KR102262759B1 - A composition for reducing side effects of GABAA receptor agonist, comprising phloroglucinol as an effective ingredient - Google Patents

Abstract

The present invention provides a pharmaceutical composition for alleviating side effects of _{a GABA A} receptor agonist comprising a turmeric extract as an active ingredient, a pharmaceutical composition for preventing or treating sleep disorders comprising a complex of a _{turmeric extract and a GABA A receptor agonist as an active ingredient, and turmeric} It relates to a health functional food composition for improving the side effects of _{GABA A} receptor agonists comprising the extract as an active ingredient.
The pharmaceutical composition for alleviating the side effects of _{GABA A} receptor agonists using the turmeric extract of the present invention as an active ingredient does not cause side effects _{of conventional GABA A receptor agonists.} In addition, turmeric extract, the active ingredient in health food composition for improving side effects of the GABA _A receptor agonist side effect reduction a pharmaceutical composition or a GABA _A receptor agonist for the agent of the present invention can reduce the side effects of the GABA _A receptor agonists . In addition, GABA _A receptor agonists which turmeric extract and the GABA _A receptor agonist for the active ingredient to the surface prevent failure or pharmaceutical composition for the treatment of the present invention, increasing the amount of water sikina lowers the quality of sleep may cause a variety of side effects The _{side effects of GABA A} receptor agonists can be alleviated by reducing the amount of the agent.

Description

A composition for reducing side effects of GABAA receptor agonists using turmeric extract as an active ingredient {A composition for reducing side effects of GABAA receptor agonist, comprising phloroglucinol as an effective ingredient}

The present invention provides a pharmaceutical composition for alleviating side effects of _{a GABA A} receptor agonist comprising a turmeric extract as an active ingredient, a pharmaceutical composition for preventing or treating sleep disorders comprising a complex of a _{turmeric extract and a GABA A receptor agonist as an active ingredient, and turmeric} It relates to a health functional food composition for improving the side effects of _{GABA A} receptor agonists comprising the extract as an active ingredient.

Sleep can be defined in many ways, but it is mainly defined as a state of immobility 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 most common problems of 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 it is the cause of 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 at least one of sleep initiation or maintenance of sleep 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 bring side effects such as difficulty waking up the next morning and daytime insomnia.

Non-benzodiazepine hypnotic drugs shorten the time to fall asleep, but have fewer side effects than benzodiazepine hypnotic drugs, such as difficulty waking up the next morning. However, non-benzodiazepine hypnotics still include residual sedation and psychomotor disorders, daytime anxiety, anterograde amnesia and cognitive deficits, rebound insomnia, drug resistance and dependence. In addition, there is a possibility that patients taking non-benzodiazepine sleeping pills may experience daytime drowsiness, thus increasing the risk of impaired activity and accidents, particularly 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 electroencephalogram (EEG), that is, It is known to alter sleep structure by reducing delta activity or enhancing radiofrequency activity. In addition, although non-benzodiazepine hypnotic drugs such as zolpidem or zopiclone have been reported to have few side effects that occur with benzodiazepine hypnotic drugs, follow-up studies have shown that they also have incomplete daytime psychomotor disorders, 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, while preventing repetitive 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 turmeric 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

An object of the present invention is to provide a pharmaceutical composition using turmeric extract as an active ingredient and reducing the side effects of benzodiazepine-binding site agonists of _{GABA A receptors.}

In addition, the present invention increases the amount of sleep but reduces the quality of sleep to reduce the content of GABAA receptor agonists that can cause various side effects, and to provide a pharmaceutical composition for preventing or treating sleep disorders in which a turmeric extract is combined. will be.

In addition, the present invention is to provide a health functional food composition using turmeric extract as an active ingredient and improving the 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 insomnia, which is administered to insomnia patients who are administered a benzodiazepine-binding site agonist _{of the GABA A receptor, and contains a turmeric extract as an active ingredient.}

The present invention for achieving the above object relates to a pharmaceutical composition for alleviating the side effects of a benzodiazepine binding site agonist of _{the GABA A receptor comprising a turmeric extract as an active ingredient.}

The side effect of the benzodiazepine binding site agonist of the GABA _A receptor may be to inhibit the delta activity of brain waves.

The pharmaceutical composition for alleviating the side effects of the benzodiazepine binding site agonist of the GABA _A receptor may be a pharmaceutical composition for the prevention or treatment of sleep disorders.

