KR20220056941A - A composition for the prevention, improvement or treatment of sleep disorders or insomnia with reduced side effects of GABAA receptor agonist, containing Glehnia littoralis extract - Google Patents

Abstract

The present invention relates to a composition for GABA_A receptor agonist tolerance inhibition or side effect reduction or treatment containing a Glehnia littoralis extract as an active ingredient, or a composition for sleep disorder or insomnia prevention, amelioration, or treatment containing a single Glehnia littoralis extract or a Glehnia littoralis extract-GABA_A receptor agonist compound as an active ingredient. A pharmaceutical composition for sleep disorder or insomnia prevention or treatment or a health functional food composition for sleep disorder or insomnia prevention or amelioration of the present invention containing a Glehnia littoralis extract as an active ingredient induces or maintains sleep quickly and reliably, prevents repeated awakening symptoms, does not alter the physiological structure of sleep, is free from residual sedation that may cause incomplete daytime activities or cognitive abilities, causes no tolerance even in the event of long-term administration, and is free from existing GABA_A receptor agonist side effects. In addition, in the pharmaceutical composition for sleep disorder prevention or treatment of the present invention containing a Glehnia littoralis extract and a GABA_A receptor agonist as active ingredients, the content of the GABA_A receptor agonist, which may cause various side effects by causing a decline in sleep quality while increasing the amount of sleep, is reduced. Accordingly, GABA_A receptor agonist side effects can be reduced or tolerance attributable to long-term GABA_A receptor agonist administration can be inhibited.

Description

A composition for the prevention, improvement or treatment of sleep disorders or insomnia for suppressing tolerance or alleviating side effects of GABAA receptor agonists using Gaetbangpung extract as an active ingredient {A composition for the prevention, improvement or treatment of sleep disorders or insomnia with reduced side effects of GABAA receptor agonist, containing Glehnia littoralis extract}

The present invention relates to a composition for inhibiting tolerance or improving or treating side effects of a GABA _A receptor agonist comprising an extract of Gaetbangpung ( Glehnia littorali s) as an active ingredient, or a composition of Gaetbangpung extract alone or a combination of a Gaetbangpung extract and a GABA _A receptor agonist It relates to a composition for preventing, improving or treating sleep disorders or insomnia, comprising as an active ingredient.

Sleep can be defined in many ways, but it is mainly defined as a state of motion in which the ability to perceive and respond to the external environment is reversible, repetitive, and normally stationary. The sleep is achieved by brain activity, but is also deeply related to physiological changes in other body parts.

Sleep disturbance is one of the common problems experienced by modern people, and it is a very common disease that has been experienced or suffered by more than 20% of the population. The sleep disorder refers to a state in which a person does not get a healthy sleep, fails to maintain arousal during the day despite getting enough sleep, or has difficulty sleeping or waking due to disordered sleep rhythm. Mental problems can also be a major cause, which is caused by excessive stress, anxiety, tension, and fear.

Sleep disturbance can cause a variety of personal and social problems and cause learning disabilities, decreased efficiency, traffic accidents, safety accidents, emotional disorders, social adjustment disorders, dissatisfaction with marriage, and industrial accidents. In addition, if sleep disorders are not properly treated, medical, neurological, and psychiatric diseases already suffered may worsen or recovery may be delayed, and serious diseases such as myocardial infarction and stroke may result.

Insomnia is the most common disease among all sleep disorders, and insomnia can be defined as a condition in which there is a problem with either the initiation of sleep or maintenance of sleep for 3 or more days per week, accompanied by daytime fatigue or disability.

The GABA _A receptor is a phantameric protein that forms a membrane ion channel, and is closely related to the regulation of sedation, sleep, anxiety, muscle tone, convulsions, and memory loss, through which GABA (gamma-aminobutyric acid) acts. .

GABA _A receptor agonists include benzodiazepine hypnotics and non-benzodiazepine hypnotics. Non-benzodiazepine GABA _A receptor agonists include zolpidem, zopiclone, zaleflon, and trazodone. Zolpidem is N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide; Zopiclone is 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[ 3,4-b]pyrazine; Zaleflon is N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide; Trazodone is 2-[3-{4-(m-chlorophenyl)-1-piperazinyl]propyl]s-triazolo[4,3-a]-pyridine-3(2H)-1 monohydrochloride .

Benzodiazepine-based sleeping pills are very effective in shortening the time to fall asleep and increasing the time to sleep, but are known to cause side effects such as difficulty in waking up the next morning and daytime insomnia.

Non-benzodiazepine sleeping pills shorten the time to fall asleep, but have fewer side effects than benzodiazepine sleeping pills, making it difficult to wake up the next morning. However, non-benzodiazepine hypnotic drugs still include residual sedation and psychomotor disorders, daytime anxiety, anterograde amnesia and cognitive deficits, rebound insomnia, drug tolerance and dependence. In addition, there is a possibility that patients taking non-benzodiazepine hypnotic drugs may experience daytime sleepiness, thus increasing the risk of impaired activity and, in particular, traffic accidents.

For example, changes in delta activity during NREM sleep are physiological indicators of sleep quality and depth, but in the case of zolpidem, the amplitude of delta waves in slow wave sleep in the electroencephalogram (EEG), that is, It is known to alter sleep structure by reducing delta activity or enhancing radiofrequency activity. In addition, it has been reported that non-benzodiazepine hypnotic drugs such as zolpidem or zopiclone have few side effects seen with benzodiazepine hypnotic drugs, but in subsequent studies, they also showed incomplete daytime psychomotor disorder, drug tolerance, withdrawal symptoms, or dependence. has been reported

Therefore, for the treatment of insomnia, a drug that can achieve an appropriate balance between sleep action and side effects must be developed. Therefore, an ideal sleeping pill can induce or maintain sleep quickly and reliably, prevent repeated sleepiness symptoms, and It should not alter the sleep structure, and in particular there should be no residual sedation that could lead to incomplete daytime activity or cognitive abilities.

The present inventors completed the present invention by confirming that Gaetbangpung extract has the effect of alleviating the side effects of conventional GABA _A receptor agonists in the process of researching on natural products that can achieve an appropriate balance between sleep action and side effects. .

KR 10-1875307 B KR 10-1820761 B

The present invention rapidly and reliably induces or maintains sleep, can prevent recurrent sleepiness symptoms, must not alter the physiological sleep structure, and in particular has no residual sedation that can cause incomplete daytime activity or cognitive ability. It is to provide a health functional food composition that uses Gaetbangpung extract as an active ingredient, and can suppress resistance or reduce side effects of benzodiazepine-binding site agonists of GABA _A receptors.

