WO2021080393A1 - Composition for ameliorating sleep disorders caused by caffeine, containing lemon and orange extracts - Google Patents

Composition for ameliorating sleep disorders caused by caffeine, containing lemon and orange extracts Download PDF

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Publication number
WO2021080393A1
WO2021080393A1 PCT/KR2020/014626 KR2020014626W WO2021080393A1 WO 2021080393 A1 WO2021080393 A1 WO 2021080393A1 KR 2020014626 W KR2020014626 W KR 2020014626W WO 2021080393 A1 WO2021080393 A1 WO 2021080393A1
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extract
caffeine
lemon
orange
sleep disorders
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PCT/KR2020/014626
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French (fr)
Korean (ko)
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박지호
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주식회사 노아스로스팅
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/31—Foods, ingredients or supplements having a functional effect on health having an effect on comfort perception and well-being
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2300/00—Processes
    • A23V2300/14—Extraction

Definitions

  • the present invention relates to a composition for improving sleep disorders due to caffeine comprising a lemon extract and/or orange extract as an active ingredient.
  • Caffeine is a type of alkaloid contained in the fruits, leaves, and seeds of some plants. It is found in the seeds of coffee beans, tea leaves, and cacao and cola fruits.
  • Caffeine is contained in a variety of foods such as coffee, chocolate, cola, tea, soft drinks, tonic beverages and medicines, and coffee is being spotlighted as the most popular beverage among foods containing caffeine.
  • Coffee contains approximately 50 to 150 mg of caffeine per 200 mL.
  • the caffeine contained in coffee exhibits effects such as fatigue recovery and arousal, so modern people tired of stress and fatigue drink more than one cup of coffee a day.
  • caffeine when consumed in large amounts or when a person with a weak mental and physical body takes caffeine, anxiety, nervousness, insomnia, headache, heart tremor, and palpitations can occur.
  • One aspect of the present invention for achieving the above object relates to a food composition for improving sleep disorders caused by caffeine, including any one or more of lemon (Citrus limon ) extract and orange extract ( Citrus sinensis).
  • lemon Citrus limon
  • Lemon contains flavonoid glycosides such as Hesperidin, Naringin, Eriocitrin, and Eriodictyol glucoside.
  • Citric acid Malic acid, It contains many useful ingredients such as organic acids such as quinic acid and vitamin C.
  • the lemon extract may be a lemon peel extract.
  • the lemon peel contains as many useful ingredients as in the leaves or fruits, especially compounds such as Narigin, Naringenin, Hesperidin, Tangeretin, and Noviletin. Includes.
  • “orange ( Citrus sinensis )” is a plant belonging to the citrus genus, and contains components such as vitamin C, vitamin B1, B2, flavonoids, beta-catonin, citric acid, pectin, and carotene that lemon does not have. It contains a lot of useful ingredients such as the
  • the orange extract may be an orange peel extract.
  • the orange peel is not widely used for food, such as flesh and fruit juice, but is widely used for medicinal purposes.
  • it contains Narigin, Naringenin, Hesperidin, Tangeretin, Nobiletin, etc., so it has anti-inflammatory effects, neurological relief, and stress relief.
  • peel refers to the skin covering the outside of the flesh, and is divided into exocarp, mesocarp, and endocarp in a botanical sense, and the peel of lemon and orange according to the present invention Shall refer to the surgical skin and the mesoderm.
  • Naringin contained in the lemon and/or orange peel is a glycoside of flavonoid pigments, and has strong bacteriostatic and antibacterial effects through antioxidant, metal-blocking, and synergistic ascorbic acid, so it has excellent antibacterial activity.
  • Naringenin is known to have antibacterial and antiviral activity, as well as anti-inflammatory, antioxidant, and anticancer activity.
  • Hesperidin is known to lower blood pressure and blood sugar through lipid degradation, strengthening capillaries and improving fat metabolism, thereby lowering the level of LDL cholesterol in the blood.
  • Tangeretin is known to have anti-inflammatory, antioxidant, and anti-cancer activities along with neuroprotective action.
  • the nobiletin is known to be effective as a therapeutic agent for asthma by regulating lipid metabolism and relaxing bronchial smooth muscles, and has an effect of preventing heart disease.
  • the nerve activity caused by caffeine was alleviated or inhibited when the lemon peel extract containing any one or more of naringin, narcenin, hesperidin, tangeretin and nobiretin was treated (Fig. 4), it can be seen that the lemon peel extract is effective in relieving nerve activity.
  • the nerve activity caused by caffeine was alleviated or inhibited when the lemon peel and orange peel mixed extract was treated (FIG. 8), and the lemon and orange peel mixed extract was also excellent in alleviating nerve activity. It can be seen that it is effective.
  • extract refers to separating the active ingredient contained in the extract material by contacting the solvent and the extract material under specific conditions, and the extract is used to extract the active ingredient in the raw material by the extraction process for lemon extract and/or orange extract.
  • extract refers to separating the active ingredient contained in the extract material by contacting the solvent and the extract material under specific conditions, and the extract is used to extract the active ingredient in the raw material by the extraction process for lemon extract and/or orange extract.
  • the lemon extract and/or orange extract may be extracted according to a conventional method known in the art for extracting an extract from a natural product, that is, using a conventional solvent under conditions of a normal temperature and pressure.
  • the lemon extract and/or orange extract may be extracted using water, alcohol, ethyl acetate acetone, nucleic acid, dichloromethane, or a mixed solvent thereof, and more specifically, water may be used.
  • the extraction method may use various methods such as hot water extraction, cold needle extraction, reflux extraction, and ultrasonic extraction, and preferably hot water extraction, but is not limited thereto.
  • Caffeine (1,3,7-trimetnylxanthine) of the present invention is a psychotropic substance widely used as a central nervous system stimulant, and is present in coffee trees and cacao fruits, and is also included in cola and chocolate.
  • the caffeine is a substance that acts as an inhibitor of the binding of adenosine and adenosine receptors (Adenosine A1 Receptor and Adenosine A2a Receptor).
  • the adenosine is a neuromodulator that promotes sleep and suppresses arousal by inhibiting the production of neurotransmitters and promoting GABA (gamma-aminobutyric acid) production.