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

In addition, the non-benzodiazepine drug may be one or more sleeping pills selected from zolpidem, zopiclone, and zaleplon.

The present invention also relates to a pharmaceutical composition for preventing or treating sleep disorders, comprising a turmeric extract and _{a benzodiazepine binding site agonist of the GABA A receptor as active ingredients.}

The benzodiazepines daily dosage of the binding site agonists of the GABA _A receptor is the active ingredient with respect to the benzodiazepine binding site the active ingredient unit daily dosage capacity of 100 parts by weight of a pharmaceutical composition containing only the efficacy of the GABA _A receptor , may be 20 to 80 parts by weight.

In addition, the above-described pharmaceutical composition for preventing or treating sleep disorders may include 10 to 100 mg of the turmeric extract and 2 to 10 mg of a 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 may be insomnia.

In addition, the present invention relates to a health functional food composition for improving the side effects of benzodiazepine-binding site agonists of _{GABA A receptors comprising a turmeric extract as an active ingredient.}

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

The present invention also 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 a turmeric extract as an active ingredient.}

The pharmaceutical composition for alleviating the side effects of _{GABA A} receptor agonists using the turmeric extract of the present invention as an active ingredient does not cause side effects _{of conventional GABA A receptor agonists.}

In addition, turmeric extract, the active ingredient in health food composition for improving side effects of the GABA _A receptor agonist side effect reduction a pharmaceutical composition or a GABA _A receptor agonist for the agent of the present invention can reduce the side effects of the GABA _A receptor agonists .

In addition, GABA _A receptor agonists which turmeric extract and the GABA _A receptor agonist for the active ingredient to the surface prevent failure or pharmaceutical composition for the treatment of the present invention, increasing the amount of water sikina lowers the quality of sleep may cause a variety of side effects The _{side effects of GABA A} receptor agonists can be alleviated by reducing the amount of the agent.

1a is a graph showing the effect of each concentration of the turmeric extract of Example 1 on the elevation time of mice administered with pentobarbital sleeping dose (45 mg/kg, ip) compared with DH and RDM, FIG. 1b is a pen It is a graph showing the effect of each concentration of the turmeric extract of Example 1 on the sleep time of mice administered tobarbital sleeping dose (45 mg/kg, ip) compared with DH and RDM. Oral administration of control (0.5% CMC-saline 10 mL/kg), DH (30 mg/kg), RDM (620 mg/kg) and KFRI-S075 (10, 25, 50, 100 mg/kg) (po) After 45 minutes, pentobarbital was administered. Each graph represents the mean value (means SEM, n=10). * means that there is a significant difference at p<0.05 compared to the control group, and ** means that there is a significant difference at p<0.01 compared to the control group (Dunnet's test). CON is control; DH is doxepin hydrochloride; RDM stands for Redolmin.
Figures 2a and 2b is a graph showing the effect of the turmeric extract (CLWE) of Example 2 on the elevation time and sleep time of mice administered pentobarbital sleeping dose (45 mg / kg, ip).
Figure 3a is a graph showing the effect of each concentration of the turmeric extract of Example 1 on the elevation time of the mouse through sleep structure analysis compared with the commercially available sleeping pills DZP, DH, RDM, Figure 3b is a non-REM sleep (NREMS) increase effect It is a graph showing the effect of each concentration of the turmeric extract of Example 1 on the comparison with the commercially available sleeping pills DZP, DH, and RDM. * means that there is a significant difference at p<0.05 compared to the control group, and ** means that there is a significant difference at p<0.01 compared with the control group ( t- test).
Figure 4a is a graph showing the EEG (elctroencephalogram) power density and delta activity in non-REM sleep of the turmeric extract (100 mg / kg) of Example 1, Figure 4b is diazepam (DPZ, 6 mg / kg) ) is a graph showing EEG (elctroencephalogram) power density and delta activity in non-REM sleep, and FIG. 4c is an EEG (elctroencephalogram) in non-REM sleep of doxepin hydrochloride (DH, 15 mg/kg). It is a graph showing power density and delta activity, and FIG. 4d is a graph showing EEG (elctroencephalogram) power density and delta activity in non-REM sleep of redolmin (RDM, 620 mg/kg). . Vehicle represents the control group, * means that there is a significant difference at p<0.05 compared to the control group, and ** means that there is a significant difference at p<0.01 compared to the control group ( t- test).
5 is a graph showing the sleep duration according to the presence or absence of 2-pridylethylamine dihydrochloride (PD), a histamine H1 receptor (H1R) agonist, of the turmeric extract of Example 1 compared with the effect of the sleeping agent DH (30 mg/kg) . CON 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 (Dunnet's test).
Figure 6 is a diagram elucidating the mechanism of action of the turmeric extract of Example 1 as a histamine receptor antagonist using a histamine H1 receptor (H1R) knockout mouse (a mouse designed to be deficient in H1R). WT refers to normal mice, and KO refers to histamine H1 receptor (H1R) knockout mice. * means that there is a significant difference at p<0.05 compared to the control group, and ** means that there is a significant difference at p<0.01 compared to the control group (Dunnet's test).
7 is a negative control (Vehicle) in Experimental Example 4; zolpidem (ZPD); And it is a graph showing the effect of shortening the elevation time according to the combined administration of the turmeric extract (KFRI-S075) and zolpidem (ZPD) of Example 1 and the concentration thereof. * means that there is a significant difference at p<0.05 compared to the control group, and ** means that there is a significant difference at p<0.01 compared to the control group (Dunnet's test).
8 is a negative control (Vehicle) in Experimental Example 4; zolpidem (ZPD); And it is a graph analyzing the NREMS sleep time according to the combined administration of the turmeric extract (KFRI-S075) and zolpidem (ZPD) of Example 1 and its concentration. * means that there is a significant difference at p<0.05 compared to the control group, and ** means that there is a significant difference at p<0.01 compared to the control group (Dunnet's test).
Figure 9a is a turmeric extract of Example 1 in Experimental Example 5 (KFRI-S075) 25 mg / kg; It is a graph showing delta activity according to the combined administration of zolpidem (ZPD) 5 mg / kg, Figure 9b is the turmeric extract of Example 1 (KFRI-S075) 50 mg / kg; It is a graph showing the delta activity according to the combined administration of zolpidem (ZPD) 5 mg / kg, Figure 9c is a graph showing the delta activity according to the administration of zolpidem (ZPD) 5 mg / kg.

