or a salt thereof, and the mass ratio of (A) component / (B) component Is 0.05 to 1000, and the content of the component (A) is 0.1% by mass or more.
本発明の内服組成物に含有される(A)成分は、メチルチオアデノシンまたはその塩である。 <(A) component>
The component (A) contained in the internal use composition of the present invention is methylthioadenosine or a salt thereof.
マウスやモルモットの睡眠には、ヒトのIII層およびIV層の睡眠に対応した一般的な判定基準はないため、マウスやモルモットの睡眠にはデルタパワー値そのものを用い、さらにデルタパワー値に時間を乗じた値を、深睡眠の大きさとし得る。
「深睡眠を促進する」とは、対比される状態(例えば、本発明の内服組成物の摂取前の状態)と比べて、1)深睡眠の状態がより長時間観察されること、2)深睡眠の深さがより深まること、または、3)深睡眠への移行がより円滑に進むこと、のいずれかの効果が観察されることをいう。すなわち、マウスやモルモットを用いた実験系では、上記のデルタパワー値に時間を乗じた値が大きくなることをいう。 “Deep sleep” means sleep in which the depth of sleep is more than a certain level in humans, and sleep state at a depth of layer III or higher when non-REM sleep is classified into four stages of I to IV layers I mean. During sleep in layers III and IV, the occupancy of the delta wave (0.5-4.5 Hz) to the entire electroencephalogram (0.5-20 Hz) is above a certain level. It is known that the power value is high. Therefore, deep sleep can also be defined as sleep with a high delta power value. The delta power value can be measured using, for example, a polysomnography inspection apparatus, and the “depth of sleep”, which is the sum of sleep depth and time, is obtained by multiplying the delta power value by time. Defined.
For mouse and guinea pig sleep, there is no general criterion for human layer III and IV sleep, so the delta power value itself is used for mouse and guinea pig sleep, and the time is added to the delta power value. The multiplied value may be the size of deep sleep.
“Promoting deep sleep” means that 1) the state of deep sleep is observed for a longer time than the state to be compared (for example, the state before ingestion of the internal use composition of the present invention), 2) It means that the effect of either deeper deep sleep or 3) the smooth transition to deep sleep is observed. That is, in an experimental system using a mouse or guinea pig, the value obtained by multiplying the delta power value by time increases.
本発明の内服組成物に含有される(B)成分は、S-アデノシルメチオニンまたはその塩である。 <(B) component>
The component (B) contained in the internal use composition of the present invention is S-adenosylmethionine or a salt thereof.
本発明はまた、メチルチオアデノシンまたはその塩の苦味を抑制する方法も提供する。 [Method for suppressing the bitter taste of methylthioadenosine or a salt thereof]
The present invention also provides a method for suppressing the bitter taste of methylthioadenosine or a salt thereof.
<(A)成分>
・メチルチオアデノシン
シグマ-アルドリッチ社製
「5’-Deoxy-5’-(methylthio)adenosine」
<(B)成分>
・S-アデノシルメチオニン
シグマ-アルドリッチ社製
「S-(5’-Adenosyl)-L-methionine chloride
dihydrochloride」
<(B’)成分>((B)成分の比較成分)
・5’-アデニル酸(AMP)
シグマ-アルドリッチ社製
「Adenosine 5’-monophosphate monohydrate」
<その他の成分>
・結晶セルロース
旭化成ケミカルズ社製「セオラスFD-101」
・メチルセルロース
シグマ-アルドリッチ社製
「Methyl cellulose」
(20℃での2%水溶液の粘度:25cP) The main raw materials used in the following examples are summarized below.
<(A) component>
・ Methylthioadenosine Sigma-Aldrich "5'-Deoxy-5 '-(methylthio) adenosine"
<(B) component>
S-adenosylmethionine “S- (5′-Adenosyl) -L-methionine chloride” manufactured by Sigma-Aldrich
dihydrochloride "
<(B ′) component> (comparison component of (B) component)
・ 5'-adenylic acid (AMP)
"Adenosine 5'-monophosphate monohydrate" manufactured by Sigma-Aldrich
<Other ingredients>
・ Crystalline cellulose “Theolas FD-101” manufactured by Asahi Kasei Chemicals
・ Methylcellulose "Methyl cellulose" manufactured by Sigma-Aldrich
(Viscosity of 2% aqueous solution at 20 ° C .: 25 cP)
(A)成分、(B)成分(比較例1については(B’)成分)、及び結晶セルロースを、下記表1に示す配合量にて粉末混合し、組成物を得た。得られた組成物について、下記手順に従って、経口摂取時の苦味および睡眠促進効果を評価した。結果を表1に示す。 Examples 1 to 7 and Comparative Examples 1 to 4
(A) component, (B) component ((B ') component about the comparative example 1), and crystalline cellulose were powder-mixed with the compounding quantity shown in following Table 1, and the composition was obtained. About the obtained composition, the bitterness at the time of oral ingestion and the sleep promoting effect were evaluated according to the following procedure. The results are shown in Table 1.