  • the GABA gamma-aminobutyric acid
  • GABA gamma-aminobutyric acid
  • anxiety relief convulsion prevention or amelioration, sedation, and sleep induction and improvement effects
  • sleep disturbance may occur due to inactivation of GABA.
  • caffeine stimulates the central and peripheral nervous systems to help improve concentration and prevent drowsiness, but excessive intake may cause sleep disturbances such as nervous irritability, excitement or insomnia, and may affect the endocrine system. have.
  • the lemon extract and/or orange extract can act competitively with caffeine to antagonize the adenosine receptor, thereby inhibiting the production of neuroactive substances and effectively increasing the production of GABA, thereby implementing an anti-insomnia effect.
  • the "antagonism” means that substances with similar structures surround and compete against a specific binding site limited to each other.
  • the lemon extract has the effect of alleviating nerve activity due to caffeine, it was confirmed that the effect of alleviating nerve activity in a concentration-dependent manner of the lemon extract. Furthermore, it was confirmed that the lemon extract continuously alleviates nerve activity through the result of maintaining the nerve activity without increasing even after washing treatment (FIGS. 4 and 5).
  • the lemon extract and/or orange extract may prevent or improve sleep disorders caused by caffeine, and more specifically, may minimize sleep disturbances due to caffeine.
  • “sleep” is an important physiological function of animals with developed brain, and refers to a behavior indispensable for survival.
  • the brain must have good sleep before it can exert its ability to process high-level information.
  • “sleep disorder” is a condition characterized by waking up without recovery, waking up in the middle of the night, having difficulty falling asleep again after waking up, having difficulty falling asleep, waking up too early, etc. It is a disease reported to affect about 15% of all adults per year in Korea.
  • the sleep disorder is widely used as meaning any and all types and grades of sleep loss. Sleep disturbances can persist acutely or chronically.
  • the sleep disorder may include all types of sleep disorders known in the art, and may be a sleep disorder due to stress, health conditions, pain, medication, jet lag, or noise, and specifically, sleep caused by caffeine. It could be a disability.
  • prevention means any action that inhibits or delays the occurrence of sleep disorders in advance. Prevention can be complete or partial. In this case, it may mean a phenomenon in which the degree of sleep disorder of the individual decreases compared to the case where the composition for preventing or improving the sleep disorder is not used.
  • improvement refers to any action that at least reduces the severity of a parameter related to the condition being treated, for example, symptoms. It includes all actions in which the symptoms of sleep disorders are improved or beneficially changed by using the lemon extract and/or orange extract of the present invention.
  • lemon extract and/or orange extract uses substances derived from natural products as they are unlike chemical substances, fatal side effects caused by ingestion or administration thereof can be minimized.
  • the sleep disorder may be caffeine-induced insomnia or circadian rhythm sleep disorders.
  • insomnia refers to a state where it is difficult to fall asleep, awakening frequently while sleeping, or showing unpleasant symptoms alone or in combination when waking up in the morning. It is known that the insomnia may occur when caffeine is taken, and the composition of the present invention has been confirmed to improve the reduction of sleep time due to caffeine (FIG. 6), and can be used for improving the insomnia.
  • circumadian rhythm sleep disorders are disorders that occur when a problem occurs in the body organs in charge of the circadian rhythm or the alignment between the internal circadian rhythm and external factors is broken.
  • Representative diseases include delayed or advanced sleep phase syndrome, and may occur when the biological cycle changes due to the influence of physiological or neurological activity by compounds such as caffeine. It has been confirmed that the composition of the present invention can alleviate neuronal activity caused by caffeine, and thus can improve circadian rhythm sleep disorders due to changes in the circadian cycle caused by caffeine.
  • the form of the food may be coffee, but is not limited thereto.
  • the coffee may be ground coffee or instant coffee, and the form of the coffee is not particularly limited.
  • the coffee may include no-caffeine coffee.
  • coffee beans you can use beans from Jamaica Blue Mountain, Indonesia Toraja, Colombia Souprimo, Guatemala Antigua, Kenya Arabica, Brazil Santos, Ethiopia Mocha Yegachev. These beans can be used by drying the green beans and grinding them after roasting, and roasting is by heating the green beans and roasting them.By applying heat to the green coffee beans, it causes physical and chemical changes in the internal structure of the green beans to determine the unique taste and aroma of coffee. It is a processing treatment.
  • sugars and fats may be added to the coffee beans.
  • the saccharide is any one selected from white sugar, glucose, dextrin, fructose, oligosaccharide, propolis, trehalose, sorbitol, xylitol, mannirol, mantyrol, ramnirol, inosyrol, erythrolol, paratinose, and quersirol You can use the above.
  • the fat or oil may be used any one or more selected from powdered milk, skim milk powder, and plant ingredients.
  • Coffee containing the lemon extract and/or orange extract of the present invention not only prevents sleep disturbance, which is one of the side effects caused by coffee, but also inhibits neurological hyperactivity caused by an overdose of caffeine.
  • the lemon extract and/or orange extract do not alter the original taste of coffee by being added to or included in coffee, and by acting competitively with caffeine, the insomnia effect that may be caused by caffeine can be minimized.
  • Foods to which the lemon extract and/or orange extract of the present invention can be added include not only coffee but also sausage, meat, bread, chocolate, snacks, candy, confectionery, ramen, pizza, other noodles, gums, and dairy including ice cream.
  • foods to which the lemon extract and/or orange extract of the present invention can be added include not only coffee but also sausage, meat, bread, chocolate, snacks, candy, confectionery, ramen, pizza, other noodles, gums, and dairy including ice cream.
  • the liquid component added in addition to the lemon extract and/or orange extract of the present invention is not limited thereto, but may contain various flavoring agents or natural carbohydrates, etc. as an additional component like a conventional beverage. .
  • the natural carbohydrates described above are monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.) and polysaccharides (e.g., common sugars such as dextrin, cyclodextrin, etc.), and xylitol, sorbitol. And sugar alcohols such as erythritol.
  • the type of food may be a food additive, and the food additive refers to a substance used by a method such as adding, mixing, infiltrating or adding to food for the preparation, processing, or preservation of food.
  • the food additives include natural products and synthetic products, and can be classified according to functions and uses. Currently, 370 kinds of chemical synthetic products and 50 kinds of natural additives are approved as food additives in Korea.
