JP2023124847A - Sleep improver - Google Patents

Abstract

To provide a new sleep improver.SOLUTION: A sleep improver contains at least one chromone glycoside selected from the group consisting of uncinoside A and uncinoside B, an aglycon thereof, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 2

Description

TECHNICAL FIELD The present invention relates to a sleep improving agent.

Patent Document 1 discloses a composition of the genus Forget-me-not, and a composition having an antidepressant-like action containing, as an active ingredient, a hot water extract in which the plant of the genus Forget-me-not is daylily.

Patent Document 2 discloses an agent for increasing muscle mass and an agent for improving muscle atrophy containing daylilies.

International publication WO2009/145363A1 JP 2015-189683 A

The present invention provides a new sleep-improving agent.

As a result of intensive studies, the present inventors found that a composition containing unsinoside A and unsinoside B is useful as a sleep-improving agent, a sleep-inducing agent, and the like.

That is, the present invention is the following sleep improving agent.

Section 1.
a sleep-improving agent,
containing at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof;
Sleep improver.

Section 2.
2. The sleep-improving agent according to item 1, further comprising daylilies or an extract thereof.

Item 3.
The daylily or its extract contains at least one chromone glycoside selected from the group consisting of Unsinoside A and Unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof. ,
At least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof is inherent in the daylily or an extract thereof. 3. The sleep-improving agent according to item 2 above.

Section 4.
at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, which is inherent in the daylily or an extract thereof; 4. The sleep-improving agent according to item 2 or 3, which is a mixture with an externally added agent.

The present invention can provide a new sleep-improving agent.

FIG. 1 shows an HPLC chart and fractionated peaks of the Hypnocallis extract, which is a sleep-improving agent of the present invention. FIG. 2 shows the chemical structure of the peak fractionated by HPLC of Hypnocallis extract, which is a sleep-improving agent of the present invention. FIG. 3 shows a ¹ H-NMR chart of Unsinoside A, a sleep-improving agent of the present invention. FIG. 4 shows a chart of ¹³ C-NMR chart A of Unsinoside A, a sleep improving agent of the present invention. FIG. 5 shows a 2D-NMR (C—H COZY) chart of Unsinoside A, a sleep-improving agent of the present invention. FIG. 6 depicts a flow chart of study participants for the first study. FIG. 7 is a diagram showing the generation mechanism of non-REM sleep. FIG. 8 is a diagram showing that non-REM sleep induction by Hypnocallis is not mediated by the prostaglandin D ₂ (PGD ₂ )/adenosine system sleep center. FIG. 9 is a diagram showing the time course of hypothermia of hypothermia in mice by Hypnocallis. FIG. 10 depicts a flow chart of study participants for the second study.

The present invention will be described in detail below.

However, this embodiment is a description for better understanding of the gist of the invention.

This embodiment does not limit the content of the invention unless otherwise specified.

[Sleep improver]
The sleep-improving agent of the present invention contains at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, and promotes sleep. It is possible to improve (induce sleep).

Aglycones are the non-sugar moieties that remain after the glycosyl group of a glycoside is replaced by a hydrogen atom.

(1) Unsinoside A and B
Uncinoside A, Uncinoside A
5-hydroxy-2,6,8-trimethylchromone 7-O-β-D-glucopyranoside (systematic name: 2,6,8-trimethyl-5-hydroxy-7-(β-D-glucopyranosyloxy)- 4H-1-benzopyran-4-one, 5-hydroxy-2,6,8-trimethyl-7-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-( hydroxymethyl)oxan-2-yl]oxy}-4H-chromen-4-one)
Molecular formula: _C18H22O9 , molecular weight _{: 382.365}
It is one of the chromone glycosides.

Uncinoside B, Uncinoside B
5-acetoxyl-2,6,8-trimethylchromone 7-O-β-D-glucopyranoside (systematic name: 2,6,8-trimethyl-5-acetoxy-7-(β-D-glucopyranosyloxy)- 4H-1-benzopyran-4-one, 2,6,8-trimethyl-4-oxo-7-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-( hydroxymethyl)oxan-2-yl]oxy}-4H-chromen-5-yl acetate)
Molecular formula: _{C20H24O10 ,} molecular weight _: 424.402
It is a compound of chromone glycosides.

The sleep-improving agent of the present invention is preferably daylilies or an extract thereof containing at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, and aglycones thereof (glycosyl groups of glycosides). at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, containing a non-sugar moiety remaining after substituting a hydrogen atom), or a pharmaceutically acceptable salt thereof , its aglycon, or a pharmaceutically acceptable salt thereof, is endogenous to daylily, or an extract thereof.

In the sleep improving agent of the present invention, preferably, at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof is daylily, or It is a mixture of what is inherent in the extract and what is added externally (extrinsic).

At least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, contained in the sleep-improving agent of the present invention is preferably used to improve sleep. It may be an endogenous substance contained in the daylily or its extract to be blended with the agent at the same time, or the sleep improving agent of the present invention may be used separately from the daylily or its extract. It may be externally added (extrinsic) or both (intrinsic + exogenous).

In preparing the sleep-improving agent of the present invention, at least one chromone glycoside selected from the group consisting of exogenous unsinoside A and unsinoside B, its aglycone, or a pharmaceutically acceptable salt thereof is externally added. Depending on the situation, it may contain .

In the preparation of the sleep-improving agent of the present invention, daylilies or an extract thereof is used, and at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable There is no need to externally add the salt used, and it may be used as it is.

In preparing the sleep-improving agent of the present invention, at least one chromone glycoside selected from the group consisting of Unsinoside A and Unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof,
(a) using exogenous material (external attachments);
(b) using daylilies, or those derived from extracts thereof (endogenous);
(c) derived from daylilies or extracts thereof (endogenous) and not exogenous;
(d) using a mixture of an exogenous substance (externally added) and an endogenous substance (derived from daylilies);
There are aspects such as

The sleep-improving agent of the present invention improves sleep by containing at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof. , useful for provoking

(2) Forget- me-not Scientific name: Hemerocallis fulva L. var.

Daylilies are called by various dialects in Okinawa Prefecture. The dialect names in Okinawa Prefecture include Kuwanso, Nebuigusa, Kansou, Guwansou, Gansho, Kwansou, Kwansiya, Gansou, Hansou, Fufansa, Fanza, Fufantsua, Nibuikanso, Panso, Kanzobana, Upunsa, and Bilati. Those called by these dialect names are all included in the daylilies (Japanese name) of the present invention.