In addition, the present invention is to provide a health functional food composition for improving sleep disorders or insomnia, which is administered to insomnia patients who are being administered a benzodiazepine-binding site agonist of the GABA _A receptor, and contains Gaetbangpung extract as an active ingredient. .

In addition, the present invention is to provide a pharmaceutical composition for preventing or treating sleep disorders or insomnia comprising a Gaetbangpung extract as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition comprising Gaetbangpung extract as an active ingredient, which can reduce the side effects of a GABA _A receptor agonist or suppress resistance following long-term administration of a GABA _A receptor agonist.

In addition, the present invention increases the amount of sleep but lowers the quality of sleep to reduce the content of GABA _A receptor agonists that can cause various side effects, and a pharmaceutical composition for preventing or treating sleep disorders or insomnia combined with a Gaetbangpung extract is to provide

The present invention for achieving the above object is for the prevention or improvement of sleep disorders or insomnia for inhibiting tolerance of a benzodiazepine-binding site agonist of the GABA _A receptor using an extract of Gaetbangpung ( Glehnia littorali s) as an active ingredient or for alleviating side effects It relates to a health functional food composition.

The Gaetbangpung extract may be administered at a concentration of 50 to 1000 mg/kg/day.

The resistance of the benzodiazepine-binding site agonist of the GABA _A receptor is an effect of reducing the effect of treating sleep disorders according to long-term administration, and the side effect of the benzodiazepine-binding site agonist of the GABA _A receptor is inhibition of the delta activity of brain waves and residual It may be any one or more selected from the sedative action.

The benzodiazepine binding site agonist of the GABA _A receptor may be a non-benzodiazepine-type drug.

The non-benzodiazepine-based drug may be at least one selected from zolpidem, zopiclone, and zaleplon.

The Gaetbangpung extract may be extracted with water, a lower alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof.

The mixed solvent may be an aqueous solution of 20 to 80% by volume of methanol, ethanol, butanol or propanol, preferably 60 to 80% of an aqueous ethanol solution.

The health functional food composition may be administered to a sleep disorder or insomnia patient who is being administered a benzodiazepine binding site agonist of the GABA _A receptor.

The dosage form of the health functional food composition may be a powder, granules, tablets, capsules or beverages.

In addition, the present invention relates to a health functional food composition for improving insomnia, which is administered to insomnia patients who are administered a benzodiazepine-binding site agonist of the GABA _A receptor, and contains Gaetbangpung extract as an active ingredient.

In addition, the present invention relates to a pharmaceutical composition for preventing or improving sleep disorders or insomnia for inhibiting resistance to or alleviating side effects of a benzodiazepine-binding site agonist of GABA _A receptors containing an extract of Gaetbangpung ( Glehnia littorali s) as an active ingredient.

The present invention also relates to a pharmaceutical composition for preventing or treating sleep disorders or insomnia, comprising an extract of Gaetbangpung ( Glehnia littorali s) and a benzodiazepine-binding site agonist of GABA _A receptors as active ingredients.

The daily dose of the GABA _A receptor benzodiazepine binding site agonist is 100 parts by weight of the daily dose of the active ingredient of a pharmaceutical composition comprising only the benzodiazepine binding site agonist of the GABA _A receptor as an active ingredient , may be 20 to 80 parts by weight.

In addition, the pharmaceutical composition for preventing or treating sleep disorders may include 10 to 500 mg of the Gaetbangpung extract and 2 to 10 mg of the benzodiazepine-binding site agonist of the GABA _A receptor in a daily dose.

The pharmaceutical composition may alleviate the side effects of benzodiazepine binding site agonists of GABA _A receptors.

The sleep disorder or insomnia prevention or treatment may be for a decrease in waking time, an increase in sleep duration, or an increase in non-REM sleep.

A health functional food composition for preventing or improving sleep disorders or insomnia, or a pharmaceutical composition for preventing or treating sleep disorders or insomnia, comprising the Gaetbangpung extract of the present invention as an active ingredient, while inducing or maintaining sleep quickly and reliably, and repeatedly locking symptoms , does not alter the physiological sleep structure, does not have residual sedation that can cause incomplete _daytime activity or cognitive ability, does not develop tolerance even with long-term administration, No side effects occur.

In addition, the pharmaceutical composition for the prevention or treatment of sleep disorders comprising the Gaetbangpung extract and the GABA _A receptor agonist of the present invention as an active ingredient increases the amount of sleep but lowers the quality of sleep, thereby causing various side effects. GABA _A receptors By reducing the content of the agonist, the side effects of the GABA _A receptor agonist may be alleviated or the tolerance following long-term administration of the GABA _A receptor agonist may be suppressed.

1 is an experimental flow chart for sleep structure analysis.
2 shows Gaetbangpung extract (KS-093) 300 mg/kg alone administration in Test Example 1; Gaetbangpung extract 300 mg/kg + zolpidem (ZPD) 5 mg/kg co-administration; Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combined administration; It is a graph analyzing the elevation time and sleep structure according to the administration of zolpidem 5 mg/kg and 10 mg/kg alone. Vehicle represents the control group, and ** means that there is a significant difference in p<0.01 compared to the control group (t-test). KS-093 is an abbreviation for Gaetbangpung extract, ZPD is an abbreviation for zolpidem, and NREMS and REMS are abbreviations for non-rapid eye movement sleep and rapid eye movement sleep, respectively.
3 shows Gaetbangpung extract (KS-093) 300 mg/kg alone administration in Test Example 1; Gaetbangpung extract 300 mg/kg + zolpidem (ZPD) 5 mg/kg co-administration; Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combined administration; It is a graph showing EEG (elctroencephalogram) power density and delta activity in non-REM sleep following administration of zolpidem 5 mg/kg and 10 mg/kg alone. Vehicle represents the control group, * means that there is a significant difference at p<0.05 compared with the control group, and ** means there is a significant difference at p<0.01 compared with the control group (t-test). KS-093 is an abbreviation of Gaetbangpung extract, ZPD is an abbreviation of zolpidem, and NREMS is an abbreviation of non-rapid eye movement sleep.
4 is an experimental flowchart for measuring EEG in mice by long-term administration.
5 is 300 mg/kg of Gaetbangpung extract + 5 mg/kg of zolpidem (ZPD) combined administration in Test Example 2; Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combined administration; After long-term administration of zolpidem (ZPD) 5 mg/kg and 10 mg/kg alone for 3 weeks, it is a graph analyzing the elevation time and sleep structure according to the number of administration days and withdrawal days. BL (baseline) represents the control group, * means that there is a significant difference at p<0.05 compared to the control group, and ** means there is a significant difference at p<0.01 compared with the control group (t-test). KS-093 is an abbreviation for Gaetbangpung extract, ZPD is an abbreviation for zolpidem, and NREMS and REMS are abbreviations for non-rapid eye movement sleep and rapid eye movement sleep, respectively. Also, WD is an abbreviation for withdrawal.
6 shows Gaetbangpung extract 300 mg/kg + zolpidem (ZPD) 5 mg/kg co-administration in Test Example 2; Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combined administration; After long-term administration of zolpidem (ZPD) 5 mg/kg and 10 mg/kg alone for 3 weeks, it is a graph showing the change in NERM sleep time by time according to the number of administration days and withdrawal days. BL (baseline) represents the control group, * means that there is a significant difference at p<0.05 compared to the control group, and ** means there is a significant difference at p<0.01 compared with the control group (t-test). KS-093 and ZPD are abbreviations of Gaetbangpung extract and zolpidem, respectively, and NREMS is an abbreviation of non-rapid eye movement sleep. Also, WD is an abbreviation for withdrawal.
7 shows Gaetbangpung extract 300 mg/kg + zolpidem (ZPD) 5 mg/kg co-administration in Test Example 2; Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combined administration; After long-term administration of zolpidem (ZPD) 5 mg/kg and 10 mg/kg alone for 3 weeks, EEG (elctroencephalogram) power density and delta activity (Delta) in non-REM sleep according to the number of administration days and withdrawal days It is a graph showing activity). Vehicle represents the control group, * means that there is a significant difference at p<0.05 compared with the control group, and ** means there is a significant difference at p<0.01 compared with the control group (t-test). KS-093 and ZPD are abbreviations of Gaetbangpung extract and zolpidem, respectively, and NREMS is an abbreviation of non-rapid eye movement sleep. Also, WD is an abbreviation for withdrawal.