  • preservatives fungicides, antioxidants, coloring agents, coloring agents, bleaching agents, seasonings, sweeteners, flavoring agents, expanding agents, reinforcing agents, and improving agents , Emulsifiers, thickeners and stabilizers, coating agents, gum base agents, defoaming agents, solvents, release agents, insect repellents, quality improvers and other additives for food manufacturing.
  • the form of the food additive may include a powder, granule, tablet, capsule or liquid form, but is not limited thereto.
  • the type of food may specifically be a health functional food.
  • the health functional foods include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavors, coloring agents and enhancers (cheese, chocolate, etc.), pectic acid and its salts, organic acids, protective colloidal growth It may contain an agent, a pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated beverages, and the like.
  • the health functional food of the present invention may contain pulp for the manufacture of fruit and vegetable beverages. These components may be used alone or in combination, and the proportion of these additives is generally selected in the range of 0.001 to 50 parts by weight per total weight of the composition.
  • the health functional food is a food that emphasizes the biological regulation function of food, and is a food that has added value to act and express it for a specific purpose using physical, biochemical, and bioengineering methods.
  • the ingredients of these health functional foods are designed and processed to sufficiently exert the body's control functions related to the body defense, regulation of body rhythm, prevention and recovery of diseases to the living body, and food supplementary additives, sweeteners, or functional foods acceptable as foods. It may contain raw materials.
  • the lemon extract and/or orange extract of the present invention is used as a health functional food (or a health functional beverage additive)
  • the lemon extract and/or orange extract is added as it is or used with other foods or food ingredients, and a conventional method It can be used appropriately according to.
  • the amount of the lemon extract and/or orange extract mixed may be appropriately determined according to the purpose of use (prevention, health or improvement, therapeutic treatment).
  • Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating sleep disorders caused by caffeine, comprising any one or more of a lemon extract and an orange extract.
  • the sleep disorder may be caffeine-induced insomnia or circadian rhythm sleep disorders.
  • the lemon extract may be a lemon peel extract.
  • the orange extract may be an orange peel extract.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier, excipient, or diluent in addition to the lemon extract and/or orange extract of the present invention for administration.
  • the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.
  • the pharmaceutical composition of the present invention can be applied in any dosage form, and more specifically, may be an oral dosage form.
  • the parenteral formulation may be a spray type such as injection, application, or aerosol.
  • the composition of the present invention has the effect of pacifying excessive neuronal activity caused by caffeine and at the same time improving sleep disorders.
  • it can inhibit the continuous action of caffeine beyond the effect of inhibiting the neurological activity of caffeine in a short time.
  • It can be widely used for improving sleep disorders while stabilizing the nerve activity induced by caffeine.
  • FIG. 1 is a photograph showing the preparation process of a hippocampal section of a 7-day-old male white paper.
  • (a) is a picture showing the process of extracting the entire brain of a white paper
  • (b) is a picture showing the process of extracting the hippocampal tissue from the extracted brain
  • (c) is a picture of the extracted hippocampus after sectioning and inserting it.
  • 6-well plate (6-well plate) is a picture showing the process of putting.
  • FIG. 2 is a photograph showing the MEA setting process of a hippocampal section.
  • (a) is an enlarged picture of one probe of the MEA
  • (b) is a picture of an amplifier connected to the MEA on which the hippocampus is placed
  • (c) is a picture of a hippocampal slice placed on the MEA
  • (d) Is a photograph showing the area of each hippocampus located in an array.
  • MMA microelectrode array
  • A experimental protocol
  • B spike detection process
  • Figure 4 shows the results confirming that the nerve activity by caffeine was alleviated during the lemon extract treatment (a: comparison of nerve activity before washing when caffeine alone treatment and caffeine and lemon extract treatment, b: caffeine alone treatment and caffeine and lemon extract Comparison of nerve activity after washing during treatment)
  • Figure 5 shows the results of detection of low-level spikes (lls) and high-level spikes (hls) during lemon extract treatment (a: low-level spike, lls) detection result, b: high-level spike (hls) detection result)
  • Figure 6 shows the results confirming that the nerve activity by caffeine was alleviated when orange extract treatment (a: caffeine alone treatment and caffeine and orange extract treatment before washing nerve activity comparison, b: caffeine alone treatment and caffeine and orange extract Comparison of nerve activity after washing during treatment)
  • Preparation Example 2 Preparation of orange peel extract 100 g of orange peel (Gio Herb Co., Yangju, Korea) was added 10 times (w/v) of distilled water, followed by hot water extraction at 121° C. for 40 minutes.
  • the extract is Whatman No. 1 Filtered using filter paper (Whatman International Ltd., Maidstone, UK), and the filtered extract was concentrated at 40°C for 5 hours using a concentrator (Eyela Co., Tokyo, Japan).
  • the concentrated extract was lyophilized for 7 days at -70°C and 5 mTorr with a freeze dryer (Ilsin Bio Co., Yangju., Korea), then pulverized with a grinder (Ilsin Bio Co., Yangju., Korea) for experiments.
  • the yield is 9.8%.
  • Hippocampal organotypic slice culture (HOSC)
  • the method of organotypic culturing of the brain hippocampus slices using a thin film has already used a commonly used method.
  • the cerebral hippocampus was excised from Sprague Dawley white young rats (Orientbio Co., Seungnam, Korea) between 5 and 7 days old, and sliced to a thickness of 350 ⁇ m using a tissue slicer (Mickle Laboratory Engineering Co., UK).
  • a tissue slicer Mickle Laboratory Engineering Co., UK.
  • After placing 5 to 6 pieces in a thin film insert (Millicell-CM; Millipore, MA) with a 0.4 ⁇ m hole, put it in a 6-well plate (SPL Life Sciences Co., Korea) and 5% CO at 36°C. 2 (Dong-A Co., Seoul, Korea) was cultured in an incubator maintained.
  • aCSF sterile artificial spinal cord solution
  • MEA1060 Multi Channel Systems Inc., Reutlingen, Germany
  • an artificial spinal cord solution into which a 5% CO 2 and 95% O 2 mixed gas was added was perfused at a rate of 3 mL/min, and the MEA and the artificial spinal cord solution were maintained at 33°C (Fig. 2). ).
