KR101351883B1 - Novel use of rice hull extract for improving, preventing or treating sleep disorders, anxiety, or depression - Google Patents

Abstract

The present invention provides a novel use of chaff extract for improving, preventing or treating sleep disorders, anxiety or depression. Chaff extract has almost the same level of diazepam as the drug used as a conventional sleep inducing agent or improved sleep time, increased sleep duration and increased nonram sleep. Chaff extract is a natural product and has no side effects of forming cognitive impairment, resistance or dependence even after prolonged use.

Description

New use of rice hull extract for improving, preventing or treating sleep disorders, anxiety, or depression

The present invention relates to novel uses of rice hull extracts for improving, preventing or treating sleep disorders, anxiety or depression.

Sleep constitutes one-third of human life and is the most fundamental and essential physiological phenomenon and is a very important factor in health maintenance and mental stability. Chronic sleep deprivation and disability negatively impacts overall physical and mental health, including cardiovascular disease and hypertension, memory and learning, metabolic control and weight, immunity and cancer resistance, diabetes, safety concerns, and mood. Currently, about 30% of the world's population is suffering from insomnia, and 10% is suffering from chronic sleep disorders.

According to a survey by the National Sleep Foundation USA, 2008, about 50% of US adults experience insomnia at least once a week, and about 50% of Americans are satisfied with their sleep . In recent years, the prevalence of insomnia and sleep disorders in Korea is rapidly approaching that of developed countries. The number of patients with sleep disorders has increased from 51,000 in 2001 to 228,000 in 2008, 4.5 times more than in the past eight years (National Health Insurance Corporation, 2009 ).

In Korea, there is not much interest in sleeping, and especially, there is no awareness of medical treatment or illness. On the other hand, according to statistics, about 15% of adults are known to need medication due to insomnia due to anxiety symptoms. Insomnia is caused by various factors such as stress, tension, and fear. Drugs include benzodiazepines Serotonin antagonists, etc. However, there is a serious problem in that cognitive impairment, tolerance, and dependence are formed when these drugs are used for a long period of time. Therefore, the necessity of natural supplements as a means to replace the sleeping pills long-term users and limiters, and the demand for sleep-enhancing health functional food is increasing.

Rice is a valuable food resource, one of the world's three major crops, which half of the world's population uses as a staple food, and is a key national resource that cannot be replaced by other crops, especially in Asia. Rice, which is rice husk, which is the surface of rice, is called brown rice, rice rice with rice husk and rice husk is removed and rice is called white rice.

Because chaff is used as a feed or compost rather than edible, little has been reported about the bioactive activity of chaff, and in particular, the relationship between chaff extract and sleep, anxiety or depression has not been revealed.

The present invention aims to discover components derived from natural products that can replace existing drugs that have been used for the treatment of sleep disorders, anxiety or depression.

The present inventors have tried to prepare a natural composition having a high effect of preventing or treating sleep disorders, anxiety or depression. As a result, the chaff extract has completed the present invention by elucidating the efficacy of preventing or treating sleep disorders, anxiety or depression.

The present invention is a novel use for improving, preventing or treating sleep disorders, anxiety or depression of chaff extract, pharmaceutical composition for the prevention or treatment of sleep disorders, anxiety or depression comprising a chaff extract as an active ingredient, a therapeutically effective amount of Provided is a method for preventing or treating sleep disorders, anxiety or depression comprising administering chaff extract to a subject.

In the present invention, improvement of sleep disorder, prevention or treatment may mean decrease in the time of the face, increase of the sleep duration, or increase of the sleeping surface.

In the following examples, chaff extract exhibits approximately the same or improved reduction in elevation and increased sleep duration compared to diazepam, a medicament that is conventionally used as a sleeping, anti-anxiety or antidepressant, and increases nonram sleep time. Shows. Therefore, chaff extract can be used as an active ingredient of the composition for the prevention or treatment of sleep disorders, anxiety or depression. Unlike conventional sleeping pills, chaff extract is harmless to the human body, which is approved as a food, has no side effects, and has an excellent effect of inducing sleep and prolonging sleep, and thus can be useful for preventing or treating sleep disorders, anxiety or depression. have. In the examples of the present invention, an experiment for anxiety or depression was not performed separately. However, for example, ingredients used for improvement, prevention, or treatment of sleep disorders, such as diazepam, , Prophylactic or therapeutic, as is well known to those skilled in the art.