Hereinafter, the present invention will be described in detail.

The present invention relates to a health functional food composition for preventing or improving sleep disorders or insomnia for suppressing tolerance or alleviating side effects of benzodiazepine-binding site agonists of GABA _A receptors using an extract of Gaetbangpung ( Glehnia littorali s) as an active ingredient. .

The sleep disorder or insomnia may be caused by various causes. The sleep disorder or insomnia may be due to caffeine administration, and specifically, coffee, high-caffeine energy drinks, cola, green tea, black tea, cocoa, etc. may be due to ingestion of foods containing caffeine, but is not limited thereto.

The prevention, improvement or treatment of the sleep disorder or insomnia may be an effect of reducing sleep latency, increasing sleep duration, or increasing non-REM sleep, but is not limited thereto.

In addition, the sleep disorder is disrupted sleep caused by a number of causes, including dysfunctional sleep mechanisms, abnormalities in physiological functions during sleep, abnormalities in the biological clock, and sleep disorders induced by factors unrelated to the sleep process. pattern, and may be, for example, insomnia. The insomnia may include middle-of-the-night insomnia, late night insomnia, prolonged waking insomnia after initiation of sleep, sleep maintenance insomnia, and insomnia following waking up at night.

Gaetbangpung is a perennial herb belonging to the Umbelliferae family. It is a medicinal plant that grows wild on sandy beaches along the coast of Korea and is distributed in Japan, Manchuria, and China. Its roots are called northern ginseng, empty wind, or liberation wind. It has been traditionally used as an anti-inflammatory, antitussive expectorant, and digestive tract.

On the other hand, there is a windbreak ( ledebouriella seseloides ) as a plant with a name similar to that of Glehnia littorali s. The windbreak is a medicinal material made using the roots and rhizomes of the windbreak, meaning that it blocks the wind and treats wind diseases. very important in doing Specifically, the windbreak is effective for all wind symptoms such as external headache, chills, fever, general pain, sore throat, and extremity joint pain, tetanus, muscle spasm, paralysis, It is used for skin itchiness and ringworm, and pharmacological effects such as antipyretic, anti-inflammatory, antispasmodic, immune activation, anti-allergy, anti-ulcer, antibacterial, and skin-improving bacteria suppression have been reported.

In addition, there is Sikhbangpung as a plant with a name similar to Gaetbangpung. In the case of Sikhbangpung, it is called 'Bangpungnamul (Gae oil herb)' and is more popular for food than for medicinal purposes.

The Gaetbangpung, Bangpung, and Sikhbangpung have similar names, but have different scientific names, habitats and forms, have different genes, and are separate plants with different index components. In particular, the Gaetbangpung, Bangpung and Sikhbangpung show different medicinal effects due to differences in index components or physiologically active components. Specifically, it was confirmed that imperatorin and panaxydiol, which are index components contained in Gaetbangpung, were not contained in the windbreak and dietary windbreak (“Differential data collection of windbreak, dietary wind and liberation wind,” refer to the Korea Food and Drug Administration).

Gaetbangpung of the present invention may be one or more above-ground parts, rhizomes, or roots selected from flowers, stems, leaves, immature fruits and fruits, and preferably one selected from flowers, stems, leaves, immature fruits and fruits. It may be one or more above-ground parts, and more preferably, one or more above-ground parts selected from leaves and stems. Gaetbangpung, which was previously used as a medicinal herb, refers to the root of Gaetbangpung, and items listed in the "Korean Pharmacopoeia (KP)" are also listed as the root of Gaetbangpung. However, in the present invention, it is more preferable in terms of sleep effect to use the above-ground part of Gaetbangpung as a raw material.

The gaetbangpung is mixed with an extraction solvent in a weight ratio of 1: 10 to 30, preferably 1: 15 to 25, more preferably 1: 18 to 22 to 65 to 95 ° C, preferably 70 to 90 ° C, more Preferably, extraction is performed at 75 to 85° C. for 1 to 10 hours, preferably for 1 to 5 hours, and then concentrated under reduced pressure to prepare an extract. When the weight ratio of Gaetbangpung and the extraction solvent is out of the above range, the active ingredient of Gaetbangpung may be extracted in a small amount in the extract.

The extraction solvent for extracting each of the extracts is water, a lower alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. The lower alcohol may include 20 to 80% methanol, ethanol, butanol or propanol.

The extraction solvent is not particularly limited, but the extract extracted with an aqueous solution of 60 to 80% ethanol preferably acts for the prevention, improvement or treatment of sleep disorders or insomnia.

The Gaetbangpung extract may be a fraction obtained by refractionating Gaetbangpung with water, a lower alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof with a second organic solvent. Preferably, the Gaetbangpung extract may be a fraction obtained by refractionating the ethanol extract of Gaetbangpung with hexane, ethyl acetate, butanol or water.

The term "extract" used while referring to Gaetbangpung in the present specification includes not only the crude extract obtained by treating the extraction solvent, but also the processed product of the Gaetbangpung extract. For example, the Gaetbangpung extract may be prepared in a powder state by an additional process such as distillation under reduced pressure and freeze-drying or spray-drying.