  • Stabilized hippocampal tissue was recorded for 3 minutes, and then artificial cerebrospinal fluid containing 1 mM caffeine (Sigma, St. Louis, Mo, USA) or 1 mM caffeine and analysis samples (lemon peel extract 100 ⁇ g/ml, 200 ⁇ g) /ml, 400 ⁇ g/ml) were perfused under the same conditions for 20 minutes each, and then recorded for 3 minutes.After washing for 20 minutes with artificial cerebrospinal fluid alone, 3 minutes were recorded to obtain data for a total of 9 minutes. .
  • MEA with hippocampal tissue reads data at a sampling rate of 25 kHz for each channel through a total of 60 channels, and is recorded through a computer using MC_Rack and MC_Data Tool (Multi Channel Systems, GmbH) software.
  • a band pass filter of 4 steps was used to extract meaningful spikes from all recorded signals, and the equation is as follows.
  • X represents an effective value (RMS) for noise
  • ⁇ is a factor that determines each threshold.
  • the threshold was composed of a total of 3 factors (0.6, 1 and 3). If the ⁇ value is more than 0.6, it is set as a meaningful spike, and the threshold at this time is -21.63 ⁇ V. This process was performed using a MATLAB (Mathworks Inc., Natick, Massachusetts, USA) program for all 60 channels (FIG. 3).
  • low-level spikes (lls) and high-level spikes (hls) in order to examine the physiological activity of the brain by classifying the phenomenon in which hybridization occurs due to synchronization between spikes, etc. was measured separately.
  • the nerve activity measurement method is the same as the method of 1-3 above, and as an analysis sample, 100 ⁇ g/ml, 200 ⁇ g/ml, and 400 ⁇ g/ml of orange peel extract were used instead of lemon peel extract.
  • the method for measuring nerve activity was the same as the method of 1-3 above, and 200 ⁇ g/ml of a mixed extract of lemon peel and orange peel was used as the analysis sample.
  • the extract of a mixture of lemon peel and orange peel has an excellent effect on alleviating nerve activity by caffeine. Specifically, when only caffeine was treated, nerve activity continued to be more than 200% even after washing, but when treated with a lemon peel and orange peel extract, the degree of nerve activity was significantly reduced, and it was confirmed that the nerve activity alleviating effect persisted after washing (Fig. 8). In addition, it was confirmed that the mixed extract of lemon and orange peel alleviates caffeine nerve activation in both the low-concentration spike and the high-concentration spike (FIG. 9).
  • the lemon peel and/or orange peel extract has an excellent efficacy in alleviating nerve activity caused by caffeine.

Abstract

The present invention relates to a composition for ameliorating sleep disorders caused by caffeine, containing a lemon extract and/or an orange extract as active ingredients.

Description

레몬 추출물 및 오렌지 추출물을 포함하는 카페인에 의한 수면장애 개선용 조성물Composition for improving sleep disorders caused by caffeine containing lemon extract and orange extract
본 발명은 레몬 추출물 및/또는 오렌지 추출물을 유효성분으로 포함하는 카페인으로 인한 수면장애 개선용 조성물에 관한 것이다. The present invention relates to a composition for improving sleep disorders due to caffeine comprising a lemon extract and/or orange extract as an active ingredient.
카페인(Caffeine)은 일부 식물의 열매, 잎, 씨앗 등에 함유된 알칼로이드(alkaloid)의 일종으로 커피 열매의 씨앗, 찻잎, 카카오와 콜라 열매 등에 들어있다.Caffeine is a type of alkaloid contained in the fruits, leaves, and seeds of some plants. It is found in the seeds of coffee beans, tea leaves, and cacao and cola fruits.
카페인은 커피, 초콜릿, 콜라, 차, 소프트드링크, 강장 음료 및 약품 등 다양한 식품에 함유되어 있으며, 커피는 카페인이 함유되어 있는 식품 중 가장 대중적인 음료로 각광받고 있다. Caffeine is contained in a variety of foods such as coffee, chocolate, cola, tea, soft drinks, tonic beverages and medicines, and coffee is being spotlighted as the most popular beverage among foods containing caffeine.
커피는 200mL 기준으로 대략 50~150 mg의 카페인을 함유하고 있다. 커피에 함유된 카페인은 피로회복 및 각성 작용 등의 효과를 나타내므로, 스트레스와 피로에 지친 현대인들은 하루에 한 잔 이상 커피를 마시고 있다.Coffee contains approximately 50 to 150 mg of caffeine per 200 mL. The caffeine contained in coffee exhibits effects such as fatigue recovery and arousal, so modern people tired of stress and fatigue drink more than one cup of coffee a day.
하지만 카페인을 다량 복용하거나 심신이 허약한 사람이 카페인을 복용하는 경우, 불안, 신경과민, 불면증, 두통, 심장 떨림, 심계항진 등이 발생할 수 있다.However, when caffeine is consumed in large amounts or when a person with a weak mental and physical body takes caffeine, anxiety, nervousness, insomnia, headache, heart tremor, and palpitations can occur.
(한국등록특허 제10-1265253호).(Korean Patent Registration No. 10-1265253).
따라서 카페인으로 인한 수면장애 등의 부작용을 최소화할 수 있는 새로운 식음 제품을 개발하기 위하여 많은 연구가 진행되고 있으나, 대중들의 기호를 충족시킬 수 있도록 카페인의 함량을 유지하면서 카페인에 의한 부작용을 보완할 수 있는 방법은 아직까지 부재한 실정이다.Therefore, many studies are being conducted to develop new food and beverage products that can minimize side effects such as sleep disorders caused by caffeine, but it is possible to supplement side effects caused by caffeine while maintaining the content of caffeine to satisfy the public's taste. There is still no way to do it.
본 발명의 목적은 레몬 추출물 및 오렌지 추출물 중 어느 하나 이상을 포함하는, 카페인에 의한 수면장애 개선용 식품 조성물을 제공하는 것이다. It is an object of the present invention to provide a food composition for improving sleep disorders caused by caffeine, comprising any one or more of a lemon extract and an orange extract.
본 발명의 목적은 레몬 추출물 및 오렌지 추출물 중 어느 하나 이상을 포함하는, 카페인에 의한 수면장애 예방 및 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing and treating sleep disorders caused by caffeine, comprising any one or more of a lemon extract and an orange extract.