In addition, through the following examples chaff extract was found to exhibit an antagonistic action on the histamine receptor. Therefore, the present invention also provides an antihistamine comprising chaff extract as an active ingredient.

In the present invention, the chaff extract may be extracted from the chaff using water, an organic solvent or a mixture thereof as an extraction solvent. The kind of the organic solvent used at this time and the mixing ratio of water and the organic solvent are not particularly limited.

For example, the organic solvent may be one or more solvents selected from the group consisting of lower alcohols, hexane, acetone, ethyl acetate, chloroform, and diethyl ether. The lower alcohol may be an alcohol having 1 to 6 carbon atoms. For example, as the lower alcohol, methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, 2-butoxyethanol or ethylene glycol can be used. Organic solvents include polar solvents such as acetic acid, dimethyl-formamide (DMFO) and dimethyl sulfoxide (DMSO), acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, 2,2,4-trimethylpentane, and decane. , Cyclohexane, cyclopentane, diisobutylene, 1-pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene And nonpolar solvents such as benzene, diethyl ether, diethyl sulfide, chloroform, dichloromethane, 1,2-dichloroethane, anneal, diethylamine, ether, carbon tetrachloride and THF (Tetrahydrofuran).

In one embodiment, the chaff extract may be a lower alcohol extract of chaff, preferably an ethanol extract of chaff.

In another embodiment, the rice extract may be a hexane extract of rice.

As used herein, the term " extract " also includes fractions obtained by further fractionating the extract. That is, chaff extract is not only obtained by using the above-described extraction solvent, but also includes the one obtained by further applying a purification process. In addition, fractions obtained by passing the extract or fraction through an ultrafiltration membrane having a constant molecular weight cut-off value, separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity), etc. Fractions obtained through the various purification methods described above are also included in the chaff extract of the present invention.

In one embodiment, the chaff extract may be a fraction obtained by re-fractionation of the organic solvent extract of chaff into a second organic solvent. In another embodiment, the chaff extract may be a fraction obtained by re-fractionation of the lower alcohol extract of chaff with a second organic solvent. In another embodiment, the chaff extract may be a fraction of the ethanol extract of the chaff re-fractionated with hexane. As can be seen in the following examples, fractions of the chaff extract containing a large amount of the fat-soluble components of the chaff shows a very good surface induction and sleep prolonging effect.

As used herein, the term 'chaff extract' includes not only the crude extract obtained by treating the extract solvent on the chaff, but also processed products of the chaff extract. For example, chaff extract may be prepared in powder form by additional processes such as distillation under reduced pressure and freeze drying or spray drying.

On the other hand, the term 'comprising as an active ingredient' herein means containing an amount sufficient to achieve the efficacy or activity of chaff extract.

In one embodiment of the invention, the chaff extract in the composition of the invention is for example at least 0.001 mg / kg, preferably at least 0.1 mg / kg, more preferably at least 10 mg / kg, even more preferably Is included at least 100 mg / kg, even more preferably at least 250 mg / kg, most preferably at least 0.1 g / kg. Since chaff extract has no side effects on the human body even when excessively administered as a natural product, the upper limit of the amount of chaff extract included in the composition of the present invention can be carried out by those skilled in the art.

The pharmaceutical composition of the present invention can be prepared by using pharmaceutically acceptable and physiologically acceptable adjuvants in addition to the above-mentioned active ingredients. Examples of the adjuvants include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, A lubricant or a flavoring agent can be used.

The pharmaceutical composition may be formulated into a pharmaceutical composition containing at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration.

The pharmaceutical composition may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions, emulsions, drops or injectable solutions. For example, for formulation into tablets or capsules, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Also, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included as a mixture. Suitable binders include, but are not limited to, natural and synthetic gums such as starch, gelatin, glucose or beta-lactose, natural sugars such as corn sweeteners, acacia, tracker candles or sodium oleate, sodium stearate, magnesium stearate, Benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Acceptable pharmaceutical carriers for compositions that are formulated into a liquid solution include sterile water and sterile water suitable for the living body such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.

Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field.

The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, the composition can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, etc., .

The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate and responsiveness of the patient, Usually, a skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-10 g / kg.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it with a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person skilled in the art to which the present invention belongs Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

The present invention also provides a food composition for preventing or improving sleep disorders, anxiety or depression comprising chaff extract as an active ingredient.