In Okinawa Prefecture, it is called "Kwansou" in the dialect. Another name for quanso is tokiwakanzou. As a traditional vegetable that has been rooted in Okinawa for a long time, the daylily is truly unique to Okinawa, not only in its natural distribution area, but also in terms of records of its use as a folk remedy and as a food ingredient.

The sleep improving agent of the present invention contains at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, and preferably further, Contains daylilies or extracts thereof.

The sleep improving agent of the present invention is preferably daylilies or an extract thereof containing at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable and at least one chromone glycoside selected from the group consisting of Unsinoside A and Unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof is daylily, or its It is inherent in the extract.

In the sleep improving agent of the present invention, preferably, at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof is daylily, or It is a mixture of what is inherent in the extract and what is added externally.

The sleep-improving agent of the present invention, by using daylily, is at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B contained in daylily, its aglycone, or its pharmaceutical It is useful for improving sleep (inducing sleep) by containing a salt that is acceptable for .

Sites where Daylily is Used In the sleep-improving agent of the present invention, daylily may be preferably used as it is or as a processed product of daylily.

The processed products of daylilies are preferably powdered products of daylilies, extracts of daylilies extracted with various solvents, dried products of the extracts (dry extracts), and powdered dry extracts made from these powders. etc.

When the plant body of daylily is used as it is, or when the plant body is extracted, preferably, the whole plant is used, as well as flowers, buds, leaves (and petioles), stems (and fleshy stems), roots ( roots and aerial roots). Preferably, the whole plant of daylilies is used in terms of raw material yield and extraction efficiency.

The plant body to be extracted is preferably leaves, stems, buds, flowers, or roots in a raw state (undried matter), or after being dried, pulverized into an appropriate size and powdered (dried matter ), frozen (frozen), etc.

Method for extracting the plant of daylily In the sleep improving agent of the present invention, the method for preparing the extract of the plant of daylily is preferably a method combining an extraction step, a separation (filtration) step, a drying step, etc. A method in which a fractionation step is further combined with the method, and the like.

Extraction process In the sleep improving agent of the present invention, when an extract (processed product of daylily) extracted with a solvent of daylily is used, the production method (extraction method), extraction conditions, etc. are the same as the processed product of daylily). is used, preferably the daylily is directly subjected to solvent extraction to obtain an extract. A method known in the art may be used for the solvent extraction, and a conventionally known extraction method such as water extraction, hot water extraction, hot water extraction, alcohol extraction, supercritical extraction, etc. is preferably used.

The type of extraction solvent is preferably water, an organic solvent, a mixed solvent of these, or the like.

The water of the extraction solvent is preferably water at any temperature, such as cold water, normal temperature water, hot water, hot water, and steam, and may be subjected to sterilization treatment, ion exchange treatment, osmotic pressure adjustment, or buffering. .

The organic solvent of the extraction solvent is preferably a hydrophilic organic solvent such as monohydric alcohols having 1 to 5 carbon atoms (ethanol, methanol, propanol, isopropanol, etc.), polyhydric alcohols having 2 to 5 carbon atoms (glycerin , isopropylene glycol, propylene glycol and butylene glycol), esters (such as methyl acetate) and ketones (such as acetone). These hydrophilic organic solvents may be used alone or in combination of two or more.

For the solvent extraction of daylilies, hot water and hot water are preferably used in terms of safety and extraction efficiency of the active ingredient.

The extraction method is preferably immersion extraction, stirring extraction, reflux extraction, shaking extraction, ultrasonic extraction, or the like.

The extraction conditions are preferably room temperature extraction, heating extraction (heating extraction), pressurized extraction, supercritical extraction, etc., and more preferably heating extraction.

The extraction temperature is preferably appropriately determined according to the type of extraction solvent and the like.

For the solvent extraction of daylilies, when the extraction is performed with heating, the specific extraction conditions are preferably about 30° C. to 100° C., and may be performed in a boiling state. The extraction time is preferably about 5 minutes to 6 hours, more preferably about 10 minutes to 3 hours.

The solvent extraction of daylilies is preferably pH-adjusted.

The extraction operation may preferably be performed once, or may be performed multiple times by repeating extraction of the extraction residue obtained after performing the extraction operation multiple times. Furthermore, preferably, before and after the extraction step, treatment such as filtration may be performed as necessary.

Separation (filtration) step In the sleep improving agent of the present invention, the step of separating the plant body of daylily and the extract (processed product of daylily) extracted with a solvent of daylily is preferably , It is a method of separating insoluble matter, which is an extraction residue, and an extract, and it is a method by extraction separation using an adsorbent / absorbent such as centrifugal separation, filter press, filtration (pressure, normal pressure) and chromatography. be. The extract separated from the liquid extract may be used as it is, or may be further purified by fractionation or the like.

In the separation step, the necessary components are preferably fractionated, purified and concentrated from the resulting separated product.

The separation step is preferably carried out by a method such as chromatography using an anion exchange resin, cation exchange resin, silica gel, polystyrene resin that adsorbs aromatic compounds as a carrier, dialysis, molecular sieve, concentration under reduced pressure, freeze drying, or the like. be.

After the separation step, preferably, if necessary, a step of collecting the supernatant by centrifugation or the like may be performed.

In the sleep improving agent of the present invention, before and after each step of using the extract (processed product of daylilies) extracted with a solvent of daylilies, treatment such as filtration is preferably performed as necessary. Gauze, filtration filters, commercially available filters, etc. are preferably used for filtration. The obtained extract is subjected to a sterilization treatment or the like, if necessary.

Drying step In the sleep improving agent of the present invention, the plant body of daylily and the extract (processed product of daylily) extracted with a solvent of daylily are preferably used as they are, or dried and powdered. I use something like that. The obtained extract is subjected to purification, concentration treatment, etc., if necessary.

The purification treatment is preferably performed by filtration, adsorption using an ion exchange resin, activated carbon column, or the like, decolorization, or the like. The concentration treatment preferably utilizes a conventional method such as an evaporator.

The obtained extract is preferably pulverized by a drying process such as spray drying, vacuum drying, freeze drying and the like.

The obtained extract (purified product, concentrate, etc.) is preferably subjected to a freeze-drying process to powderize it, or a method of adding an excipient such as dextrin, cornstarch, gum arabic and spray-drying it. Depending on the method of pulverizing, it is pulverized and made into a processed product.