상기와 같은 목적을 달성하기 위한 본 발명의 일 측면은 레몬(Citrus limon) 추출물 및 오렌지 추출물(Citrus sinensis) 중 어느 하나 이상을 포함하는, 카페인에 의한 수면장애 개선용 식품 조성물에 관한 것이다.One aspect of the present invention for achieving the above object relates to a food composition for improving sleep disorders caused by caffeine, including any one or more of lemon (Citrus limon ) extract and orange extract ( Citrus sinensis).
본 발명에서, “레몬(Citrus limon)”은 귤속에 속하는 식물로 상큼한 맛과 향이 뛰어나 식용 또는 약재로 활용된다. 레몬은 헤스페리딘(Hesperidin), 나린진(Naringin), 에리오시트린(Eriocitrin), 에리오딕티올 글루코사이드(Eriodictyol glucoside) 등의 플라보노이드 배당체가 들어 있으며, 시트릭 애씨드(Citric acid), 말릭 애씨드(Malic acid), 퀴닉 애씨드(Quinic acid) 등의 유기산 및 비타민 C등의 유용한 성분을 많이 함유하고 있다.In the present invention, "lemon ( Citrus limon )" is a plant belonging to the citrus genus and has excellent fresh taste and aroma, and is used as an edible or medicinal material. Lemon contains flavonoid glycosides such as Hesperidin, Naringin, Eriocitrin, and Eriodictyol glucoside. Citric acid, Malic acid, It contains many useful ingredients such as organic acids such as quinic acid and vitamin C.
구체적으로 상기 레몬 추출물은 레몬 과피 추출물일 수 있다. Specifically, the lemon extract may be a lemon peel extract.
상기 레몬 과피는 잎이나 열매 속 못지 않게 유용한 성분을 많이 함유하고 있는데, 특히 나리진(Narigin), 나르제닌(Naringenin), 헤스페리딘(Hesperidin), 탄제레틴(Tangeretin), 노비레틴(Nobiletin) 등의 화합물을 포함한다.The lemon peel contains as many useful ingredients as in the leaves or fruits, especially compounds such as Narigin, Naringenin, Hesperidin, Tangeretin, and Noviletin. Includes.
본 발명에서 “오렌지(Citrus sinensis)”는 귤속에 속하는 식물로 비타민 C, 비타민 B1, B2, 플라보노이드, 베타카토닌, 시트릭 애씨드, 팩틴 등의 성분을 함유하고 있으며, 레몬에는 없는 카로틴도 포함하고 있는 등 유용한 성분을 많이 포함하고 있다.In the present invention, “orange ( Citrus sinensis )” is a plant belonging to the citrus genus, and contains components such as vitamin C, vitamin B1, B2, flavonoids, beta-catonin, citric acid, pectin, and carotene that lemon does not have. It contains a lot of useful ingredients such as the
구체적으로 상기 오렌지 추출물은 오렌지 과피 추출물일 수 있다.Specifically, the orange extract may be an orange peel extract.
상기 오렌지 과피는 과육, 과즙과 같이 식용에 많이 활용되지는 않으나 약용에는 많이 활용되고 있다. 특히 나리진(Narigin), 나르제닌(Naringenin), 헤스페리딘(Hesperidin), 탄제레틴(Tangeretin), 노비레틴(Nobiletin) 등을 함유하고 있어, 항염작용, 신경완화, 스트레스 완화 등에 효과가 있다. The orange peel is not widely used for food, such as flesh and fruit juice, but is widely used for medicinal purposes. In particular, it contains Narigin, Naringenin, Hesperidin, Tangeretin, Nobiletin, etc., so it has anti-inflammatory effects, neurological relief, and stress relief.
본 발명에서 “과피”는 과육의 외측을 덮고 있는 껍질을 의미하는 것으로, 식물학적인 의미에서 외과피(exocarp), 중과피(mesocarp) 및 내과피(endocarp)로 나누어지며, 본 발명에 따른 레몬 및 오렌지의 과피는 외과피 및 중과피를 지칭하는 것으로 한다. In the present invention, "peel" refers to the skin covering the outside of the flesh, and is divided into exocarp, mesocarp, and endocarp in a botanical sense, and the peel of lemon and orange according to the present invention Shall refer to the surgical skin and the mesoderm.
상기 레몬 및/또는 오렌지 과피에 함유된 나린진(naringin)은 플라보노이드 색소의 배당체로서 항산화 작용, 금속봉쇄 작용, 아스콜빈산 상승작용을 통해 강력한 정균 및 항균 작용을 하므로 항균 활성이 우수하다.Naringin contained in the lemon and/or orange peel is a glycoside of flavonoid pigments, and has strong bacteriostatic and antibacterial effects through antioxidant, metal-blocking, and synergistic ascorbic acid, so it has excellent antibacterial activity.
상기 나르제닌(Naringenin)은 항균, 항바이러스 활성뿐만 아니라, 항염증, 항산화, 항암 활성이 있는 것으로 알려져 있다.Naringenin is known to have antibacterial and antiviral activity, as well as anti-inflammatory, antioxidant, and anticancer activity.
상기 헤스페리딘(Hesperidin)은 지질 분해 작용으로 혈압 및 혈당을 낮추고, 모세혈관 강화작용, 지방대사 개선작용을 통해 혈중 LDL 콜레스테롤 수치를 낮추는 것으로 알려져 있다.Hesperidin is known to lower blood pressure and blood sugar through lipid degradation, strengthening capillaries and improving fat metabolism, thereby lowering the level of LDL cholesterol in the blood.
상기 탄제레틴(Tangeretin)은 신경보호 작용과 함께, 항염증, 항산화, 항암 활성이 있는 것으로 알려져 있다.Tangeretin is known to have anti-inflammatory, antioxidant, and anti-cancer activities along with neuroprotective action.
상기 노비레틴(Nobiletin)은 지질대사를 조절하고 기관지 평활근을 이완시켜 천식 치료제로서 효과가 있으며, 심장질환 예방효과가 있는 것으로 알려져 있다.The nobiletin is known to be effective as a therapeutic agent for asthma by regulating lipid metabolism and relaxing bronchial smooth muscles, and has an effect of preventing heart disease.