The food composition according to the present invention can be formulated in the same manner as the above pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, alcoholic beverages, confectioneries, diet bars, dairy products, meat, chocolates, pizza, ram noodles, other noodles, gums, ice cream, .

The food composition of the present invention may include not only chaff extract as an active ingredient, but also components commonly added in food production, and include, for example, proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents. Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings. For example, when the food composition of the present invention is prepared with a drink and drinks, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts may be further included in addition to the chaff extract of the present invention.

The present invention provides a health functional food comprising a food composition for preventing or improving sleep disorders, anxiety or depression comprising the chaff extract as an active ingredient. Health functional food is a food prepared by adding chaff extract to food materials such as beverages, teas, spices, gums, confectionery, or by encapsulating, powdering, and suspension. Meaning, unlike the general medicine has the advantage that there is no side effect that can occur when taking a long-term use of the drug as a food raw material. The health functional food of the present invention thus obtained is very useful because it can be consumed on a daily basis. Although the amount of chaff extract added in such a dietary supplement cannot be uniformly defined depending on the kind of the dietary supplement, the additive may be added within a range that does not impair the original taste of the food. To 50% by weight, preferably 0.1 to 20% by weight. In the case of health functional foods in the form of pills, granules, tablets or capsules, they may be added usually in the range of 0.1 to 100% by weight, preferably 0.5 to 80% by weight. In one embodiment, the health functional food of the present invention may be in the form of a pill, tablet, capsule or beverage.

The present invention also provides the use of chaff extract for the manufacture of a medicament or food for the prevention, treatment or amelioration of sleep disorders, anxiety or depression. As described above, chaff extract may be used for the purpose of preventing, treating or improving sleep disorders, anxiety or depression.

The present invention also provides a method of preventing, treating or ameliorating sleep disorders, anxiety or depression comprising administering to a mammal an effective amount of chaff extract.

The term "mammal " as used herein refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.

As used herein, the term "effective amount" refers to the amount of active ingredient or pharmaceutical composition that elicits a biological or medical response in a tissue system, animal, or human, as contemplated by a researcher, veterinarian, physician or other clinician, ≪ / RTI > inducing a reduction of the symptoms of the disease or disorder. It will be apparent to those skilled in the art that the effective amount and the administration frequency of the active ingredient of the present invention will vary depending on the desired effect. Thus, the optimal dosage to be administered can be readily determined by those skilled in the art and will vary with the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, The age, body weight, sex, diet, time of administration, route of administration and fraction of the composition, duration of treatment, concurrent medication, and the like. In the prophylactic, therapeutic or ameliorating method of the present invention, for adults, chaff extract is preferably administered at a dose of 0.001 mg / kg to 10 g / kg when administered once to several times a day.

The composition comprising the chaff extract as an active ingredient in the treatment method of the present invention may be administered in a conventional manner through oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, intraocular or intradermal routes. May be administered.

Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the technical field to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

Chaff extract is almost the same level as diazepam, a drug used as a conventional sleep inducing agent, and provides improved effect of reducing sleep time, increasing sleep duration, and increasing non-ram sleep, and it is extracted from natural chaff. (cognitive impairment) There are no side effects that form tolerance or dependence.

Figure 1A is a graph showing the effect of HWE on the elevation of the mice administered the pentobarbital sleeping dose (45 mg / kg, ip), Figure 1B is a pentobarbital sleeping dose (45 mg / kg, ip) It is a graph showing the effect of HWE on the sleep time of the mice administered. After 45 minutes of oral administration (po) with DZP (2 mg / kg) and HWE (50, 100, 250, 500 mg / kg), pentobarbital was administered to the control (0.5% CMC-saline 10 mL / kg) Each graph represents the mean value (means ± SEM, n = 10). * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. CON is the control; DZP stands for diazepam.
Figure 2A is a graph showing the effect of HEE on the elevation of the mice administered the pentobarbital sleeping dose (45 mg / kg, ip), Figure 2B is a pentobarbital sleeping dose (45 mg / kg, ip) It is a graph showing the effect of HEE on the sleep time of the mice administered. After 45 minutes of oral administration (po) with DZP (2 mg / kg) and HEE (50, 100, 250, 500 mg / kg) in the control group (0.5% CMC-saline 10 mL / kg) . Each graph represents the mean value (means ± SEM, n = 10). * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. CON is the control; DZP represents diazepam.