In addition, the Gaetbangpung extract of the present invention is broadly meant to include a Gaetbangpung processed product formulated to be administered to an animal, for example, Gaetbangpung powder. Although the present invention conducted the experiment with Gaetbangpung, it will be foreseeable by those skilled in the art that the desired effect can be achieved even in the same form as Gaetbangpung.

In the following examples, it was confirmed that the Gaetbangpung extract exhibits almost similar effects of reducing the elevation time and increasing the sleep duration compared to zolpidem, which is conventionally used as a sleeping agent, and increases the non-REM sleep time. In addition, it was confirmed that when the Gaetbangpung extract was administered in combination with zolpidem, the side effects of zolpidem, which deteriorated sleep quality, were suppressed by reducing delta activity. Therefore, the Gaetbangpung extract can be used as an active ingredient in a composition for preventing, improving or treating sleep disorders. Unlike conventional sleeping pills, Gaetbangpung extract is a non-toxic ingredient that is approved as a food and has no side effects as well as an elevation-inducing and sleep-extending effect, so it can be usefully used for the prevention, improvement or treatment of sleep disorders. there is.

As used herein, the "GABA _A receptor agonist" specifically means "a benzodiazepine binding site agonist of the GABA _A receptor". The "GABA _A receptor agonist" may be a benzodiazepine-based GABA _A receptor agonist or a non-benzodiazepine-based GABA _A receptor agonist, preferably a non-benzodiazepine-based GABA _A receptor agonist. The non-benzodiazepine-based GABA _A receptor agonist may be one or more hypnotic agents selected from zolpidem, zopiclone, zaleplon and trazodone, and preferably zolpidem, zopiclone or zaleplon.

In the above, zolpidem, zopiclone and zaleplon are non-benzodiazepine drugs used for the treatment of insomnia, and are often jet- Drugs that are called Z-drugs and exhibit similar characteristics (J. Med. Toxicol. (2013) 9:155-162 "The Clinical and Forensic Toxicology of Z-drugs", Naren Gunja; Reference 1). These jet-drugs exert their effect by increasing the delivery of gamma aminobutyric acid (GABA) at the same GABA _A receptor as benzodiazepines.

In addition, zolpidem exerts its effect through activation of the alpha1-containing GABA _A benzodiazepine binding site receptor, zopiclone exhibits preferential agonist activity on the alpha 1 subunit of the GABA _A receptor, and zaleplon shows benzodiazepine binding site receptor activity. It exerts its effect through selective binding to the diazepine binding site receptor (alpha1 subunit). The pharmacokinetics of the three jet-drugs are similar in that they are all rapidly absorbed and have a short half-life.

That is, all jet-drugs such as zopiclone and zaleplon, including zolpidem, ① bind mainly to the alpha 1 subunit among GABA _A benzodiazepine binding site receptors, ② are equally inhibited by flumazenil, ③ absorption It has a similar pharmacokinetic profile that is faster and has a short half-life, and ④ shows similar characteristics in side effects such as tolerance, residual sedation, dependence, and toxicity.

Therefore, from the results that the Gaetbangpung extract according to the present invention shown in the Examples below has the effect of inhibiting tolerance or side effects of zolpidem, Zopiclone or Zaleplon, also known as jet-drugs together with zolpidem, can also be used with Gaetbangpung extract. When administered in combination, it is sufficiently predictable that similar results will be obtained.

In the present invention, "agonist" is a substance that interacts with GABA _A receptors, activates GABA _A receptors, and initiates physiological or pharmacological response properties of the GABA _A receptors, unless otherwise specified, and "antagonist" means efficacy It refers to a substance that competitively binds to a receptor at the same site as an agent, but does not activate an intracellular response initiated by an active form of the receptor, thereby inhibiting an intracellular response by an agonist.

On the other hand, the inhibition of the resistance of the benzodiazepine-binding site agonist of the GABA _A receptor means that the resistance, which decreases the therapeutic effect of sleep disorder with long-term administration, is suppressed.

Suppression of the tolerance means that even after administration for 2 weeks or more, preferably 3 weeks or more, more preferably 4 weeks or more, the effect of treating sleep disorders on the first day of administration, for example, the effect of reducing sleep time or shortening of NREM sleep time. The change is not statistically significant, or 150 or less, preferably 140 or less, more preferably 130 or less, even more preferably 120 or less, most preferably 110 or less when the elevation time on the first day of administration is taken as 100. or 80 or more, preferably 85 or more, more preferably 90 or more, still more preferably 95 or more, and most preferably 100 or more when the NREM sleep time of the first administration day is 100 or more.

The reduction in the side effects of the benzodiazepine binding site agonist of the GABA _A receptor means that any one or more side effects selected from inhibition of delta activity of brain waves and residual sedative action are alleviated. The reduction in the inhibition of the delta activity of the brain wave means that the delta activity of the brain wave after administration is 80 or more, preferably 85 or more, more preferably 90 or more, still more preferably when the delta activity of the brain wave on the first administration day is 100. is 95 or more, and most preferably 100 or more. Relief of the residual sedative effect means that there is no NREM sleep enhancing effect after 8 hours, preferably after 7 hours, more preferably after 6 hours, even more preferably after 5 hours after administration.

Meanwhile, in the present specification, the term "contained as an active ingredient" means including an amount sufficient to achieve the efficacy or activity of the Gaetbangpung extract. The daily dose of the Gaetbangpung extract of the present invention may be 10 to 1,000 mg/kg, preferably 20 to 500 mg/kg, more preferably 50 to 500 mg/kg, It may be more preferably 100 to 500 mg/kg, more preferably 100 to 300 mg/kg or 200 to 500 mg/kg, more preferably 200 to 400 mg/kg, and most Preferably, it may be 200 to 300 mg/kg. When the dosage of the Gaetbangpung extract of the present invention is less than the lower limit, the sleep effect may not appear to the desired degree, and when it exceeds the upper limit, the sleep effect may not increase as much as the dosage increases. Since the Gaetbangpung extract is a natural product and there is no side effect to the human body even when administered in excess, the upper limit of the quantity of the Gaetbangpung extract contained in the composition of the present invention can be selected and implemented by those skilled in the art within an appropriate range.

In addition, the Gaetbangpung extract of the present invention exhibits a significant sleep effect only at a concentration of 500 mg/kg or more in each of the existing plant extracts, such as a windbreak extract, Ecklonia cava extract or rice bran extract, while as a plant extract, it is significant even at a relatively low dose concentration. It may exhibit an effect of inhibiting tolerance of a GABA _A receptor agonist or improving side effects, or a sleep effect.