본 발명의 일 실시예에서, 나린진, 나르제닌, 헤스페리딘, 탄제레틴 및 노비레틴 중 어느 하나 이상을 포함하고 있는 레몬 과피 추출물을 처리한 경우 카페인에 의한 신경 활성이 완화 또는 억제됨을 확인하였는 바(도 4), 상기 레몬 과피 추출물이 신경 활성 완화에 효능이 있음을 알 수 있다. In an embodiment of the present invention, it was confirmed that the nerve activity caused by caffeine was alleviated or inhibited when the lemon peel extract containing any one or more of naringin, narcenin, hesperidin, tangeretin and nobiretin was treated (Fig. 4), it can be seen that the lemon peel extract is effective in relieving nerve activity.
본 발명의 일 실시예에서 나린진, 나르제닌, 헤스페리딘, 탄제레틴 및 노비레틴 중 어느 하나 이상을 포함하고 있는 오렌지 과피 추출물을 처리한 경우 카페인에 의한 신경 활성이 완화 또는 억제됨을 확인하였는 바(도 6), 상기 오렌지 과피 추출물은 신경 활성 완화에 효능이 있음을 알 수 있다.In an embodiment of the present invention, it was confirmed that when the orange peel extract containing any one or more of naringin, narcenin, hesperidin, tangeretin, and nobiretin was treated, the nerve activity caused by caffeine was alleviated or inhibited (FIG. 6 ), it can be seen that the orange peel extract is effective in relieving nerve activity.
본 발명의 일 실시예에서, 레몬 과피 및 오렌지 과피 혼합 추출물을 처리한 경우 카페인에 의한 신경 활성이 완화 또는 억제됨을 확인하였는 바(도 8), 상기 레몬 및 오렌지 과피 혼합 추출물 또한 신경 활성 완화에 우수한 효능이 있음을 알 수 있다.In one embodiment of the present invention, it was confirmed that the nerve activity caused by caffeine was alleviated or inhibited when the lemon peel and orange peel mixed extract was treated (FIG. 8), and the lemon and orange peel mixed extract was also excellent in alleviating nerve activity. It can be seen that it is effective.
본 발명에서 “추출물”은 용매와 추출 재료를 특정 조건하에서 접촉시킴으로써 추출 재료에 함유된 유효성분을 분리해낸 것으로, 상기 추출물은 레몬 추출물 및/또는 오렌지 추출물에 대한 추출 공정에 의해 원료 내의 유효성분을 포함할 수 있다.In the present invention, "extract" refers to separating the active ingredient contained in the extract material by contacting the solvent and the extract material under specific conditions, and the extract is used to extract the active ingredient in the raw material by the extraction process for lemon extract and/or orange extract. Can include.
상기 레몬 추출물 및/또는 오렌지 추출물은 천연물로부터 추출물을 추출하는 당업계에 공지된 통상적인 방법에 따라, 즉, 통상적인 온도, 압력의 조건 하에서 통상적인 용매를 사용하여 추출할 수 있다.The lemon extract and/or orange extract may be extracted according to a conventional method known in the art for extracting an extract from a natural product, that is, using a conventional solvent under conditions of a normal temperature and pressure.
구체적으로, 상기 레몬 추출물 및/또는 오렌지 추출물은 물, 알코올, 에틸아세테이트 아세톤, 핵산, 디클로로메탄 또는 이들의 혼합 용매를 사용하여 추출할 수 있으며, 보다 구체적으로는 물을 사용할 수 있다. Specifically, the lemon extract and/or orange extract may be extracted using water, alcohol, ethyl acetate acetone, nucleic acid, dichloromethane, or a mixed solvent thereof, and more specifically, water may be used.
상기 추출 방법은 열수 추출, 냉침 추출, 환류 추출, 초음파 추출 등의 다양한 방법을 사용할 수 있으며, 바람직하게는 열수 추출을 사용할 수 있으나 이에 제한되는 것은 아니다.The extraction method may use various methods such as hot water extraction, cold needle extraction, reflux extraction, and ultrasonic extraction, and preferably hot water extraction, but is not limited thereto.
본 발명의 카페인(1,3,7-trimetnylxanthine)은 중추신경계통 각성제로 널리 사용되는 향정신성 물질로 커피 나무, 카카오 열매 등에 존재하며 콜라, 초콜릿 등에도 포함되어있다. 상기 카페인은 아데노신과 아데노신 수용체(Adenosine A1 Receptor 및 Adenosine A2a Receptor)결합의 억제제로 작용하는 물질이다.Caffeine (1,3,7-trimetnylxanthine) of the present invention is a psychotropic substance widely used as a central nervous system stimulant, and is present in coffee trees and cacao fruits, and is also included in cola and chocolate. The caffeine is a substance that acts as an inhibitor of the binding of adenosine and adenosine receptors (Adenosine A1 Receptor and Adenosine A2a Receptor).
상기 아데노신은 신경 조절자로 신경전달물질의 생성 억제 및 GABA(감마-아미노부티르산) 생성 촉진을 통해 수면을 촉진하고 각성을 억제하는 물질이다. The adenosine is a neuromodulator that promotes sleep and suppresses arousal by inhibiting the production of neurotransmitters and promoting GABA (gamma-aminobutyric acid) production.
상기 GABA(감마-아미노부티르산)은 불안 완화, 경련 예방 또는 개선, 진정작용, 및 수면 유도 및 개선 효과와 관련이 있으며 GABA의 불활성화에 의해 수면장애가 발생할 수 있다. The GABA (gamma-aminobutyric acid) is associated with anxiety relief, convulsion prevention or amelioration, sedation, and sleep induction and improvement effects, and sleep disturbance may occur due to inactivation of GABA.
상기 GABA와 카페인이 함께 작용하면 카페인의 효과가 보다 우월하여 카페인에 의해 아데노신 수용체가 억제되고, 억제된 아데노신 수용체는 신경전달물질을 과발현시키고 GABA의 생성을 억제한다.When the GABA and caffeine act together, the effect of caffeine is more superior and the adenosine receptor is inhibited by caffeine, and the inhibited adenosine receptor overexpresses neurotransmitters and inhibits the production of GABA.