The present invention relates to a pharmaceutical composition for alleviating the side effects of benzodiazepine-binding site agonists of _{GABA A} receptors containing turmeric extract as an active ingredient.

The turmeric extract is not particularly limited, but bisdimethoxycurcumin: curcumin in a weight ratio of 1:15 to 150; And/or bisdimethoxycurcumin: dimethoxycurcumin may be included in a weight ratio of 1:1.5 to 15.

In addition, the turmeric extract of the present invention includes the bisdimethoxycurcumin: curcumin in a weight ratio of 1:15 to 150, preferably in a weight ratio of 1:15 to 120, more preferably in a weight ratio of 1:17 to 120, most preferably It may be included in a weight ratio of 1: 20 to 110.

In addition, the turmeric extract of the present invention contains the bisdimethoxycurcumin:dimethoxycurcumin in a weight ratio of 1:1.5 to 15, preferably in a weight ratio of 1:1.5 to 12, more preferably in a weight ratio of 1:1.7 to 10, most Preferably it may be included in a weight ratio of 1: 2.0 to 9.

When the weight ratio of curcumin to bisdimethoxycurcumin, and/or the weight ratio of dimethoxycurcumin to bisdimethoxycurcumin in the turmeric extract is within the above range, the effect of reducing the side effects of the benzodiazepine binding site agonist of the _{GABA A receptor is more excellent} Do.

When the weight ratio of curcumin to bisdimethoxycurcumin, and/or the weight ratio of dimethoxycurcumin to bisdimethoxycurcumin in the turmeric extract is less than the lower limit, the effect of alleviating the side effects of the _{GABA A receptor agonist does not appear significantly.} It was confirmed through a specific experiment.

Turmeric is a perennial plant belonging to the ginger family, and is mainly cultivated in tropical and subtropical regions centered on India, and its stems and roots are used for food and medicinal purposes. It is widely cultivated in India, China and Southeast Asia, and in Korea, it is cultivated in Jindo, Jeollanam-do, Haenam, Jeollanam-do, Buan, Siheung, Gyeonggi, and Cheongyang, Chungcheongnam-do. Ears of flowers come out before leaves, are broad egg-shaped, and are wrapped in light green bracts. Yellow flowers bloom in the leaf axils from April to June. The upper bract has a slightly narrow butterfly, and the tip is pale magenta, and there are no flowers in the leaf axil. The outside of the rhizome is pale yellow, and the inside is scarlet and smells like camphor. The rhizome of turmeric is used as an herbal medicine. It is a yellowish medicine with a spicy and bitter taste. It is effective in anticancer, Alzheimer's treatment, antioxidant, anti-inflammatory, detoxification, liver disorder suppression, pain relief, and menstrual irregularities. In India, it is used as a medicine for bruises and sprains, and as a spice for curry powder.