10名の被験者において、実施例および比較例で調製した組成物約50mgを経口摂取した際の苦味の程度についてアンケートを行い、下記スコア基準に基づきスコア(1~5点)をつけ平均値を算出した。算出したスコアの平均値から下記評価基準に基づき経口摂取時の苦味の程度を評価した。評価に際してはメチルチオアデノシンそのものの苦味を基準とし、これを1点として評価した。 (Evaluation of bitterness when taken orally)
A questionnaire was conducted on the degree of bitterness when about 50 mg of the compositions prepared in Examples and Comparative Examples were orally ingested by 10 subjects, and an average value was calculated by assigning scores (1 to 5 points) based on the following score criteria. did. Based on the average value of the calculated scores, the degree of bitterness during oral intake was evaluated based on the following evaluation criteria. In the evaluation, the bitterness of methylthioadenosine itself was used as a standard, and this was evaluated as one point.
5点:苦味を感じない
4点:苦味をやや感じる
3点:苦味を感じる
2点:苦味を強く感じる
1点:苦味を耐えがたく感じる [Score criteria]
5 points: feel no bitterness 4 points: feel bitterness 3 points: feel bitterness 2 points: feel bitterness strongly 1 point: feel bitterness unbearable
◎:平均値4点以上
○:平均値3点以上4点未満
×:平均値3点未満 〔Evaluation criteria〕
◎: Average value 4 points or more ○: Average value 3 points or more and less than 4 points ×: Average value 3 points or less
実施例および比較例で調製した組成物90mgを、0.5質量%メチルセルロース水溶液10mLに添加し、攪拌して懸濁液を得た。 (Evaluation of sleep promotion effect)
90 mg of the composition prepared in Examples and Comparative Examples was added to 10 mL of 0.5 mass% methylcellulose aqueous solution and stirred to obtain a suspension.
◎:平均値150%以上
○:平均値110%以上150%未満
△:平均値100%以上110%未満
×:平均値100%未満 〔Evaluation criteria〕
◎: Average value 150% or more ○: Average value 110% or more and less than 150% △: Average value 100% or more and less than 110% ×: Average value less than 100%
経口摂取時の苦みと睡眠促進効果の評価結果から下記評価基準に基づき総合評価を行った。 (Comprehensive evaluation)
Based on the evaluation results of bitterness and sleep promoting effect at the time of oral intake, comprehensive evaluation was performed based on the following evaluation criteria.
◎:経口摂取時の苦みと睡眠促進効果の両方の評価結果が「○」又は「◎」
○:経口摂取時の苦みの評価結果が「○」又は「◎」であり、睡眠促進効果の評価結果が「△」
×:経口摂取時の苦みと睡眠促進効果のいずれか一方の評価結果が「×」 〔Evaluation criteria〕
◎: The evaluation result of both bitterness and sleep promoting effect when taken orally is "○" or "◎"
○: The evaluation result of bitterness when taken orally is “○” or “◎”, and the evaluation result of sleep promotion effect is “△”
×: The evaluation result of either bitterness or sleep promoting effect when taken orally is “×”
<評価サンプルの調製>
メチルチオアデノシン(MTA)含有酵母は、以下のようにして調製した。市販のS-アデノシルメチオニン含有酵母培養物粉末(メーカー名:三菱ガス化学株式会社、商品名:SAMe含有乾燥酵母)を120℃で20分間加熱処理した。得られた酵母培養物中のメチルチオアデノシン含有量は320mg、酵母培養物(MTAを含む)の乾燥重量は5000mg、MTA以外の酵母培養物の乾燥重量は4680mgであった。すなわち、酵母培養物に対するメチルチオアデノシン含有量の質量比は6.4質量%であった。 Example 8 and Comparative Example 5
<Preparation of evaluation sample>
Methylthioadenosine (MTA) -containing yeast was prepared as follows. Commercially available S-adenosylmethionine-containing yeast culture powder (manufacturer name: Mitsubishi Gas Chemical Co., Ltd., trade name: SAMe-containing dry yeast) was heat-treated at 120 ° C. for 20 minutes. The methylthioadenosine content 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 cultures other than MTA was 4680 mg. That is, the mass ratio of the methylthioadenosine content to the yeast culture was 6.4% by mass.