이에 따라, 카페인의 적당한 섭취는 중추신경계와 말초신경계를 자극하여 집중력 향상, 졸음 방지에 도움을 주지만 과하게 섭취할 경우에 신경과민, 흥분 또는 불면 등의 수면 장애를 유발하며 내분비계에도 영향을 미칠 수 있다.Accordingly, proper intake of caffeine stimulates the central and peripheral nervous systems to help improve concentration and prevent drowsiness, but excessive intake may cause sleep disturbances such as nervous irritability, excitement or insomnia, and may affect the endocrine system. have.
상기 레몬 추출물 및/또는 오렌지 추출물은 카페인과 경쟁적으로 작용하여 아데노신 수용체를 길항시킴으로써 신경활성 물질의 생성을 억제하고 GABA의 생성을 효과적으로 증가시켜 항불면 효과를 구현할 수 있다. 상기 “길항”은 구조가 유사한 물질끼리 한정된 특정 결합 부위(binding site)를 둘러싸고 경합하는 것이다. The lemon extract and/or orange extract can act competitively with caffeine to antagonize the adenosine receptor, thereby inhibiting the production of neuroactive substances and effectively increasing the production of GABA, thereby implementing an anti-insomnia effect. The "antagonism" means that substances with similar structures surround and compete against a specific binding site limited to each other.
본 발명의 일 실시예에서는 레몬 추출물이 카페인으로 인한 신경 활성을 완화시키는 효능이 있는지 여부를 확인한 결과, 레몬 추출물의 농도 의존적으로 신경 활성이 완화되는 효과를 확인하였다. 나아가 워싱(washing) 처리 이후에도 신경 활성이 증가하지 않고 유지되는 결과를 통해 레몬 추출물이 신경 활성을 지속적으로 완화시키는 것임을 확인하였다(도 4 및 도 5).In one embodiment of the present invention, as a result of confirming whether the lemon extract has the effect of alleviating nerve activity due to caffeine, it was confirmed that the effect of alleviating nerve activity in a concentration-dependent manner of the lemon extract. Furthermore, it was confirmed that the lemon extract continuously alleviates nerve activity through the result of maintaining the nerve activity without increasing even after washing treatment (FIGS. 4 and 5).
본 발명의 일 실시예에서는 오렌지 추출물이 카페인으로 인한 신경 활성을 완화시키는 효능이 있는지 여부를 확인한 결과, 오렌지 추출물의 농도 의존적으로 신경 활성이 완화되는 효과를 확인하였다. 나아가 워싱(washing) 처리 이후에도 신경 활성이 지속적으로 안정화되는 것을 확인하였다(도 6 및 도 7).In one embodiment of the present invention, as a result of confirming whether the orange extract has the effect of alleviating nerve activity due to caffeine, it was confirmed that the effect of alleviating nerve activity in a concentration-dependent manner of the orange extract. Furthermore, it was confirmed that the nerve activity was continuously stabilized even after washing treatment (FIGS. 6 and 7 ).
본 발명의 일 실시예에서는 레몬 및 오렌지 혼합 추출물을 처리한 후 워싱(washing) 처리하더라도 레몬 추출물 또는 오렌지 추출물을 처리한 경우와 마찬가지로 신경 활성이 지속적으로 안정화됨을 확인하였다(도 8 및 도 9) In one embodiment of the present invention, even if the lemon and orange mixture extract was treated and then washed, it was confirmed that nerve activity was continuously stabilized as in the case of treatment with lemon extract or orange extract (FIGS. 8 and 9).
또한 구체적으로, 상기 레몬 추출물 및/또는 오렌지 추출물은 카페인으로 인한 수면 장애를 예방 또는 개선할 수 있으며 보다 구체적으로, 카페인으로 인한 수면장애를 최소화시킬 수 있다. In addition, the lemon extract and/or orange extract may prevent or improve sleep disorders caused by caffeine, and more specifically, may minimize sleep disturbances due to caffeine.
본 발명에서 "수면"은 뇌가 발달된 동물들의 중요한 생리기능으로서, 생존을 위해 불가결한 행동을 말한다. 뇌는 질 좋은 수면이 있어야 비로소 고차원의 정보를 처리할 수 있는 능력을 발휘할 수 있다.In the present invention, "sleep" is an important physiological function of animals with developed brain, and refers to a behavior indispensable for survival. The brain must have good sleep before it can exert its ability to process high-level information.
본 발명에서 “수면장애”는 회복되지 않은 채로 기상하는 것, 한밤중에 기상하는 것, 깬 후 다시 잠드는 데 어려움을 겪는 것, 잠드는 데 어려움을 겪는 것 또는 너무 일찍 기상하는 것 등으로 특징지어지는 병태를 의미하고, 우리나라 연간 전체 성인 가운데 약 15 % 정도에 영향을 주는 것으로 보고된 질환이다.In the present invention, "sleep disorder" is a condition characterized by waking up without recovery, waking up in the middle of the night, having difficulty falling asleep again after waking up, having difficulty falling asleep, waking up too early, etc. It is a disease reported to affect about 15% of all adults per year in Korea.
상기 수면장애는 임의의 및 모든 수면 상실의 유형 및 등급을 의미하는 것으로서 널리 사용되고 있다. 수면 장애는 급성 또는 만성으로 지속될 수 있다.The sleep disorder is widely used as meaning any and all types and grades of sleep loss. Sleep disturbances can persist acutely or chronically.
상기 수면장애는 당업계에서 알려져 있는 모든 종류의 수면장애를 포함할 수 있고, 스트레스, 건강 상태, 통증, 투약, 시차증(jet lag) 또는 소음 등에 의한 수면장애일 수 있으며, 구체적으로 카페인에 의한 수면장애일 수 있다.The sleep disorder may include all types of sleep disorders known in the art, and may be a sleep disorder due to stress, health conditions, pain, medication, jet lag, or noise, and specifically, sleep caused by caffeine. It could be a disability.
본 발명에서 “예방”이란 수면장애의 발생을 사전에 억제 또는 지연시키는 모든 행위를 의미한다. 예방은 완전할 수 있으며 또는 부분적일 수도 있다. 이 경우 개체의 수면장애 정도가 상기 수면장애 예방 또는 개선용 조성물을 사용하지 않은 경우와 비교하여 감소하는 현상을 의미할 수 있다. In the present invention, "prevention" means any action that inhibits or delays the occurrence of sleep disorders in advance. Prevention can be complete or partial. In this case, it may mean a phenomenon in which the degree of sleep disorder of the individual decreases compared to the case where the composition for preventing or improving the sleep disorder is not used.