The health functional food composition of the present invention may be administered to a sleep disorder or insomnia patient who is being administered a benzodiazepine binding site agonist of the GABA _A receptor.

The health functional food composition according to the present invention may be formulated and used as a health functional food by itself, or the active ingredient may be added to various foods. Examples of the food include beverages, alcoholic beverages, sweets, diet bars, dairy products, meat, chocolate, pizza, ramen, other noodles, gums, ice cream, vitamin complexes, and health supplements. That is, the health functional food composition is a food composition prepared by adding Gaetbangpung extract to various food materials, encapsulation, powdering, suspension, etc. Unlike other products, since it uses food as a raw material, it has the advantage that there are no side effects that may occur during long-term use of the drug. The health functional food composition of the present invention obtained in this way is very useful because it can be ingested on a daily basis.

The health functional food composition of the present invention may include not only Gaetbangpung extract as an active ingredient, but also ingredients commonly added during food production, for example, protein, carbohydrate, fat, nutrients, seasonings and flavoring agents. may include Examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agent, natural flavoring agents [taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)] and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the health functional food composition of the present invention is prepared as a drink or beverage, citric acid, high fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts may be additionally included in addition to the Gaetbangpung extract of the present invention. can

The amount of Gaetbangpung extract added in such a health functional food composition cannot be uniformly defined as it varies depending on the type of health functional food, but it can be added in a range that does not impair the original taste of the food, It is usually in the range of 0.01 to 50% by weight, preferably 0.1 to 20% by weight. In addition, in the case of a health functional food composition in the form of pills, granules, tablets or capsules, it is usually added in an amount of 0.1 to 100% by weight, preferably 0.5 to 80% by weight. In one embodiment, the dietary supplement composition of the present invention may be in the form of powder, granules, tablets, capsules or beverages.

In addition, the present invention is to be administered to a sleep disorder or insomnia patient who is administering a benzodiazepine binding site agonist of the GABA _A receptor, and provides a health functional food composition for improving sleep disorder or insomnia comprising Gaetbangpung extract as an active ingredient do.

As used herein, the terms "gaetbangpung extract", "GABA _A receptor agonist", and "sleep disorder" are the same as described above.

In addition, the present invention relates to a pharmaceutical composition for preventing or treating sleep disorders or insomnia for suppressing tolerance or alleviating side effects of a benzodiazepine-binding site agonist of GABA _A receptors containing an extract of Gaetbangpung ( Glehnia littorali s) as an active ingredient. .

As used herein, the terms "gaetbangpung extract", "GABA _A receptor agonist", and "sleep disorder" are the same as described above.

The pharmaceutical composition of the present invention may be prepared by using a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant includes an excipient, a disintegrant, a sweetener, a binder, a coating agent, a swelling agent, a lubricant, and a lubricant. agent or flavoring agent, etc. may be used.

The pharmaceutical composition may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the active ingredients described above for administration.

Formulations of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops or injectables. For example, for formulation in the form of a tablet or capsule, the active ingredient may be combined with an orally, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. In addition, if desired or required, suitable binders, lubricants, disintegrants and color-developers may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium 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.

In the composition formulated as a liquid solution, acceptable pharmaceutical carriers are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostats may be added as needed. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.

Furthermore, by using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA by an appropriate method in the art, it can be preferably formulated according to each disease or component.

The pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., preferably oral administration.

In the pharmaceutical composition for the prevention or treatment of sleep disorders or insomnia for suppression of resistance to the benzodiazepine-binding site agonist of the GABA _A receptor or alleviation of side effects, the preferred dosage of the Gaetbangpung extract is the patient's condition, weight, degree of disease, drug Although it varies depending on the form, administration route and period, it may be appropriately selected by those skilled in the art. According to a preferred embodiment of the present invention, the daily dose of the pharmaceutical composition of the present invention may be 0.001-10 g/kg.

In addition, the present invention relates to a pharmaceutical composition for preventing or treating sleep disorders or insomnia, comprising an extract of Gaetbangpung ( Glehnia littorali s) and a benzodiazepine-binding site agonist of the GABA _A receptor as active ingredients.

As used herein, the terms "gaetbangpung extract", "GABA _A receptor agonist", "sleep disorder" and "pharmaceutical composition" are the same as described above.

The prevention, improvement or treatment of the sleep disorder may be an effect of reducing sleep latency, increasing sleep duration, or increasing non-REM sleep, but is not limited thereto.

In the pharmaceutical composition for the prevention or treatment of sleep disorders using the Gaetbangpung extract and the GABAA receptor agonist as active ingredients, the preferred dosage of the Gaetbangpung extract or the GABAA receptor agonist is the patient's condition, body weight, disease severity, drug form, administration Depending on the route and period, it may be appropriately selected by a person skilled in the art.

For example, the Gaetbangpung extract may be 10 to 1,000 mg/kg, preferably 20 to 500 mg/kg, and more preferably 50 to 400 mg/kg, based on a daily dose.

In addition, for example, the daily dose of the GABA _A receptor agonist is 20 to 80 parts by weight, preferably based on 100 parts by weight of the daily dose of the pharmaceutical composition comprising only the GABA _A receptor agonist as an active ingredient. Preferably 25 to 70 parts by weight, more preferably 30 to 60 parts by weight, still more preferably 35 to 50 parts by weight. For example, in the case of zolpidem, which is a non-benzodiazepine-based GABA _A receptor agonist, 2 to 10 mg/kg, preferably 2.5 to 9 mg/kg, more preferably 3 to 8 mg/kg, based on a daily dose kg, more preferably 3.5 to 7 mg/kg, and most preferably 4 to 6 mg/kg.

Administration in the pharmaceutical composition may be administered once a day, may be administered in divided several times. However, the scope of the present invention is not limited by the dosage.

In addition, the present invention provides the use of the Gaetbangpung extract for the manufacture of a medicament or food for alleviating the side effects of the benzodiazepine binding site agonist of the GABA _A receptor. As described above, Gaetbangpung extract can be used for prevention, improvement or alleviation of side effects of benzodiazepine-binding site agonists of GABA _A receptors.

Hereinafter, the efficacy of the Gaetbangpung extract according to the present invention will be described in detail with reference to Examples.

<Example>

Example. Gaetbangpung ethanol extract (KS-093)

After mixing the pulverized product of domestic Gaetbangpung above ground (leaf and stem) and 70% ethanol aqueous solution in a weight ratio of 1:20, extraction was performed at 80° C. for 3 hours to obtain an ethanol extract of Gaetbangpung. The obtained extract was used after filtration and concentration under reduced pressure, and then powdered by freeze-drying.