[ Example ]

[Experimental Method]

Experimental animal

ICR mice (18-22 g, male) and SD rats (200-250 g, male) were distributed from Koatech and Orient Bio Co., respectively, and were adapted for one week in an experimental animal breeding box. Respectively. Animals were fed at a temperature of 23 ± 1 ℃, a humidity of 55 ± 5%, a light - dark cycle (9:00 am - 9:00 pm) and an illuminance of 3000 Lux. All animals were maintained in accordance with the Guidelines for the Use of Laboratory Animals by the Korea Food Research Institute (KFRI-IACUC, Korea Food Research Institutional Animal Care and Use Committee).

Pentobarbital-induced sleep test

The pentobarbital sleep induction experiment was conducted within a certain time from 1 pm to 5 pm, and 10 mice (n = 10) per group were used after fasting for 24 hours before the experiment. All samples were prepared using 0.5% CMC-saline solution and administered orally (po) to mice 45 minutes before pentobarbital administration. In the general control group, 0.5% CMC-saline solution was treated at a concentration of 10 mg / kg, and diazepam was used as a positive control to compare the effect of the extract on sleep. Pentovavital (Hanlim Pharmaceutical Co., Ltd.) was administered via intraperitoneal injection (ip) at a concentration of 45 mg / kg (hypnotic dosage) according to the experimental design. After the pentobarbital treatment, each individual was moved to a separate space to measure sleep latency and sleep duration. The time of the elevation was set as the elapsed time until the righting reflex was lost for more than 1 minute after the peritoneal injection of pentobarbital, and the sleeping time was set as the time until the regular reflection was restored again. Mice that did not show sleep behavior after 10 minutes of pentobarbital administration were excluded from the experiment.

< Manufacturing example  1> Preparation of Chaff Extract

Water and ethanol extracts were prepared from selected raw materials to explore the effects of sleep enhancement. (HWE) was prepared by adding 1 L of distilled water to 100 g of ground sample and heating it to 100 ℃ for 1 hour. The rice husk ethanol extract (HEE) was prepared by adding 10% (w / v) 50 ℃ incubator for 1 day and then ultrasonicated three times for 90 minutes per day. All the extracts were filtered and concentrated under reduced pressure, lyophilized and powdered for use in the experiment.

The yields of water and ethanol extract of rice husk are shown in Table 1. The water extract (HWE) yield of rice husk was 5%.

extract HE yield
(%, g / g) HWE HEE 5.14 0.96

Abbreviation: Water extract of rice hull (HWE); Ethanol extract of rice hull

< Experimental Example  1> with chaff extract Pentobaby  Sleep induction experiment

Sleep induction effect by pentobarbital (45 mg / kg, ip) after oral administration (po) of water extract (HWE) and ethanol extract (HEE) of chaff at 50, 100, 250 and 500 mg / kg Was analyzed. As a result, as can be seen in Figure 1, the water extract (HWE) of the chaff showed a significant decrease in the elevation time, the sleep duration was significantly significant at the concentration of 250 and 500 mg / kg Increased to ( p <0.01). In addition, as can be seen in Figure 2, the ethanol extract (HEE) of the chaff showed a significant decrease in elevation ( p <0.01) at concentrations other than 50 mg / kg, the dose-dependent sleep duration of An increase was seen ( p <0.01). (HEE) of rice hulls showed a significant increase in the duration of sleep, while that of the rice hull extract (HWE) and rice husk ethanol extract (HEE) Respectively.

< Experimental Example  2> chaff Water extract  Sleep Mechanism: Histamine Receptor Efficacy agent , 2- blood Ridylethyleneamine Dihydrochloride  chaff Water extract  Effect on sleep induction effect

In the United States, antihistamine and natural herb products are the most representative of nonprescription sleep aids. In particular, antihistamines are antagonists of histamine receptors and are representative of cold medicines, and are the only hypnotics that can be easily purchased without a doctor's prescription. This is possible because the pharmacological side effects and dependence is low.

The effect of the histamine receptor antagonist on the sleep-inducing effect is inhibited by histamine receptor agonists. In this experimental example, the mechanism of action of chaff water extract was revealed using antagonists (pyrilamine maleate salt, PMS) and agonists (2-pyridylethylamine dihydrochloride, PD) acting on histamine receptors.