On the other hand, there is turmeric, which is difficult to distinguish from turmeric. Although turmeric and turmeric are from the same ginger family and contain a large amount of curcumin, there is a difference in basic properties. In terms of weakness, turmeric is warm and turmeric is cool, and turmeric is used by drying the rhizome of turmeric, but turmeric is used by drying the tuber of turmeric.

The main components of these turmeric (薑黃; Curcuma longa L.) are curcuminoid pigment components such as curcumin, dimethoxycurcumin, and bisdemethoxycurcumin, and ar-turmerone, curlone, α -Volatile essential oil components such as turmerone, β-turmerone, bisacumol, and zingiberene and starch.

The turmeric is mixed with an extraction solvent in a weight ratio of 1: 5 to 25, preferably 1: 8 to 15, at 40 to 70 °C, preferably 50 to 60 °C for 10 to 20 hours, preferably 15 to 18 hours. After extraction for a while, concentration under reduced pressure is performed to prepare an extract. When the weight ratio of the turmeric and the extraction solvent is out of the above range, the active ingredient of the turmeric may be extracted in a small amount in the extract.

The extraction solvent for extracting each extract 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 in the prevention, improvement or treatment of sleep disorders.

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

The term "extract" used while referring to turmeric in the present specification includes not only the crude extract obtained by treating the extraction solvent but also the processed product of the turmeric extract. For example, the turmeric 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 turmeric extract of the present invention is broadly meant to include a processed turmeric product formulated so that turmeric can be administered to animals, for example, turmeric powder. Although the present invention has been conducted with turmeric, it will be expected by those skilled in the art that the desired effect can be achieved even in the form of a processed turmeric product.

As used herein, the term “contained as an active ingredient” means including an amount sufficient to achieve the efficacy or activity of the turmeric extract.

The daily dose of the turmeric extract of the present invention may be 10 to 1,000 mg/kg, preferably 20 to 500 mg/kg, more preferably 20 to 300 mg/kg, and most Preferably, it may be 25 to 100 mg/kg. If the dosage of the turmeric extract of the present invention is less than the lower limit, the side effect alleviation effect may not appear to the desired degree, and if it exceeds the upper limit, the effect may not increase as the dosage increases or there may be toxicity. . On the other hand, as a result of animal experiments, when the dosage of the turmeric extract of the present invention was within the above range, side effects such as cytotoxicity did not appear while significant side effect alleviation effect appeared.

The turmeric extract of the present invention can exhibit a significant effect even at an exceptionally very low concentration as a plant extract.

The pharmaceutical composition of the present invention may be prepared 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 injectable solutions. 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.

The preferred dosage of the turmeric extract in the pharmaceutical composition for alleviating the side effects of the benzodiazepine binding site agonist of the GABA _A receptor varies depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but those skilled in the art can be appropriately selected by 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.

On the other hand, the alleviation of the side effect means that the side effect of suppressing the delta activity of brain waves is reduced. 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, even more preferably, when the delta activity of the brain wave on the day of the first administration is 100. is 95 or more, most preferably 100 or more.

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 sleeping pills 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 shown in the following examples that the turmeric extract according to the present invention has the effect of inhibiting the side effects of zolpidem, zopiclone or zaleplon, also known as jet-drugs, together with zolpidem, when administered in combination with turmeric extract It is sufficiently predictable to show similar results.

"Agonist" in the present invention, if there is no other explanation to interact with the GABA _A receptor, and activate the GABA _A receptor, a substance for initiating a physiological or pharmacological response characteristic of the GABA _A receptor "antagonist" is 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.

In addition, the present invention relates to a pharmaceutical composition for preventing or treating sleep disorders, comprising a _{turmeric extract and a benzodiazepine binding site agonist of GABA A receptor as active ingredients.}

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 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 a late night awakening.