<Test Example>

Test Example 1: Single-dose sleep structure analysis

1) Experimental animals

C57BL/6N mice (28-30 g, 12 weeks old, male) were purchased from Coretech Co., Ltd. (Pyeongtaek, Gyeonggi Province) and used for the experiment after being acclimatized to a breeding box for experimental animals for a week, and the breeding of animals was carried out at a temperature of 23 ㅁ1℃, humidity 55ㅁ5%, light-dark cycle (light on from 07:00 to 19:00), illumination was carried out under the conditions of 3000 Lux, feed and drinking water were freely provided, and all animals were KFRI-IACUC (Korea Food Research Institute, Institutional Animal Care and Use Committee) was managed according to the guidelines for use of laboratory animals.

2) Sleep structure analysis

An experimental flow chart for sleep structure analysis is shown in FIG. 1 .

After acclimatization of C57BL/6N mice for 1 week, electrode insertion surgery was performed to measure electroencephalogram (EEG) and electromyogram (EMG). Mice were anesthetized with pentobarbital (50 mg/kg, i.p.) and the head was fixed in a stereotaxic instrument. After incision of the subcutaneous connective tissue of the head, a Mouse EEG/EMG Headmount (Pinnacle Technology Inc, Oregon, USA) was inserted for EEG and EMG measurement. After fixing with dental cement, disinfection of the surgical site and administration of antibiotics were performed for 3 days to prevent inflammation due to surgery, and a recovery period was provided for 7 days. In order to adapt to the EEG measurement environment, the recording device was connected 4 days before the measurement to induce them to adapt to this experimental process. EEG and EMG were measured for 24 hours from 17:00 using the PAL-8200 series (Pinnacle Technology Inc, Oregon, USA) after being stabilized for 5 minutes after oral administration of the sample. The sampling rate of EEG and EMG was set to 200 Hz (epoch time: 10 s), and data was recorded by setting a filter area of 0.1-25 Hz for EEG and 10-100 Hz for EMG. Sleep structure analysis was performed by the fast Fourier transform (FFT) algorithm, and the SleepSign program (Ver. 3.0, Kissei Comtec, Nagono, Japan) was used. The analysis results were divided into Wake (wakefulness), REMS (rapid eye movement sleep, theta band: 6-10 Hz), and NREMS (non-rapid eye movement sleep, delta band: 0.65-4 Hz), and the sleep latency ( Elevation time) was set as the time it takes for NREM sleep in 10-second epoch units to appear more than 12 times consecutively.

The results of all animal experiments were expressed as the mean and standard error (meanw SEM), and the significant difference between the two groups was evaluated through t-test, and the significance level was expressed as p<0.05(*), p<0.01( **) level, the results showing significance are marked with an asterisk.

3) Effect of shortening elevation time and change in sleep structure due to single administration

Gaetbangpung extract (KS-093) 300 mg/kg administration group significantly reduced the elevation time by about 34.4 minutes. Elevation time of the representative non-benzodiazepine-based sleeping pills, zolpidem (ZPD) 5 and 10 mg/kg alone, also showed a significant decrease of about 39.9 minutes and 42.0 minutes compared to the respective control groups (see FIG. 2). In the group administered with Gaetbangpung extract (KS-093) 300 mg/kg + zolpidem 5 mg/kg and Gaetbangpung extract (KS-093) 300 mg/kg + zolpidem 10 mg/kg combined administration group, the elevation time was different for each control group. It decreased by about 31.4 minutes and 42.4 minutes compared to the zolpidem alone, and showed a similar effect on reducing the elevation time compared to the 5 and 10 mg/kg administration groups.

Meanwhile, after oral administration of control (vehicle), Gaetbangpung extract (KS-093), zolpidem (ZPD), Gaetbangpung extract, and zolpidem complex drug to C57BL/6N mice, brain waves for 2 hours were analyzed to determine sleep structure and As a result of checking the sleep time, Gaetbangpung extract and zolpidem did not affect REM sleep, but significantly increased NREM sleep (see FIG. 2 ). At concentrations of zolpidem 5 and 10 mg/kg, NREM sleep time was significantly (p<0.01) increased by about 2.1 and 2.9 times, respectively, Gaetbangpung extract 300 mg/kg + Zolpidem 5 mg/kg and Gaetbangpung extract In the 300 mg/kg + zolpidem 10 mg/kg combination group, the NREM sleep time increased by 2.0 times and 2.4 times (p<0.01), respectively (p<0.01), which did not reach the effect at the zolpidem 10 mg/kg concentration, but zolpidem 5 It was similar or somewhat superior to the sleep-promoting effect at the mg/kg concentration.

4) Changes in delta activity following single administration

Changes in delta activity during NREM sleep can be said to be physiological indicators of sleep quality and depth (Bastien et al., 2003; Chen et al., 2012), and zolpidem shortens the waking time and increases the amount of sleep. However, it has been reported to decrease delta activity during NREM sleep (Kopp et al., 2004; Alexandre et al., 2008).

Typical properties of lowering the delta activity of zolpidem were confirmed not only in the 10 mg/kg administration group, but also in the 5 mg/kg administration group, the dosage of which was reduced by half (see FIG. 3 ). When zolpidem 5 and 10 mg/kg were orally administered, the delta activity in the 0.5-4 Hz region was significantly (p<0.05 and p<0.01, respectively) reduced, increasing the amount of NREM sleep but decreasing the quality of sleep. confirmed that. However, there was no significant change in delta activity in the group administered with Gaetbangpung extract 300 mg/kg alone, and the delta activity that was significantly reduced at concentrations of zolpidem 5 and 10 mg/kg was 300 mg/kg of Gaetbangpung extract + zolpidem. No change was observed in the 5 mg/kg combination treatment group and Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combination treatment group. It was judged to have a sleep-promoting effect while suppressing.

Test Example 2: Sleep structure according to long-term administration

1) Experimental method

The method of preparing the experimental animals and analyzing the sleep structure was performed using the method of Test Example 1. As with the single administration of Test Example 1, the baseline (BL) was measured on day 0 after a recovery period of 7 days and an adaptation period of 4 days after mouse surgery, and each sample was orally administered for 21 days on the 1st, 7th, 14th EEG was performed on the first and 21st days, and EEG was also measured and analyzed during the withdrawal period of 2 days. An experimental flow chart for analyzing sleep structure according to long-term administration is shown in FIG. 4 . Each sample (gaetbangpung extract 300 mg/kg + zolpidem (ZPD) 5 mg/kg; Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg; zolpidem (ZPD) 5 mg/kg and 10 mg/kg alone) was administered once a day.