The processed product is dissolved in pure water, ethanol, or the like, if necessary.

A preferred method for obtaining a concentrated extract of daylilies A plant body of daylilies is extracted at 40°C or higher to obtain an extract.

The extract is then centrifuged, filtered, concentrated, pH adjusted and sterilized to obtain an extract of daylilies.

Additionally, the concentrate is spray-dried to obtain an extract of daylilies (dried extract powder).

Commercially available extracts of daylilies are preferably used. Preferably, an extract of Kwansou extract (trade name: Hypnocallis (R)) available from Somunoquest Co., Ltd. is used.

(3) Uses (forms) of health foods, etc. of sleep-improving agents
For applications such as drinks, jellies, gummies, and various health foods, the concentrated extract of daylily is preferably an extract extracted from leaves of daylily.

As the concentrated powder of the daylily extract, the daylily leaf extract is available as a spray-dried powder. The concentrated powder of the daylily extract contains the components at a concentration that is twice as high as that of the daylily concentrated extract.

The daylily dry leaf powder is preferably available as a sterile powder of daylily dry leaves.

For uses such as tea, the dried leaves of daylilies are preferably obtained by cutting the leaves of daylilies and drying them.

In recent years, the concept of food has expanded, and there are many pharmaceutical-like substances that are ingested for specific uses, such as those that impart specific physiological functions. Even when the term “medicine” is used, it also means health foods and the like.

The sleep-improving agent of the present invention does not mean only pharmaceuticals used for sleep improvement (sleep induction). The sleep-improving agent of the present invention is a pharmaceutical-like composition (health food, etc.) that has the function of improving sleep (inducing sleep) and is taken for the purpose of maintaining health. It also refers to pharmaceutical-like compositions that are eaten.

The sleep-improving agent of the present invention is not limited to compositions used for pharmaceutical applications, but also includes the following health foods and the like that can improve sleep (induce sleep).

・Health food (food with health claims)
Food for specified health use : Tokuho. Foods that contain health functional ingredients that affect the physiological functions of the body, are recognized to have specific effects, and are permitted by the Consumer Affairs Agency to display such effects. Products are labeled with a statement stating that they can be expected to have specific effects and a certificate such as "Food for Specified Health Uses licensed by the Consumer Affairs Agency."

Foods with nutrient function claims : Foods that are used to supply and complement nutritional components that tend to be in short supply due to aging and disordered eating habits. In order to sell it, it is necessary to meet the standards set by the Ministry of Health, Labor and Welfare, and to display the nutrition function label and warning label of the determined nutritional ingredients.

• Supplements : Dietary supplements, health supplements. It is a food that supplements nutrients that are likely to be deficient, and is a condensed form of nutrients in the form of capsules, tablets, or beverages.

・Food for special dietary use : food for the sick, powdered milk for pregnant and breastfeeding women, food for the elderly, etc. approved by the Ministry of Health, Labor and Welfare. It has a food for special use mark. Foods for specified health use are also classified as foods for special dietary uses.

・Functional food : Processed food that is said to have the effect of adjusting the physical condition. Instead of nutrition and taste, it artificially enhances bioregulatory functions. Unlike food with health claims, it cannot show efficacy.

Since the sleep-improving agent of the present invention has the effect of improving sleep (inducing sleep), it can be suitably provided as a health food or the like.

The sleep improving agent of the present invention contains at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, and preferably further, It contains daylilies or an extract thereof, exerts a hitherto unknown effect of improving sleep (inducing sleep), and functions as a sleep-improving agent.

The present invention is a sleep-improving agent that is completely different from the uses of the prior art.

(4) Administration (ingestion) of sleep-improving drugs
(4-1) Intake amount of daylily (Kwansou) The sleep improving agent of the present invention is the dosage and intake of daylily itself or its processed product, which is called Acceptable Daily Intake (ADI). It is a defined numerical range.

The permissible daily intake is the amount of intake per day that is considered to have no effect on humans even if it continues to ingest a specific substance used in food for a lifetime, and is normal body weight. The value is shown per 1 kg (unit: mg/kg body weight/day) (Igaku Shoin, Igaku Daijiten, published on March 1, 2003).

As a specific calculation method, first, the maximum dose (maximum no observed adverse effect level, NOAEL: No Observed Adverse Effect Level, NOAEL) that does not affect experimental animals is obtained.

This is then multiplied by a safety factor, and the allowable daily intake is calculated, taking into account the human body weight. As a safety factor, 1/100 is generally used in consideration of the species difference between experimental animals such as mice (rodents) and humans. In other words, the amount that affects humans (tolerable daily intake) is 1/100 or higher than the maximum no-observed-adverse-effect level obtained in experimental animals.

ADI = NOAEL x 1/100
Based on the concept of the permissible daily intake, the minimum dose (minimum effective dose) of the active ingredient that exhibits the effect is determined for the dosage and intake of the active ingredient for humans.

(4-2) Intake of at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, its aglycone, or a pharmaceutically acceptable salt thereof The sleep-improving agent of the present invention is unsinoside At least one chromone glycoside selected from the group consisting of A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof is adjusted as appropriate to determine dosage and intake.

The sleep-improving agent of the present invention contains at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmacological agent thereof, to the extent that it can improve sleep (induce sleep). including legally acceptable salts, daylily per se, or processed products thereof.

The dose of the sleep-improving agent of the present invention is preferably determined according to the purpose of the sleep-improving agent (degree of sleep improvement (sleep induction)), administration method of the sleep-improving agent, dosage form, symptoms of the patient to be administered, age, It is appropriately selected according to body weight and the like. Administration is preferably, not necessarily once a day, but divided into 2 to 4 times a day.

(5) Formulation of sleep-improving agent At least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable form thereof contained in the sleep-improving agent of the present invention A salt, preferably, more preferably, daylily, or an extract thereof, preferably contains at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, aglycones thereof , or a pharmaceutically acceptable salt thereof, daylily, or an extract (processed product) thereof is appropriately selected and set so that the daily intake is within the above range.

The sleep-improving agent of the present invention preferably contains at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, in a formulation. More preferably, daylily or its extract (processed product) may consist of itself or its processed product.

There are no particular restrictions on the blending ratio in the formulation.