In the following examples, it was confirmed that the turmeric extract exhibits the effect of reducing the elevation time and increasing the sleep duration at almost the same level or improved as compared to redolmine and diazepam, which are conventionally used as sleeping pills, and increases the non-REM sleep time. Accordingly, the turmeric extract may be used as an active ingredient in a composition for preventing, improving or treating sleep disorders. Unlike conventional sleeping pills, turmeric extract is a component that is harmless to the human body approved as a food and has no side effects as well as an elevation inducing effect and sleep prolonging effect, so it can be usefully used for the prevention, improvement or treatment of sleep disorders. .

In addition, through the following examples, it was confirmed that the turmeric extract acts as a histamine receptor antagonist, in particular, a histamine H1 receptor antagonist or a histamine H2 receptor antagonist, thereby preventing, improving or treating sleep disorders.

In the pharmaceutical composition for the prevention or treatment of sleep disorders comprising the turmeric extract and the GABAA receptor agonist as an active ingredient, the preferred dosage of the turmeric extract or the GABAA receptor agonist is the patient's condition, body weight, degree of disease, drug form, administration route, and Although depending on the period, it may be appropriately selected by a person skilled in the art.

For example, the turmeric extract may be 10 to 1,000 mg/kg based on a daily dose, more preferably 20 to 500 mg/kg, more preferably 20 to 300 mg/kg, , more preferably 25 to 100 mg/kg, and most preferably 25 to 50 mg/kg.

Also, for example a daily dose of the GABA _A receptor agonist, the active ingredient with respect to 100 parts by weight of the active ingredient daily dosage amount of a pharmaceutical composition comprising only a GABA _A receptor agonist, 20 to 80 parts by weight, preferably 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, 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.

The pharmaceutical dosage form of the pharmaceutical composition may be used in the form of a pharmaceutically acceptable salt thereof, and may be used in the form of an appropriate group as well as in combination with other pharmaceutically active compounds alone.

The pharmaceutical composition of the present invention may be prepared 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, thickeners or injectable solutions. 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.

A suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration mode, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity of the patient, usually Thus, a skilled physician can easily determine and prescribe an effective dosage for the desired treatment or prevention. According to a preferred embodiment of the present invention, the daily dose of the pharmaceutical composition of the present invention is 0.001-10 g/kg.

The pharmaceutical composition of the present invention may be prepared in a unit dose form by formulation using a pharmaceutically acceptable carrier and/or excipient, or may be prepared by internalizing in a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, or emulsion in oil or an aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.

The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, and humans by various routes. All modes of administration can be administered by, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

In addition, the present invention relates to a health functional food composition for improving the side effects of benzodiazepine-binding site agonists of _{GABA A receptors using turmeric extract as an active ingredient.}

The health functional food composition according to the present invention may be formulated in the same manner as the pharmaceutical composition 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 turmeric extract to various food materials, encapsulation, powdering, suspension, etc., and means bringing a specific effect on health when ingested. Unlike this, 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 turmeric extract as an active ingredient, but also ingredients commonly added during food production, for example, including protein, carbohydrate, fat, nutrients, seasonings and flavoring agents. can do. 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 turmeric extract of the present invention. have.

The amount of turmeric extract added in such a health functional food composition varies depending on the type of health functional food and cannot be uniformly defined, but it may be added within a range that does not impair the original taste of the food, and is usually 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 provides a health functional food composition for improving insomnia, which is administered to an insomnia patient who is administered a benzodiazepine binding site agonist _{of the GABA A receptor, and contains a turmeric extract as an active ingredient.}

The present invention also provides the use of a turmeric extract for the manufacture of a medicament or food for alleviating the side effects of benzodiazepine binding site agonists _{of GABA A receptors.} As described above, the turmeric extract may be used for prevention, improvement or alleviation of side effects of benzodiazepine binding site agonists _{of GABA A receptors.}

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

<Experiment method>

laboratory animal

ICR mice (18-22 g, male) and C57BL/6N mice (28-30 g, male) were purchased from Coretech Co., Ltd. (Pyeongtaek, Korea) and adapted to a breeding box for laboratory animals for a week, and then used in the experiment. . Animals were reared under the conditions of temperature 23±1° C., humidity 55±5%, light-dark cycle (light: 9:00 am - 9:00 pm), and illumination intensity of 3000 Lux, and feed and drinking water were freely provided. All animals were managed according to the guidelines for use of laboratory animals of the Korea Food Research Institutional Animal Care and Use Committee (KFRI-IACUC).