2) Effect of shortening elevation time and changes in sleep structure due to long-term administration

It has been reported that zolpidem (ZPD) has side effects such as tolerance when taken for a long period of 3 weeks or more, resulting in poor sleep-promoting effects (Steppuhn et al., 1992; Priest et al., 1997; Ebert et al., 2008). Therefore, in this experiment, in the case of long-term administration of Gaetbangpung extract (KS-093) in combination with zolpidem, we wanted to determine whether the side effects reported with zolpidem can be suppressed and whether side effects observed with zolpidem appear. did For each sample, mouse EEG was measured and analyzed on days 0, 1, 7, 14, and 21 during the 3-week long-term administration period.

In the case of single administration of zolpidem (5 and 10 mg/kg), the waking time was significantly decreased compared to the baseline (BL) during the 3-week oral administration period, and the NREM sleep time was also increased compared to the baseline (BL). However, as the administration period of zolpidem increased, the elevation time tended to increase, and in the 3rd week, zolpidem resistance was confirmed in experimental animals to the extent that a significant difference occurred between the first day of administration and the elevation time. In addition, the NREM sleep time showed a tendency to decrease as the administration period increased, and in the 3rd week, zolpidem resistance was confirmed to the extent that a significant difference occurred between the first day of administration and the NREM sleep time (see FIG. 5 ). Therefore, in the case of zolpidem, it was confirmed that the effect of zolpidem on reducing the rise time and increasing NREM sleep time gradually weakened when administered for more than 3 weeks.

Gaetbangpung extract 300 mg/kg + zolpidem 5 mg/kg and Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combined administration of zolpidem (5 and 10 mg/kg) alone The effect of decreasing the elevation time and increasing the NREM sleep time was not observed at all (see Fig. 5). Therefore, it was confirmed that the Gaetbangpung extract suppressed the tolerance due to long-term administration of zolpidem or reduced the occurrence of side effects. On the other hand, there was no significant difference in baseline, elevation time, and NREM sleep time during the drug withdrawal period in all experimental groups (see FIG. 5).

3) Changes in NREM sleep time according to long-term administration

Figure 6 shows the change in NREM sleep time by time period of the first day, the 21st day, and the first day of drug discontinuation (WD1) during the long-term administration period of 3 weeks. In the case of zolpidem (5 and 10 mg/kg) alone administration, NREM sleep time was significantly increased compared to baseline (BL) for the first 3 hours and 6 hours, respectively, on Day 1, but the effect gradually weakened, It showed a significant increase only at 1 hour. However, in the case of Gaetbangpung extract 300 mg/kg + zolpidem 5 mg/kg and Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg combined administration, unlike the zolpidem alone groups, both on the 1st and 21st days, during the first 2 hours, It was confirmed that the increase effect of NREM sleep time was continued by showing the NREM sleep enhancing effect. On the other hand, on the first day of drug discontinuation in all experimental groups, the NREM sleep time increased during each sample administration period again appeared similar to the baseline (BL).

4) Changes in delta activity according to long-term administration

A significant (p<0.05 and p<0.01) decrease in delta activity on the 1st day in the single administration of zolpidem (5 and 10 mg/kg) of Test Example 1-4 was found on the 21st day of long-term administration of zolpidem and drug discontinuation In the 1st day (WD1) period, it appeared similar to the baseline (BL) (see FIG. 7 ). On the other hand, in the case of Gaetbangpung extract 300 mg/kg + zolpidem 5 mg/kg and Gaetbangpung extract 300 mg/kg + zolpidem 10 mg/kg, zolpidem (5 and 10 mg/kg) alone administration on the 1st day It was confirmed that there was no decrease in the delta activity that occurred in , and maintained as it was for all periods during the long-term administration experiment (see FIG. 7 ).

The above results show that the gaetbangpung extract maintains the sleep-promoting effect of zolpidem, and in particular, it can be used as a combination drug that can alleviate the side effects of zolpidem.

Hereinafter, a formulation example of a composition containing the extract of the present invention will be described, but the present invention is not intended to limit the present invention, but merely to describe it in detail.

Formulation Example 1. Preparation of powder

300 mg of extract powder obtained in Examples

lactose 100 mg

talc 10 mg

The above ingredients are mixed and filled in an airtight bag to prepare a powder.

Formulation Example 2. Preparation of tablets

300 mg of extract powder obtained in Examples

corn starch 100 mg

lactose 100 mg

magnesium stearate 2 mg

After mixing the above ingredients, tablets are prepared by tableting according to a conventional manufacturing method of tablets.

Formulation Example 3. Preparation of capsules

300 mg of extract powder obtained in Examples

Zolpidem 5 mg

crystalline cellulose 3 mg

lactose 14.8 mg

magnesium stearate 0.2 mg

According to a conventional capsule preparation method, the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.

Formulation Example 4. Preparation of injection

300 mg of extract powder obtained in Examples

mannitol 180 mg

Sterile distilled water for injection 2974 mg

Na ₂ HPO ₄ ,12H ₂ O 26 mg

According to a conventional method for preparing injections, the content of the above components per 1 ampoule is prepared.

Formulation Example 5. Preparation of liquid formulation

300 mg of extract powder obtained in Examples

Zolpidem 5 mg

Lee Seonghwadang 10 g

mannitol 5 g

Purified water appropriate amount

According to a conventional liquid preparation method, each component is added to purified water to dissolve, an appropriate amount of lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 g by adding purified water, and then filled in a brown bottle to sterilize to prepare a liquid.

Formulation Example 6. Preparation of granules

300 mg of extract powder obtained in Examples

Zolpidem 5 mg

vitamin mixture appropriate amount

vitamin A acetate 70 μg

vitamin E 1.0 mg

vitamin B1 0.13 mg

vitamin B2 0.15 mg

vitamin B6 0.5 mg

vitamin B12 0.2 μg

vitamin C 10 mg

biotin 10 μg

Nicotinamide 1.7 mg

folic acid 50 μg

Calcium Pantothenate 0.5 mg

mineral mixture appropriate amount

ferrous sulfate 1.75 mg

zinc oxide 0.82 mg

magnesium carbonate 25.3 mg

monobasic potassium phosphate 15 mg

dicalcium phosphate 55 mg

potassium citrate 90 mg

calcium carbonate 100 mg

magnesium chloride 24.8 mg

The composition ratio of the vitamin and mineral mixture is relatively suitable for granules in a preferred embodiment, but the mixing ratio may be arbitrarily modified. It can be prepared and used in the preparation of a health functional food composition according to a conventional method.

Formulation Example 7. Preparation of functional beverage

300 mg of extract powder obtained in Examples

citric acid 1,000 mg

oligosaccharide 100 g

Plum Concentrate 2 g

Taurine 1 g

by adding purified water Total 900 mL

After mixing the above ingredients according to a conventional health drink manufacturing method, after stirring and heating at 85 ° C for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized, then refrigerated. It is used to prepare the functional beverage composition of the present invention.