At least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, preferably, more preferably, For daylilies or their extracts (processed products), the blending ratio is preferably selected and set as appropriate from the range of usually about 0.1% by weight to 99% by weight.

The sleep improving agent of the present invention includes at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, preferably, more preferably , Daylily, or its extract (processed product) is preferably added to general foods for sleep improvement (sleep induction) so that the content ratio is the above ratio per daily intake.

At least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, preferably, more preferably, daylily, or an extract thereof ( Processed products) are preferably used as one of the raw materials (additives) of foods.

The dosage form (formulation form) of the sleep improving agent is preferably selected appropriately according to the route of administration. Dosage forms (formulations) are preferably classified into oral administration agents, enteral administration agents, transgastric fistula administration agents, and the like.

Dosage forms (formulations) are preferably solid dosage forms such as tablets (including chewable tablets), pills, powders, powders, granules, and capsules; ), emulsions, suspensions, emulsions, syrups and other liquid dosage forms. The dosage form (pharmaceutical form) is preferably prepared as a dry product that can be liquefied by adding an appropriate carrier before use (eg, dry syrup, etc.). Dosage forms (formulations) are preferably solid dosage forms such as tablets (including chewable tablets), pills, powders, powders, granules and capsules, and liquid dosage forms such as jelly and solutions.

The dosage form (preparation form) is preferably administered through an appropriate administration route depending on the form of the preparation. Solid and liquid dosage form formulations are preferably administered, such as by oral administration. Liquid dosage form formulations are preferably administered by nasal (nasogastric tube) administration, enteral administration, transgastric fistula administration, and the like. Formulations for enteral administration are preferably those that are directly administered to the intestine, and those that are directly administered to the stomach through a gastrostomy that is added by making a hole across the stomach wall and the abdominal wall (gastrostomy enteral nutrition, etc.). Formulations for nasal administration preferably include formulations that are used by inserting a feeding tube through the nose to reach the esophagus (nasogastric tube nutrition, etc.).

The sleep improving agent of the present invention is preferably at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, preferably further Preferably, it consists only of daylily, its extract (processed product), itself, or its processed product (powder, extract, etc.).

The sleep improving agent of the present invention is preferably at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, preferably further Preferably, in addition to daylily or its extract (processed product), it is prepared with a usable or pharmaceutically acceptable carrier or additive.

The carrier is preferably excipients, diluents, binders, disintegrants, disintegration inhibitors, absorption enhancers, lubricants, solubilizers, buffers, emulsifiers that are usually used according to the dosage form of the formulation. , suspending agents and the like.

Additives are preferably stabilizers, preservatives, buffers, tonicity agents, chelating agents, pH adjusters, surfactants, coloring agents, flavoring agents, and flavoring agents that are commonly used according to the dosage form of the formulation. agents, sweeteners and the like.

The sleep-improving agent of the present invention also means an additive or the like for imparting an effect of improving sleep (inducing sleep).

The sleep improving agent of the present invention comprises, as an active ingredient, at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, preferably further , Preferably, it contains daylilies or an extract (processed product) thereof, and exhibits an effect of improving sleep (inducing sleep) due to the active ingredient.

(6) Action of sleep improving agent The sleep improving agent of the present invention is useful for the purpose of improving sleep (inducing sleep). INDUSTRIAL APPLICABILITY The present invention is a sleep-improving agent that can be easily taken on a daily basis over a long period of time.

The present invention will be explained more clearly by way of examples below.

However, the present invention is not limited to such examples.

(1) Preparation of sleep improving agent
At least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof
Daylily or its extract (processed product)
Kwansou (a dialect of Okinawa Prefecture) was used as daylilies.

An extract was obtained by extracting the plant body of Kwanso at 40°C or higher.

The extract was then centrifuged, filtered and concentrated, pH adjusted and sterilized to obtain a concentrate.

Additionally, the concentrate was spray-dried.

By the above preparation, hot water extracts of Phytophthora (Helophyllum spp.) (Helophyllum spp. condensed extract, H. serrata concentrated extract powder) were obtained.

(2) Extraction, isolation, and identification method of functional components contained in Helianthus annuus Extraction , isolation, and identification of functional components contained in Helianthus annuus were carried out.

Figure 1. HPLC chart of Hypnocallis extract and fractionated peak Hypnocallis extract (Kwanso dried leaves, citric acid solution, sold by Somunoquest Co., Ltd.) was partition-extracted with ethyl acetate, and acetic acid, which is a fraction showing activity, was extracted. 54 g of ethyl extract fraction was obtained. The obtained ethyl acetate extract fraction was divided into 6 fractions by HPLC, and the obtained fractions were subjected to ¹ H-NMR spectrum measurement.

HPLC analysis conditions ・Column: 5C18-ARII, 10mm (id inner diameter column) x 150mm (preparative column) ・Gradient: 0min 5% (B solvent concentration) → 25min 95% (B solvent concentration) ・Solvent: A solvent : Water, B Solvent: Methanol (MeOH)
・Detection wavelength: 240nm to 360nm
・Column temperature: 40℃
・Sample injection volume: 10 μL to 60 μL
Figure 2. Chemical structure of HPLC fractionated peak of Hypnocallis extract
HPLC-1 in FIG. 1 is a compound having a flavonoid skeleton.

HPLC-2 in Figure 1 was assumed to be Unsinoside B.

HPLC-3 in FIG. 1 is a compound having a triterpene skeleton.

HPLC-4 in Figure 1 is the aglycone of unsinoside B, 5-acetoxyl-7-dihydroxy-2,6,8-trimethylchromone.

HPLC-5 in Figure 1 is the unsinoside A aglycon.

During the separation process of unsinoside B, unsinoside A was successfully isolated.

Content of Unsinoside A The content of Unsinoside A is from 54 g of the ethyl acetate extract, which is the active fraction, for 12 kg of Hypnocallis extract (Kwanso dry leaves, citric acid solution, sold by Somunoquest Co., Ltd.). , 150 mg is obtained when converted into the isolated yield.