6名の被験者に上記実施例8のサンプルの錠剤4錠を就寝1時間前に経口摂取させ、2電極方式の携帯型脳波測定器(スリープウェル(株)社製「脳波計スリープスコープ」)を装着し、被験者の睡眠中における脳波を測定した。また、同様にして、同じ被験者6名に上記比較例5のサンプルの錠剤4錠を就寝1時間前に経口摂取させ、2電極方式の携帯型脳波測定器(スリープウェル(株)社製「脳波計スリープスコープ」)を装着し、被験者の睡眠中における脳波を測定した。各被験者に対して、実施例8のサンプルおよび比較例5のサンプルそれぞれについて、投与および脳波測定を4回行った。 <Evaluation of sleep promotion effect> (Evaluation in humans)
Six subjects took 4 tablets of the sample of Example 8 above orally one hour before going to bed, and used a two-electrode portable electroencephalograph (“Sleepwell Co., Ltd.'s“ electroencephalograph sleep scope ”). The brain waves were measured while the subject was sleeping. Similarly, the same six subjects were ingested four tablets of the sample of Comparative Example 5 one hour before going to bed, and a two-electrode portable electroencephalograph (EEG) manufactured by Sleep Well Co., Ltd. A total sleep scope ") was worn, and the brain waves during the sleep of the subject were measured. For each subject, administration and electroencephalogram measurement were performed four times for each of the sample of Example 8 and the sample of Comparative Example 5.
脳波は、スリープウェル(株)に依頼して解析した。睡眠の深さは睡眠中脳波のデルタパワー値によって知ることができ、デルタパワー値が大きいほど睡眠の深さは深い。一般に、就寝直後にノンレム睡眠が出現し、その後レム睡眠が出現する。本実験では、就寝直後に出現したノンレム睡眠中のデルタパワー値(すなわち、就寝後一旦ノンレム睡眠に入ったその後にレム睡眠が出現するまでのデルタパワー値)を、睡眠初期のデルタパワー値とした。 (Electroencephalogram analysis)
The electroencephalogram was analyzed by requesting Sleepwell. The depth of sleep can be known from the delta power value of the electroencephalogram during sleep. The greater the delta power value, the deeper the sleep depth. In general, non-REM sleep appears immediately after going to bed, and REM sleep appears thereafter. In this experiment, the delta power value during non-REM sleep that appeared immediately after going to sleep (that is, the delta power value until REM sleep appears after going into non-REM sleep after going to sleep) was taken as the delta power value in the early stage of sleep. .
デルタパワー値の変化率(%)=
{(実施例8のサンプル摂取後のデルタパワー値の平均値)/(比較例5のサンプル摂取後のデルタパワー値の平均値)}×100 [Formula (1)]
Delta power value change rate (%) =
{(Average value of delta power value after sample intake of Example 8) / (Average value of delta power value after sample intake of Comparative Example 5)} × 100
Claims (5)
- (A)成分:メチルチオアデノシンまたはその塩と、
(B)成分:S-アデノシルメチオニンまたはその塩と
を含有し、
(A)成分(メチルチオアデノシンとして)/(B)成分(S-アデノシルメチオニンとして)の質量比が0.05~1000であり、
(A)成分の含有量がメチルチオアデノシンとして0.1質量%以上である内服組成物。 (A) component: methylthioadenosine or a salt thereof,
(B) component: S-adenosylmethionine or a salt thereof,
The mass ratio of component (A) (as methylthioadenosine) / component (B) (as S-adenosylmethionine) is 0.05 to 1000,
(A) The internal use composition whose content of a component is 0.1 mass% or more as methylthio adenosine. - (A)成分(メチルチオアデノシンとして)/(B)成分(S-アデノシルメチオニンとして)の質量比が1~1000である、請求項1に記載の内服組成物。 The internal composition according to claim 1, wherein the mass ratio of the component (A) (as methylthioadenosine) / (B) component (as S-adenosylmethionine) is 1 to 1000.
- (A)成分の摂取量がメチルチオアデノシンとして0.01mg/日~1000mg/日である、請求項1又は2に記載の内服組成物。 The internal use composition according to claim 1 or 2, wherein the intake of component (A) is 0.01 mg / day to 1000 mg / day as methylthioadenosine.
- 睡眠促進用である、請求項1~3のいずれか1項に記載の内服組成物。 The internal use composition according to any one of claims 1 to 3, which is used for promoting sleep.
- (A)成分:メチルチオアデノシンまたはその塩と、(B)成分:S-アデノシルメチオニンまたはその塩とを、(A)成分(メチルチオアデノシンとして)/(B)成分(S-アデノシルメチオニンとして)の質量比が0.05~1000となるように混合する、メチルチオアデノシンまたはその塩の苦味を抑制する方法。 (A) component: methylthioadenosine or a salt thereof and (B) component: S-adenosylmethionine or a salt thereof, (A) component (as methylthioadenosine) / (B) component (as S-adenosylmethionine) A method for suppressing the bitter taste of methylthioadenosine or a salt thereof, which is mixed so that the mass ratio thereof is 0.05 to 1000.
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