Although the composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demand class, demanding country, and use.

Although the present invention has been described as the above-mentioned preferred embodiment, it is possible to make various modifications and variations without departing from the spirit and scope of the invention. It is also intended that the appended claims cover such modifications and variations as fall within the scope of the present invention.

Claims (25)

Gaetbangpung ( Glehnia littorali s) as an active ingredient, a benzodiazepine-binding site agonist of GABA _A receptors, for the prevention or improvement of sleep disorders or insomnia for resistance inhibition or side effects reduction. According to claim 1,
The Gaetbangpung extract is a health functional food composition for preventing or improving sleep disorders or insomnia, characterized in that it is administered at a concentration of 10 to 1000 mg/kg/day. According to claim 1,
Resistance of the benzodiazepine binding site agonist of the GABA _A receptor is an effect of reducing the effect of treating sleep disorders according to long-term administration,
The side effect of the benzodiazepine-binding site agonist of the GABA _A receptor is a health functional food composition for preventing or improving sleep disorders or insomnia, characterized in that any one or more side effects selected from the inhibition of delta activity of brain waves and residual sedation. According to claim 1,
The benzodiazepine binding site agonist of the GABA _A receptor is a health functional food composition for preventing or improving sleep disorders or insomnia, characterized in that it is a non-benzodiazepine-based drug. 5. The method of claim 4,
The non-benzodiazepine drug is a health functional food composition for preventing or improving sleep disorders or insomnia, characterized in that at least one selected from zolpidem, zopiclone and zaleplon. According to claim 1,
The Gaetbangpung extract is a health functional food composition for preventing or improving sleep disorders or insomnia, characterized in that it is extracted with water, a lower alcohol having 1 to 4 carbon atoms, or a mixed solvent thereof. 7. The method of claim 6,
The mixed solvent is a health functional food composition for preventing or improving sleep disorders or insomnia, characterized in that 20 to 80% by volume of an aqueous solution of methanol, ethanol, butanol or propanol. 7. The method of claim 6,
The mixed solvent is a health functional food composition for preventing or improving sleep disorder or insomnia, characterized in that it is an aqueous solution of 60 to 80% ethanol. According to claim 1,
The health functional food composition is a functional health food composition for preventing or improving sleep disorders or insomnia, characterized in that it is administered to a sleep disorder or insomnia patient who is administering a benzodiazepine binding site agonist of the GABA _A receptor. According to claim 1,
The dosage form of the health functional food composition is a health functional food composition for preventing or improving sleep disorders or insomnia, characterized in that it is a powder, granules, tablets, capsules or beverages. It is administered to patients with sleep disorders or insomnia who are taking a benzodiazepine binding site agonist of the GABA _A receptor,
A health functional food composition for improving sleep disorders or insomnia comprising Gaetbangpung extract as an active ingredient. Gaetbangpung ( Glehnia littorali s ) A pharmaceutical composition for preventing or treating sleep disorders or insomnia for inhibiting tolerance of a benzodiazepine-binding site agonist of GABA _A receptors or alleviating side effects using an extract as an active ingredient. 13. The method of claim 12,
The benzodiazepine binding site agonist of the GABA _A receptor is a non-benzodiazepine-type drug, a pharmaceutical composition for preventing or treating sleep disorders or insomnia. 14. The method of claim 13,
The non-benzodiazepine drug is a pharmaceutical composition for preventing or treating sleep disorders or insomnia, characterized in that at least one selected from zolpidem, zopiclone, and zaleplon. 13. The method of claim 12,
A side effect of the benzodiazepine binding site agonist of the GABA _A receptor is a sleep disorder or insomnia prevention or treatment pharmaceutical composition, characterized in that the inhibition of delta activity of brain waves. Gaetbangpung ( Glehnia littorali s) extract and a benzodiazepine-binding site agonist of GABA _A receptors as active ingredients. A pharmaceutical composition for preventing or treating sleep disorders or insomnia. 17. The method of claim 16,
The benzodiazepine binding site agonist of the GABA _A receptor is a non-benzodiazepine-type drug, a pharmaceutical composition for preventing or treating sleep disorders or insomnia. 18. The method of claim 17,
The non-benzodiazepine drug is a pharmaceutical composition for preventing or treating sleep disorders or insomnia, characterized in that at least one selected from zolpidem, zopiclone, and zaleplon. 17. The method of claim 16,
The daily dose of the GABA _A receptor benzodiazepine binding site agonist is 100 parts by weight of the daily dose of the active ingredient of a pharmaceutical composition comprising only the benzodiazepine binding site agonist of the GABA _A receptor as an active ingredient , A pharmaceutical composition for preventing or treating sleep disorders or insomnia, characterized in that it is 20 to 80 parts by weight. 17. The method of claim 16,
A pharmaceutical composition for preventing or treating sleep disorders or insomnia, comprising 10 to 500 mg/kg of the Gaetbangpung extract and 2 to 10 mg/kg of a benzodiazepine-binding site agonist of GABA _A receptors in a daily dose . 17. The method of claim 16,
The pharmaceutical composition is a pharmaceutical composition for preventing or treating sleep disorders or insomnia, characterized in that the side effects of the benzodiazepine binding site agonist of the GABA _A receptor are reduced. 22. The method of claim 21,
The side effect of the benzodiazepine binding site agonist of the GABA _A receptor is a sleep disorder, characterized in that it is any one or more side effects selected from inhibition of delta activity of brain waves, residual sedation, and a decrease in the therapeutic effect of sleep disorders according to long-term administration. A pharmaceutical composition for preventing or treating insomnia. 17. The method of claim 16,
The sleep disorder or insomnia prevention or treatment is a pharmaceutical composition for preventing or treating sleep disorder or insomnia, characterized in that it is for the reduction of sleep time, increase of sleep duration, or increase of non-REM sleep. Gaetbangpung ( Glehnia littorali s ) A health functional food composition for inhibiting resistance or reducing side effects of a benzodiazepine-binding site agonist of GABA _A receptors using an extract as an active ingredient. 25. The method of claim 24,
Resistance of the benzodiazepine binding site agonist of the GABA _A receptor is an effect of reducing the effect of treating sleep disorders according to long-term administration,
The side effect of the benzodiazepine-binding site agonist of the GABA _A receptor is inhibition of resistance of the benzodiazepine-binding site agonist of the GABA _A receptor, characterized in that it is any one or more side effects selected from inhibition of delta activity of brain waves and residual sedation. Or a health functional food composition for alleviating side effects.

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