Figure 3. 1H-NMR chart of Unsinoside A
Figure 4. Chart of 13C-NMR chart A of Unsinoside A
Figure 5. 2D-NMR (CH COZY) chart of Unsinoside A Isolated component: Unsinoside A
5-hydroxy-2,6,8-trimethy1chromone 7-O-β-Dglucopyranoside Positive ESI/MS: m/z 383[M+H] ^+
1H -NMR (DMSO- _d6 , δppm): 2.27(3H,s), 2.39(3H,s), 2.52(3H,s), 3.14(1H,m), 3.24(1H,m), 2.34( 1H,m), 3.50(1H,m), 3.70(1H,br.d,J=11.5Hz), 4.73(1H,d,J=7.5Hz), 6.37(1H,s)
^13C -NMR (DMSO- _d6 , δ ppm): 9.11, 9.23, 20.16, 61.19, 70.05, 74.23, 76.52, 77.19, 104.58, 106.67, 108.18, 109.92, 114.42, 152.73, 156.08, 158.91, 168.52, 182.83 . 3) Vasodilator action
In laboratory animals and humans, there is a peripheral vasodilatory effect after ingestion of the concentrated extract of Kwanso. In general, peripheral vasodilator action increases peripheral blood flow to promote heat dissipation in the body including the brain, and as a result, the temperature of the brain (brain temperature) decreases to promote sleep. Therefore, the ability of unsinoside A and unsinoside B to produce nitric oxide (NO ₂ ) was investigated.

<I Experimental method>
1. Materials :
・Human umbilical vein endothelial cells (HUVEC) manufactured by Takara Bio ・Media: Endothelial cell growth medium manufactured by Takara Bio ・Measurement reagent: NO ₂ /NO ₃ Assay Kit-C II (Colorimetric) ~Griess Reagent Kit~Dojindo・Dimethyl sulfoxide (DMSO) manufactured by Fuji Film Wako Pure Chemical
2. Culture conditions : 37°C, 5% _CO2 concentration incubator
3. Test product : Concentrated extract of Kwanso, Unsinoside A, Unsinoside B, Control
4. Test method :
1. HUVEC were seeded in a 96-well microplate at 1.0×10 ³ cells/well/300 μL. After that, preculture was performed for 48 hours.

2. The test product was dissolved in the medium, cultured for 72 hours after addition, and the supernatant was collected.

3. The recovered supernatant was centrifuged at 1000 xg for 15 minutes. The supernatant was used as a measurement sample.

Four. Dispense 80 μL each of the measurement sample into a 96-well microplate, add 10 μL each of the coenzyme solution and enzyme solution from the kit, and allow to stand in an incubator at 25° C. for 2 hours.

Five. 50 μL of reagent A was added to each well and allowed to stand for 5 minutes, after which 50 μL of reagent B was added and allowed to stand for 10 minutes.

6. Absorbance at 540 nm was measured using a microplate reader. Taking the absorbance of the medium-only control (control) plot as 100%, the NO ₂ production of each test product was compared.

<II Results>
Unsinoside A and Unsinoside B were found to have the ability to produce NO ₂ in a dose-dependent manner, similar to the concentrated extract of Kwansou extract (Table 1).

<III consideration>
It was suggested that unsinoside A and unsinoside B cause vasodilation by producing NO ₂ in vascular endothelial cells, resulting in heat dissipation and lowering of core body temperature.

(4) Sleep improvement effect of food containing Hypnocallis (R) derived from Kwansou (first test)
Effect of sleep improvement by OSA sleep questionnaire (Table 2), factor I (wake-up sleepiness), factor II (sleep onset and sleep maintenance), factor III (dreaming), factor III (dreaming), which indicates the sleep state after placebo intake (Table 2) "Sleep improvement" was derived from the amount of change in IV (fatigue recovery) depending on the intake of the extract sample.

OBJECTIVES OF THE TEST Hypnocallis® is a standardized extract derived from crocodile. A randomized, placebo-controlled, parallel-group study was conducted in 63 healthy subjects with sleep problems to examine the sleep-improving effect of Hypnocallis(R). The primary endpoints of the study were the Pittsburgh Sleep Questionnaire and the OSA Sleep Questionnaire.

Hemerocallis fulva L. var. Kwansou is a traditional vegetable designated by Okinawa Prefecture as a natural food that can be eaten for a long time by people with mild sleep disorders. Kwansou is a perennial monocotyledonous plant belonging to the family Liliaceae and belonging to the genus Forget-me-not, which grows naturally in marine subtropical climates and has orange flowers in autumn.

A large-scale refining method was carried out to remove alkaloids and sedatives from the leaves of the plant, and the active ingredient "Hypnocallis" extract with a pH of 4 was extracted.

Studies were conducted at 1 and 0.5 times the recommended effective dose of Hypnocallis.

<I Experimental method>
1. Target audience
The selection criteria for the test subjects were men and women between the ages of 20 and 65, who were mainly employed at a desk and who were aware of mild sleep disorders such as being easily tired, having difficulty falling asleep, or having light sleep. Those who go to bed (lights out) and wake up at regular times, go to bed (lights out) before 24:00, sleep for about 4 hours or more, and work 5 days a week during the day with 2 days off a week. He was a person of the day.

Exclusion criteria include suspected sleep apnea syndrome (SAS), those currently under treatment, those who have had treatment, those with nocturia, benign prostatic hyperplasia, overactive bladder, those with suspected sleep apnea syndrome (SAS), liver disease, Those who have a history of serious diseases such as renal disease, cardiovascular disease, gastrointestinal disease, respiratory disease, blood system disease, autoimmune disease, endocrine system disease and metabolic system disease, drug allergy or serious food Those who have a history of allergies, those who are pregnant, those who intend to become pregnant during the test period, those who are breastfeeding, those who regularly use drugs, quasi-drugs, supplements, etc. related to stress relief and sleep improvement. Excessive drinkers (60 g/day or more of alcohol), and those who were judged to be unsuitable as subjects by the principal investigator or principal investigator.

2. Test food The test food is a food containing Hypnocallis (R), a hot-water extract of Kwanwort with a standardized amount of unsinoside A, which is thought to be involved in sleep regulation. A tableted food containing 2000 mg/day of Hypnocallis was prepared.

Foods in which crystalline cellulose, reduced maltose starch syrup, etc. were substituted for hypnocallis were used as placebo foods. As for the intake per day, 6 grains of each test product were taken 1 hour before going to bed. Each test food was made to be indistinguishable in appearance and flavor.

3. Study Method This study was conducted as a randomized, double-blind, placebo-controlled, parallel group study. After obtaining informed consent and obtaining written consent from 198 subjects, PSQI and lifestyle interviews were conducted as screening tests, and 63 subjects who met the inclusion criteria for this study and did not meet the exclusion criteria picked a name.