Pentobarbital-induced sleep test

The pentobarbital sleep induction experiment was conducted within a certain time between 1:00 PM and 5:00 PM, and 10 mice (n=10) per group were used after fasting for 24 hours before the experiment. All samples were prepared using a 5% tween 80-saline solution and were orally administered (p.o.) to mice 45 minutes before pentobarbital administration. The general control group was treated with 5% tween 80-saline solution at a concentration of 10 mg/kg, and redolmin (RDM), diazepam (DZP), and doxepin hydrochloride (DH) were representative sleeping pills. For comparison, it was used as a positive control drug. Pentobarbital (Hanlim Pharmaceutical Co., Ltd.) was administered through an intraperitoneal injection (i.p.) at a concentration of 45 mg/kg (hypnotic dosage) according to the experimental design. After pentobarbital treatment, each individual was moved to an independent space and sleep latency and sleep duration were measured. Elevation time was set as the elapsed time from intraperitoneal injection of pentobarbital to loss of righting reflex for more than 1 minute, and sleep time was set as the time until specular reflex was restored again. Mice that did not show sleep behavior even after 10 minutes after pentobarbital administration were excluded from the experiment.

Sleep structure analysis

After adapting C57BL/6N mice for 1 week, electrode insertion surgery was performed for EEG (Electroencephalogram, EEG) and EMG (Electromyogram, EMG) measurements. The mouse was anesthetized with pentobarbital (50 mg/kg, i.p.) and the head was fixed on 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, 0.5% CMC-saline solution used in the control group was orally administered (p.o.) 4 days before the measurement, and then a recording device was connected to induce compliance with this experimental procedure. EEG and EMG were measured for 24 hours from 17:00 using the PAL-8200 series (Pinnacle Technology Inc, Oregon, USA) after oral administration of the sample was stabilized for 5 minutes. 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, REM sleep (rapid eye movement, theta band: 6-10 Hz), and NREM sleep (non-rapid eye movement, delta band: 0.65-4 Hz), and sleep latency (elevation time) was set as the time it takes for NREM sleep in 10 s epoch units to appear 12 or more times consecutively.

<Example>

Example 1. Curcuma Ethanol Extract (KFRI-S075)

Domestic (origin: Jindo-gun, Jeollanam-do) turmeric root and 70% ethanol aqueous solution were mixed in a weight ratio of 1:10 and extracted at 50° C. for 16 hours to obtain an ethanol extract of turmeric. The obtained extract was used after filtration and concentration under reduced pressure, and then powdered by freeze-drying.

Example 2. Turmeric Water Extract (KFRI-S075-W)

A turmeric water extract was obtained in the same manner as in Example 1, except that water was used instead of a 70% aqueous ethanol solution.

<Experimental example>

Experimental Example 1. Pentobarbital sleep induction experiment using the turmeric extract of Example

After oral administration (po) of the turmeric ethanol extract (KFRI-S075) of Example 1 at concentrations of 10, 25, 50 and 100 mg/kg, the sleep-inducing effect by pentobarbital (45 mg/kg, ip) analyzed.

As a result, the turmeric extract of Example 1 showed a significant effect of reducing the elevation time and increasing the sleep duration even at a concentration of 25 mg/kg, which is an exceptionally low concentration as a plant extract, and sleeping at a concentration of 500 mg/kg or more. It was confirmed that the time did not increase any more (see FIG. 1 ).

As a result of evaluating whether the turmeric water extract of Example 2 has a sleep-promoting effect like the turmeric ethanol extract of Example 1, the water extract is also not superior to the 70% alcohol extract, but significant at 25 mg/kg and 50 mg/kg concentrations. It showed a sleep-promoting effect (see FIG. 2).

In addition, it was attempted to compare the sleeping effects of the turmeric extract (KFRI-S075) of the present invention by concentration with those of commercially available sleeping pills.

As a result of comparing the sleeping effects of the turmeric extract of the present invention with the effects of various sleeping pills, in the case of the turmeric extract (KFRI-S075) of Example 1, at a concentration of 25 mg/kg, redolmin (RDM), a famous natural sleeping pill, 620 mg/kg was similar to the effect of , and at a concentration of 100 mg/kg, a sleeping effect similar to that of the synthetic sleeping pills diazepam (DZP, 6 mg/kg) and doxepin hydrochloride (DH, 15 mg/kg) was shown (see FIG. 3a ).