Chaff water extract (HWE) was orally administered 500 mg / kg 45 minutes prior to pentobarbital administration (hypnotic dosage 45 mg / kg), GABA _A Flumazenil, the antagonist of the receptor, 8 mg / kg, PD, the active agonist of the histamine receptor, 20 mg / kg 10 minutes prior to oral HWE latency and sleep duration were measured.

As shown in FIG. 3, the chaff water extract (HWE) significantly increased sleep latency due to antagonism by flumazenil ( p <0.01) and increased sleep duration. Decrease ( p <0.01). In addition, 2-pyridylethyleneamine dihydrochloride, a histamine activity agonist, significantly increased sleep latency ( p <0.01) and decreased sleep duration ( p <0.01).

Taken together, these results suggest that chaff water extract (HWE) contains components that act as an active agonist of GABA _A receptors, and has an antagonistic effect on histamine receptors and its effect is reduced by active agonists. Could know.

Thus, chaff water extract (HWE) was found to act on both GABA _A and histamine receptors.

Claims (25)

Pharmaceutical composition for the prevention or treatment of sleep disorders or anxiety comprising chaff extract as an active ingredient.
The method of claim 1,
Wherein said prevention or treatment of a sleep disorder is for a reduction in sleep time, an increase in sleep duration, or an increase in non-sleep sleep.
The method of claim 1,
The chaff extract is a pharmaceutical composition of water, an organic solvent or a mixture thereof of chaff.
The method of claim 3,
The organic solvent is at least one solvent selected from the group consisting of alcohols having 1 to 6 carbon atoms, hexane, acetone, ethyl acetate, chloroform, and diethyl ether.
The method of claim 1,
The chaff extract is a pharmaceutical composition of an alcohol extract of 1 to 6 carbon atoms of chaff.
The method of claim 1,
The chaff extract is a pharmaceutical composition of ethanol extract of chaff.
The method of claim 1,
The chaff extract is a hexane extract of chaff.
The method of claim 1,
The chaff extract is a pharmaceutical composition which is a fraction of the organic solvent extract of chaff re-fractionated with additional organic solvents of different polarity.
The method of claim 1,
The chaff extract is a pharmaceutical composition which is a fraction obtained by re-fractionation of an alcohol extract having 1 to 6 carbon atoms of chaff with additional organic solvents having different polarities.
The method of claim 1,
The chaff extract is a pharmaceutical composition that is a fraction of the ethanol extract of the chaff re-fractions with hexane.
Food composition for the prevention or improvement of sleep disorders or anxiety comprising chaff extract as an active ingredient.
12. The method of claim 11,
The prevention or improvement of the sleep disorder is for reducing the time of sleep, increase in sleep duration or increase in non-sleep sleep.
12. The method of claim 11,
The chaff extract is a food composition of water, an organic solvent or a mixture thereof of chaff.
The method of claim 13,
The organic solvent is at least one solvent selected from the group consisting of alcohols having 1 to 6 carbon atoms, acetone, hexane, ethyl acetate, chloroform, and diethyl ether.
12. The method of claim 11,
The chaff extract is a food composition of an alcohol extract of 1 to 6 carbon atoms of chaff.
12. The method of claim 11,
The chaff extract is a food composition of ethanol extract of chaff.
12. The method of claim 11,
The chaff extract is a hexane extract of chaff food composition.
12. The method of claim 11,
Wherein the chaff extract is a fraction of the organic solvent extract of the chaff re-fraction fractionation with an additional organic solvent of different polarity.
12. The method of claim 11,
The chaff extract is a food composition which is a fraction obtained by re-fractionation of the alcohol extract having 1 to 6 carbon atoms of the chaff into additional organic solvents having different polarities.
12. The method of claim 11,
The chaff extract is a food composition that is a fraction of the ethanol extract of chaff re-fractionated with hexane.
Antihistamines for the prevention or treatment of sleep disorders or anxiety comprising chaff extract as an active ingredient.
delete The method of claim 21,
The prevention or treatment of the sleep disorder is for reducing the time of sleep, increase in sleep duration or increase in non-sleep sleep antihistamine.
The method of claim 21,
The chaff extract is an antihistamine extract of water, an organic solvent or a mixture of chaff.
25. The method of claim 24,
The organic solvent is at least one solvent selected from the group consisting of alcohols having 1 to 6 carbon atoms, hexane, acetone, ethyl acetate, chloroform, and diethyl ether.

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