Selected subjects completed a one-week OSA sleep questionnaire upon awakening as a pre-dose test. After that, test foods were randomly assigned by stratified block allocation method with age, sex, and PSQI as stratification factors.

The assigned test foods were sent to the subjects, and they were asked to take 6 grains once a day for 2 weeks. Two weeks after the ingestion, the subjects filled out an OSA sleep questionnaire and were asked to keep a daily diary to record their physical condition. At the end of the ingestion period, a post-ingestion examination was conducted to interview the subjects regarding adverse events.

Four. Statistical Analysis The significance level of the test in this test was 5% on both sides, comparison between groups was performed by Student's t-test, and comparison within groups was performed by paired t-test. Statistical analysis was performed using SAS Ver.9.4 (manufactured by SAS). Multiplicity was not considered.

<II Results>
1. Analysis target
The test was conducted with a total of 63 subjects, 21 in each group, and all subjects completed the test.

All subjects were included in the analysis without any violations of study compliance requirements. Table 2 shows the background of the subjects for analysis.

Fig. 6 shows the subject selection flow.

2. OSA Sleep Questionnaire Table 3 shows the results of the OSA Sleep Questionnaire. In the Hypnocallis (R) 1000mg intake group, in the actual values measured two weeks after intake, there was a significant difference in factor I (sleepiness upon waking) and factor II (sleep onset and sleep maintenance) compared to the placebo food. was found to improve the quality of

In addition, when comparing the amount of change from before ingestion, there was a significant difference in factor I (sleepiness upon waking), factor II (sleep onset and sleep maintenance), and factor III (dreaming) compared to the placebo food. A quality improvement effect was observed.

In the Hypnocallis (R) 2000mg intake group, both the measured value after 2 weeks of intake and the amount of change from before intake were factor I (sleepiness upon waking), factor II (sleep onset and sleep maintenance), factor III (dreaming), factor A significant difference was observed in IV (recovery from fatigue) compared to the placebo food, and an effect of improving sleep quality was observed.

<III consideration>
In this study, 63 healthy subjects with sleep problems were double-blind to receive food containing 1000 mg or 2000 mg of standardized hot water extract Hypnocallis (R) containing Unsinoside A, or a placebo. A placebo-controlled, parallel-group study was conducted.

As a result, in the OSA sleep questionnaire, in the Hypnocallis 1000mg intake group, a significant difference was observed in factor I (sleepiness upon waking) and factor II (sleep onset and sleep maintenance) compared to the placebo food, indicating that sleep quality improved. showed improvement.

In addition, in the Hypnocallis 2000mg intake group, significant differences were observed in factor I (sleepiness upon waking), factor II (sleep onset and sleep maintenance), factor III (dreaming), and factor IV (fatigue recovery) compared to the placebo food. , was found to improve sleep quality.

Hypnocallis has so far been tested for sleep induction at the animal level and open-label human tests. In studies using mice, an increase in the amount of non-REM sleep and an increase in the amount of REM sleep during the resting period from 1 to 6 hours after administration of Hypnocallis was observed. In addition, frequency analysis of NREM sleep in mice at this time revealed that Hypnocallis (R) significantly increased the low-frequency delta band indicating deep NREM sleep even 6 to 9 hours after administration. These results suggest that Hypnocallis (R) induces high-quality sleep for a long time after administration.

Demonstration experiment that NREM sleep is induced peripherally by Hypnocallis administration FIG. 7 is a diagram showing the mechanism of NREM sleep generation.

Generally, prostaglandin D ₂ (PGD ₂ ), which is a sleep-inducing substance, is biosynthesized in the brain during forced wakefulness such as excessive stress or endurance of drowsiness. This prostaglandin _D2 is transported to the hypothalamus along the flow of cerebrospinal fluid and activates the neural activity of the prostaglandin _D2 /adenosine sleep center (VLPO) existing there, resulting in NREM. Known to induce sleep. This NREM sleep generation mechanism is common to mammals including mice and humans (Fig. 7).

Hayaishi O, Urade Y, Eguchi N, Huang ZL.: Review: Genes for prostaglandin D synthase and receptor as well as adenosine A _2A receptor are involved in the homeostatic regulation of NREM sleep.: Arch Ital Biol., Jul;142(4 ): 533-539.2004.

Therefore, using prostaglandin _D2 synthase gene-deficient (L-PGDS KO) mice and non-deficient wild-type (B6) mice, we investigated whether NREM sleep induction by Hypnocallis administration is central. , or not central.

In accordance with the Animal Welfare Law, KO and B6 mice were placed in a freelance, unrestrained state with a small dedicated device for measuring electroencephalograms and myoelectric potentials. I put it on. Then, hypnocallis was orally administered once to the KO and B6 mice, and NREM sleep amount and REM sleep amount were measured over time.

FIG. 8 is a diagram showing that non-REM sleep induction by Hypnocallis is not mediated by the prostaglandin D ₂ (PGD ₂ )/adenosine system sleep center.

If NREM sleep by hypnocallis is mediated by the PGD ₂ /adenosine system sleep center, the amount of NREM sleep in KO mice is reduced. As a result of the experiment, the amount of non-REM sleep in this gene-deficient (KO) mouse showed a time course similar to that in wild-type mice (it did not decrease in this study). These results suggested that non-REM sleep induction by Hypnocallis was not central (Fig. 8).

In mammals, the core body temperature drops during sleep (the resting period in nocturnal animals), but in humans, the parasympathetic nerves are dominant at night, so heat dissipation from the peripheral blood vessels of the skin before falling asleep reduces the core body temperature. is known to promote falling asleep.

FIG. 9 is a diagram showing the time course of hypothermia of hypothermia in mice by Hypnocallis.

Hypnocallis(R) was observed to dilate peripheral blood vessels in the ear a few minutes after administration to mice, and at the same time, decrease in rectal temperature persisted for several hours. This decrease rate of rectal temperature was the fastest compared to glycine (Gly) and γ-aminobutyric acid (GABA) at the same concentration. Theanine was unchanged.

In addition, in a test that confirmed changes in blood flow in humans, it was confirmed that the peripheral blood vessels in the hands expanded and blood flow improved 15 minutes after ingesting Hypnocallis (R). Therefore, combined with the results of experiments using KO mice, NREM sleep induction by Hypnocallis is demonstrated to be a peripheral effect, in which heat dissipation is promoted by improving peripheral blood flow, lowering core body temperature, and promoting sleep onset. (Fig. 9).