Experimental Example 2. Analysis of sleep structure using the turmeric extract of Examples

The purpose of this study was to compare the sleeping effects of the turmeric extract (KFRI-S075) of the present invention by concentration with those of commercially available sleeping pills.

In the case of the turmeric extract of Example 1, non-REM sleep was increased in a dose-dependent manner, which is similar to the sleep effect of other sleeping pills, DZP and DH, or improved effect than RDM (see FIG. 3b ).

Changes in delta activity during non-REM sleep are physiological indicators of sleep quality and depth [Behav. Brain Res. 210, 5456. Huang et al., 2010]. It has also been reported that DZP increases non-REM sleep and decreases delta power during non-REM sleep [PNAS. 101, 3674-3679. Kopp et al., 2004]. These typical characteristics of DZP were also clearly shown in this study. As expected, DZP significantly (p<0.01) decreased delta activity during non-REM sleep (see FIG. 4b ), and the delta activity of Example 1 did not show a significant change (see FIG. 4a ). These results mean that the turmeric extract of Example 1 increases NREM sleep without affecting physiological sleep. An ideal sleeping pill is a drug that has the characteristics of rapid rise time, maintaining sleep, and not changing physiological sleep [Sleep. 31, 259-270. Alexandre et al., 2008]. Therefore, it is judged that the turmeric extract (KFRI-S075) of the present invention can promote more safe and natural sleep than BDZ and non-BDZ drugs that have side effects such as DZP.

Experimental Example 3. In vivo mechanism of action of the turmeric extract of Examples

It was attempted to elucidate the mechanism of action of the turmeric extract of the present invention through competition experiments with drugs that have been verified to be involved in the mechanism of sleep action.

To this end, the sleep duration was measured according to the presence or absence of Example 1 and 2-pridylethylamine dihydrochloride (PD), a histamine H1 receptor (H1R) agonist.

As a result, in the case of Example 1, it was confirmed that the sleep effect was suppressed by PD. Accordingly, it can be seen that Example 1 has a sleep effect by acting on H1R (see FIG. 5 ).

In addition, the mechanism of action as the histamine receptor antagonist of Example 1 was verified using a histamine H1 receptor (H1R) knockout mouse (a mouse designed to be deficient in H1R).

As a result of the experiment, Example 1 showed excellent sleep effects, such as a decrease in elevation time and an increase in sleep duration, in normal mice, but the sleep effect was suppressed in H1R knockout mice, so that Example 1 acts on H1R to increase the sleep effect It was verified that they have (see FIG. 6).

Experimental Example 4. Example turmeric extract and GABA _A Effect of shortening waking time and change in sleep structure by concurrent administration of receptor agonists

In the group administered with KFRI-S075 25, 50 mg/kg and the representative non-benzodiazepine hypnotic drug zolpidem (ZPD) 5 mg/kg, the time to rise was reduced by about 30 minutes or more compared to the control group, and zolpidem alone 5 mg /kg administration group (reduced elevation time by about 33 minutes) showed a similar elevation time reduction effect (see FIG. 7).

On the other hand, after orally administering the negative control group, ZPD, and the combination drug of KFRI-S075 and ZPD to the test subject, the sleep structure and sleep time were confirmed by analyzing the EEG for 3 hours. As a result, Example 1 and the ZPD combination administration group had NREM sleep The time was increased compared to the control group, and showed an effect of increasing NREM sleep time similar to that of the group administered with ZPD alone (see FIG. 8 ).

Experimental Example 5. Example turmeric extract and GABA _A Changes in delta activity following concomitant administration of receptor agonists

Changes in delta activity during NREM sleep are physiological indicators of sleep quality and depth (Bastien et al., 2003; Chen et al., 2012), and ZPD shortens the waking time and increases the amount of sleep, but It has been reported to decrease delta activity during NREM sleep (Kopp et al., 2004; Alexandre et al., 2008).

A typical characteristic of lowering the delta activity of ZPD is that, when ZPD is administered orally at 5 mg/kg, the delta activity in the 0.5-4 Hz region is significantly (p<0.01) reduced, increasing the amount of NREM sleep, but sleep structure and sleep It was confirmed that it decreases the quality (see FIG. 9c).