It has been reported that oxypinnatanine improves sleep in Kwansou, but since oxypinnatanine is unstable to heat, it is considered to be inactivated during the heat production of Hypnocallis. Furthermore, when Hypnocallis (R) was subjected to component analysis, almost no hydroxyglutamines such as oxypinnatanine were detected, and it became clear that it contained Unsinoside A, which had not been reported before.

A test using human vascular endothelial cells has confirmed that unsinoside A has the effect of promoting nitric oxide (NO) production. Since the sleep-improving action of Hypnocallis (R) is thought to be due to a decrease in core body temperature, it is thought that the physical mechanism of action is that unsinoside A increases NO production and causes vasodilation. The degree of NO production was almost the same in the Unsinoside A isolate and Hypnocallis (R), for which the amount of Unsinoside A has been clarified. Conceivable.

<IV Conclusion>
A randomized, double-blind, placebo-controlled, parallel-group study was conducted on the sleep-improving effect of Hypnocallis(R) on healthy subjects with sleep problems. As a result, the HYPNOCALIS (R) 1000mg intake group and the HYPNOCALIS (R) 2000mg intake group significantly improved sleep quality compared to the placebo food intake group.

(5) Sleep improvement effect of food containing Hypnocallis (R) derived from Kwanso (second test)
A randomized, placebo-controlled, crossover, comparative study using sleep electroencephalography (Table 4), and a sleep electroencephalograph to measure cranial nerve activity during sleep at night. time, frequency of midway awakening, REM sleep (dreaming sleep) frequency, NREM sleep (deep sleep) frequency, NREM sleep breakdown, and more detailed light sleep (N1 + N2) and deep sleep (N3) frequencies are calculated, "Improvement of sleep quality" was derived from the increase or decrease in intake of the extract sample.

OBJECTIVES OF THE TEST Hypnocallis® is a standardized extract from Kwansang that contains Unsinoside A. In the first study , the OSA Sleep Questionnaire was used to report the sleep improvement effect of Hypnocallis®. In the second study , a randomized, placebo-controlled crossover comparison study will be conducted with the aim of analyzing the brain waves during sleep of Hypnocallis (R) using a sleep electroencephalograph and further examining the sleep improvement effect. Aimed at.

<I Experimental method>
1. Target audience
The selection criteria for the test subjects were men and women between the ages of 20 and 65, who were mainly employed at a desk and who were aware of mild sleep disorders such as being easily tired, having difficulty falling asleep, or having light sleep. Those who go to bed (lights out) and wake up at regular times, go to bed (lights out) before 24:00, and have a habit of sleeping for four hours or more, and work five days a week during the daytime with two days off a week. He was a person of the day.

Exclusion criteria include suspected sleep apnea syndrome (SAS), those currently under treatment, those who have had treatment, those with nocturia, benign prostatic hyperplasia, overactive bladder, those with suspected sleep apnea syndrome (SAS), liver disease, Those who have a history of serious diseases such as renal disease, cardiovascular disease, gastrointestinal disease, respiratory disease, blood system disease, autoimmune disease, endocrine system disease and metabolic system disease, drug allergy or serious food Those who have a history of allergies, those who are pregnant, those who intend to become pregnant during the test period, those who are breastfeeding, those who regularly use drugs, quasi-drugs, supplements, etc. related to stress relief and sleep improvement. Excessive drinkers (60 g/day or more of alcohol), and those who were judged to be unsuitable as subjects by the principal investigator or principal investigator.

2. Test food The test food is a food containing Hypnocallis (R), a hot-water extract of Kwanwort with a standardized amount of Unsinoside A, which is thought to be involved in sleep regulation. did.

Foods in which crystalline cellulose, reduced maltose starch syrup, etc. were substituted for hypnocallis were used as placebo foods. As for the intake per day, 6 grains of each test product were taken 1 hour before going to bed. Each test food was made to be indistinguishable in appearance and flavor.

3. Sleep electroencephalograph The electroencephalogram during sleep was analyzed using a sleep electroencephalograph ZA-9 (manufactured by Proassist) and Sleep Sign-Lite (R) (manufactured by Kissei Comtec). EEG data during sleep were recorded and measured at each subject's home using a two-channel portable electroencephalograph (Brainwave Sensor ZA-9; Proasist Co., Osaka, Japan) at a sampling rate of 128 Hz.

Before going to bed, subjects were coated with disposable Ag/AgCl on the forehead and mastoid process for electroencephalogram measurements, and below the right canthal and diagonally above the left canthus for eye movement measurements. I attached an electrode that is Raw signals were stored on an SD card and analyzed when offline. Electroencephalographic (EEG) recordings during sleep were separated into 30-second intervals and EEG categories were divided into the following regions: delta (1.0-4.0 Hz), theta (4.0-8.0 Hz), alpha (8.0-12.0 Hz). ) and beta (16.0-35.0Hz).

The mean and standard deviation (SD) of spectral densities for each region were evaluated for each subject's band. Spectral data exceeding +3 SD above the mean value in each region and observed during wakefulness were excluded from analysis as outliers. Furthermore, each regional band was normalized from the average value of all subject data.

Based on the electroencephalogram analysis results, the sleep conditions were classified into the following stages.

Awakening (Stage W)
REM sleep stage (stage R), rapid eye movement sleep
Light non-REM sleep phases (stages N1 and N2)
Deep non-REM sleep stage (stage N3).

We calculated the ratio of sleep onset latency and sleep onset time 10-12).

Four. Subjective evaluation A subjective sleep quality survey was performed using the OSA-MA (OSA sleep inventory MA version)13). The OSA-MA is a standardized questionnaire to assess sleep quality in middle-aged and elderly Japanese.

The OSA-MA is a subjective questionnaire that is completed immediately after waking up, and consists of 16 questions, each of which is measured according to a four-point rating scale and calculated as a corrected Zc score.

The Zc score is divided into five categorized factors (1st factor: sleepiness upon waking, 2nd factor: sleep onset and sleep maintenance, 3rd factor: dreaming, 4th factor: recovery from fatigue, 5th factor: sleep time). Aggregated. The higher the Zc score and factor-specific score, the better the quality of sleep.

In this test, the Zc scores for each OSA-MA question item and factor that were filled in on the morning of working days were averaged and used for evaluation. In addition, PSQIG score by Pittsburgh Sleep Questionnaire 14) and evaluation by SF-36 were also performed in each study period.

Five. As a test method screening test, 35 subjects were given informed consent and consent to conduct the test, and the Pittsburgh Sleep Questionnaire (PSQI) and lifestyle interviews were conducted. We selected 63 subjects who did not.

As a pre-ingestion test, the selected subjects completed sleep electroencephalogram measurements and an OSA sleep questionnaire for one week upon awakening. After that, test foods were randomly assigned by stratified block allocation method with age, sex, and PSQI as stratification factors.

The assigned test food was sent to the subjects, and as the I period, they were asked to take 6 grains once a day for 2 weeks. After the start of period I intake, the OSA sleep questionnaire was filled in, electroencephalograms during sleep were measured, and a diary describing changes in physical condition was made to be kept every day.

After completing the ingestion period of Phase I, a 2-week non-intake period (Washout) was provided. After that, the subjects were sent foods different from those in Phase I, and had them eat them for two weeks after the end of the non-ingestion period. After the start of period II intake, the OSA sleep questionnaire was similarly filled in, electroencephalograms during sleep were measured, and a diary describing changes in physical condition was made to be kept every day.

6. Statistical Analysis The significance level of the test in this test was set to 5% on both sides, and comparison between groups was performed by a paired t-test. Statistical analysis was performed using SAS Ver.9.4 (manufactured by SAS). Multiplicity was not considered. Regarding the results, due to the small number of cases, the variability is shown as the standard deviation.

<II Results>
1. Analysis target
The test was conducted with 20 people, and 1 person dropped out due to personal reasons, so the test was completed with 19 people. None of the study completers violated the study compliance requirements, and all study completers (19 persons) were included in the analysis.

Fig. 10 shows the subject selection flow.

Table 4 shows the background of the subjects for analysis.

2. Results of sleep electroencephalograph Table 5 shows the analysis results of the sleep electroencephalograph. In a sleep electroencephalograph analysis, the rate of awakening during sleep and sleep onset latency were significantly reduced in the HYPNOCALIS intake group compared to the placebo food group. In addition, the percentage of non-REM sleep during sleep showed a significant increase in the hypnocallis intake group compared to the placebo food group.

Non-REM sleep is further divided into three stages, the N1 stage and N2 stage are considered light sleep among Non-REM sleep, and the N3 stage is considered deep sleep among Non-REM sleep, but the results of this test In both cases, the Hypnocallis (R) intake group showed a significant increase compared to the placebo food group.

3. Results of subjective evaluation Table 6 shows the results of factor scores of the OSA Sleep Questionnaire. Compared to the placebo group, the Hypnocallis (R) intake group showed significant differences in factor I (sleepiness upon waking up), factor II (falling asleep and maintaining sleep), factor III (dreaming), and factor IV (fatigue recovery). The effect of improving the quality of sleep was recognized.

No significant changes were observed in either the Pittsburgh Sleep Questionnaire or the subjective evaluation by SF-36.

<III consideration>
We found that a hot water extract of Kwanso made under certain conditions has a sleep-improving effect. In addition, as a result of the component analysis of the hot water extract of Kwansou produced under certain conditions, it was found that unsinoside A contributes to the effect of improving sleep.

Unsinoside A is standardized in the amount of Unsinoside A in Hypnocallis (R). Furthermore, regarding the sleep-improving effect of unsinoside A, it is thought that the effect of lowering core body temperature in mice, which was confirmed with hot water extracts of Phytophthora spp. and unsinoside A are presumed to have the same effect of lowering core body temperature. Therefore, it was concluded that the substance involved in the sleep-improving effect of Hypnocallis (R) is unsinoside A.

<IV Conclusion>
Using a food containing 2000 mg of Hypnocallis (R), a standardized extract containing unsinoside A derived from huangsu, and a placebo food, sleep electroencephalograms were used as the primary endpoint for healthy subjects who were dissatisfied with the quality of sleep. A randomized, placebo-controlled, crossover controlled trial with the OSA sleep questionnaire as a secondary outcome was conducted.

As a result, the rate of awakening during sleep and sleep onset latency were significantly decreased in the Hypnocallis (R) intake group compared to the placebo food group. In addition, the percentage of non-REM sleep during sleep showed a significant increase in the Hypnocallis (R) intake group compared to the placebo food group.

In addition, regarding the OSA sleep questionnaire, the Hypnocallis (R) intake group compared with the placebo intake group, factor I (sleepiness upon waking), factor II (sleep onset and sleep maintenance), factor III (dreaming), factor IV A significant difference was observed in (recovery from fatigue). From the above results, Hypnocallis (R) was found to be effective in promoting sleep onset, increasing deep sleep, and improving sleep quality.

(4) Industrial applicability It was confirmed that ingestion of hot water extracts of Kwanso (Kwanso) (Concentrated extract of Kwanso, concentrated extract powder of Kwanso), Unsinoside A, and Unsinoside B improved sleep (induced sleep). .

In general, there is a proportional relationship between the decrease in core body temperature and the sleep onset latency (earlyness of falling asleep). Furthermore, when deep sleep (N3) increases, the cranial nerves rest the most and the feeling of recovery from fatigue increases (it is known that growth hormone secretion increases and repair and regeneration of damaged cells and tissues are promoted). It indicates that sleep onset latency is shortened, sleep awakening is decreased, and NREM sleep is increased, "improving sleep quality."

The sleep improving agent of the present invention comprises, as an active ingredient, at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, preferably further , Preferably, it contained daylilies or an extract (processed product) thereof, and exhibited an effect of improving sleep (inducing sleep) due to the active ingredient.

By ingesting the sleep improving agent of the present invention, sleep can be improved (sleep can be induced).

Claims (4)

a sleep-improving agent,
containing at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof;
Sleep improver. Furthermore, containing daylily, or its extract,
2. The sleep improving agent according to claim 1. The daylily or its extract contains at least one chromone glycoside selected from the group consisting of Unsinoside A and Unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof. ,
At least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof is inherent in the daylily or an extract thereof. ,
3. The sleep improving agent according to claim 2. at least one chromone glycoside selected from the group consisting of unsinoside A and unsinoside B, an aglycone thereof, or a pharmaceutically acceptable salt thereof, which is inherent in the daylily or an extract thereof; which is a mixture with externally added
4. The sleep improving agent according to claim 2 or 3.

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