On the other hand, the delta activity, which was significantly reduced at the ZPD 5 mg/kg concentration, showed little change in the KFRI-S075 25 mg/kg and ZPD 5 mg/kg combined administration group (see FIG. 9a ), and KFRI-S075 50 mg/kg In the kg and ZPD 5 mg/kg combination administration group, a change in delta activity was rather increased (see Fig. 9b), and the KFRI-S075 and ZPD combination drug decreased the delta activity to change the sleep structure and lower the quality of sleep. It was judged to exhibit a sleep-promoting effect while suppressing the side effects of ZPD.

Hereinafter, formulation examples of the composition containing the powder 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

50 mg of extract powder obtained in Example 1

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

50 mg of extract powder obtained in Example 1

100 mg cornstarch

Lactose 100 mg

2 mg magnesium stearate

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

Formulation Example 3. Preparation of capsules

50 mg of extract powder obtained in Example 1

Zolpidem 5 mg

3 mg of crystalline cellulose

Lactose 14.8 mg

0.2 mg magnesium stearate

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

50 mg of extract powder obtained in Example 1

mannitol 180 mg

2974 mg of sterile distilled water for injection

Na ₂ HPO ₄ ,12H ₂ O 26 mg

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

Formulation Example 5. Preparation of liquid formulation

50 mg of extract powder obtained in Example 1

Zolpidem 5 mg

10 g isomerized sugar

5 g of mannitol

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 and sterilized to prepare a liquid.

Formulation Example 6. Preparation of granules

50 mg of extract powder obtained in Example 1

Zolpidem 5 mg

appropriate amount of vitamin mixture

70 μg vitamin A acetate

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

0.5 mg of vitamin B6

0.2 μg of vitamin B12

Vitamin C 10 mg

Biotin 10 μg

1.7 mg of nicotinic acid amide

50 μg folic acid

Calcium pantothenate 0.5 mg

Mineral mixture appropriate amount

ferrous sulfate 1.75 mg

Zinc Oxide 0.82 mg

Magnesium carbonate 25.3 mg

potassium phosphate monobasic 15 mg

Dicalcium Phosphate 55 mg

Potassium citrate 90 mg

100 mg of calcium carbonate

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. After mixing the above ingredients according to a conventional granule manufacturing method, the granules 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

100 mg of extract powder obtained in Example 1

1,000 mg citric acid

100 g of oligosaccharides

2 g of plum concentrate

1 g taurine

Add purified water to total 900 mL

After mixing the above ingredients according to the usual 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 (14)

A pharmaceutical composition for alleviating the side effects of benzodiazepine-binding site agonists of GABAA receptors using turmeric extract as an active ingredient,
The benzodiazepine binding site agonist of the GABAA receptor is one or more non-benzodiazepine drugs selected from zolpidem, zopiclone and zaleplon,
The side effect of the GABAA receptor benzodiazepine binding site agonist is at least one selected from the group consisting of brain wave delta activity inhibition, residual sedation, drug resistance, withdrawal phenomenon, and drug dependence. A pharmaceutical composition for alleviating side effects of an agonist. According to claim 1,
The turmeric extract is a pharmaceutical composition for alleviating the side effects of the benzodiazepine-binding site agonist _{of the GABA A} receptor, characterized in that it is administered at a concentration of 20 to 300 mg/kg/day. delete delete delete According to claim 1,
The turmeric extract is a pharmaceutical composition for alleviating side effects of _{GABA A} receptor agonists, characterized in that the extract 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 20 to 80% by volume of methanol, ethanol, butanol or propanol aqueous solution, characterized in that the GABA _A receptor agonist side effect reduction pharmaceutical composition. 7. The method of claim 6,
The mixed solvent is a pharmaceutical composition for reducing side effects of _{GABA A} receptor agonists, characterized in that 60 to 80% of an aqueous ethanol solution. As a health functional food composition for improving the side effects of benzodiazepine binding site agonists of GABAA receptors using turmeric extract as an active ingredient,
The benzodiazepine binding site agonist of the GABAA receptor is one or more non-benzodiazepine drugs selected from zolpidem, zopiclone and zaleplon,
The side effect of the GABAA receptor benzodiazepine binding site agonist is at least one selected from the group consisting of brain wave delta activity inhibition, residual sedation, drug resistance, withdrawal phenomenon, and drug dependence. A health functional food composition for improving side effects of agonists. delete delete delete 10. The method of claim 9,
The dosage form of the health functional food composition is a health functional food composition for improving the side effects of the benzodiazepine binding site agonist _{of the GABA A} receptor, characterized in that it is a powder, granules, tablets, capsules or beverages. delete

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