본 발명에서 “개선”이란 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다. 본 발명의 레몬 추출물 및/또는 오렌지 추출물을 이용하여 수면장애 증상이 호전되거나 이롭게 변경되는 모든 행위를 포함한다. In the present invention, "improvement" refers to any action that at least reduces the severity of a parameter related to the condition being treated, for example, symptoms. It includes all actions in which the symptoms of sleep disorders are improved or beneficially changed by using the lemon extract and/or orange extract of the present invention.
상기 레몬 추출물 및/또는 오렌지 추출물은 화학물질 등과 달리 천연물 유래의 물질을 그대로 이용하는 것이므로, 이의 섭취 내지 투여에 따른 치명적인 부작용이 최소화될 수 있다.Since the lemon extract and/or orange extract uses substances derived from natural products as they are unlike chemical substances, fatal side effects caused by ingestion or administration thereof can be minimized.
더욱 구체적으로, 상기 수면장애는 카페인에 의한 불면증 또는 일주기리듬 수면장애(circadian rhythm sleep disorders)인 것일 수 있다.More specifically, the sleep disorder may be caffeine-induced insomnia or circadian rhythm sleep disorders.
본 발명에서, “불면증”은 잠들기 어렵거나 자다가 자주 깨거나 아침에 일어나면 개운하지 않은 증상을 단독 또는 복합적으로 보이는 상태를 말한다. 카페인 복용시 상기 불면증이 발생될 수 있음은 알려진 바 있으며, 본 발명의 조성물은 카페인에 의한 수면 시간 감소를 개선시키는 것을 확인하였는 바(도 6), 상기 불면증 개선 용도로 활용될 수 있다.In the present invention, "insomnia" refers to a state where it is difficult to fall asleep, awakening frequently while sleeping, or showing unpleasant symptoms alone or in combination when waking up in the morning. It is known that the insomnia may occur when caffeine is taken, and the composition of the present invention has been confirmed to improve the reduction of sleep time due to caffeine (FIG. 6), and can be used for improving the insomnia.
본 발명에서, “일주기리듬 수면장애(circadian rhythm sleep disorders)”는 일주기 리듬을 관장하는 신체기관에 문제가 생기거나 혹은 내적인 일주기 리듬과 외부적 요인 사이에 정렬이 깨지면서 생기는 장애이다. 대표적인 질환으로 지연성 혹은 전진성 수면위상 증후군 등이 있으며, 카페인 등과 같은 화합물에 의해 생리활성 또는 신경활성이 영향을 받음으로 인하여 생체 주기가 바뀌면서 발생될 수 있다. 본 발명의 조성물은 카페인에 의한 신경 활성을 완화시킬 수 있음을 확인하였는 바, 카페인에 의한 생체 주기 변화에 따른 일주기리듬 수면장애를 개선시킬 수 있다.In the present invention, “circadian rhythm sleep disorders” are disorders that occur when a problem occurs in the body organs in charge of the circadian rhythm or the alignment between the internal circadian rhythm and external factors is broken. Representative diseases include delayed or advanced sleep phase syndrome, and may occur when the biological cycle changes due to the influence of physiological or neurological activity by compounds such as caffeine. It has been confirmed that the composition of the present invention can alleviate neuronal activity caused by caffeine, and thus can improve circadian rhythm sleep disorders due to changes in the circadian cycle caused by caffeine.
또한 구체적으로, 상기 식품의 형태는 커피일 수 있으나, 이에 제한되는 것은 아니다. 상기 커피는 원두커피 또는 인스턴트 커피일 수 있으며, 커피의 형태는 특별히 제한되지 않는다. 또한 구체적으로, 상기 커피는 노카페인 커피를 포함할 수 있다.In addition, specifically, the form of the food may be coffee, but is not limited thereto. The coffee may be ground coffee or instant coffee, and the form of the coffee is not particularly limited. In addition, specifically, the coffee may include no-caffeine coffee.
원두커피는 자메이카 블루마운틴, 인도네시아 토라자, 콜롬비아 수프리모, 과테말라 안티구아, 케냐 아라비카, 브라질 산토스, 에티오피아 모카 예가체프 등의 원두를 사용할 수 있다. 이러한 원두는 생두를 건조시켜, 로스팅 후에 분쇄하여 사용할 수 있으며, 로스팅은 생두를 가열하여 볶는 것으로, 커피 생두에 열을 가하여 생두 내부 조직에 물리적, 화학적 변화를 일으킴으로써 커피 특유의 맛과 향을 결정하는 가공처리이다.For coffee beans, you can use beans from Jamaica Blue Mountain, Indonesia Toraja, Colombia Souprimo, Guatemala Antigua, Kenya Arabica, Brazil Santos, Ethiopia Mocha Yegachev. These beans can be used by drying the green beans and grinding them after roasting, and roasting is by heating the green beans and roasting them.By applying heat to the green coffee beans, it causes physical and chemical changes in the internal structure of the green beans to determine the unique taste and aroma of coffee. It is a processing treatment.
인스턴트 커피는 원두커피에 당류 및 유지 등이 더 첨가될 수 있다. 이때, 당류는 백설탕, 포도당, 덱스트린, 과당, 올리고당, 프로폴리스, 트레할로스, 솔비톨, 자일리톨, 만니롤, 만티롤, 람니롤, 이노시롤, 에리스리롤, 파라티노스 및 쿠에르시롤 중 선택된 어느 하나 이상을 사용할 수 있다. 또한, 유지는 분유, 탈지분유 및 식물 성분말 중에서 선택된 어느 하나 이상을 사용할 수 있다. In the instant coffee, sugars and fats may be added to the coffee beans. At this time, the saccharide is any one selected from white sugar, glucose, dextrin, fructose, oligosaccharide, propolis, trehalose, sorbitol, xylitol, mannirol, mantyrol, ramnirol, inosyrol, erythrolol, paratinose, and quersirol You can use the above. In addition, the fat or oil may be used any one or more selected from powdered milk, skim milk powder, and plant ingredients.
본 발명의 레몬 추출물 및/또는 오렌지 추출물을 포함하는 커피는 커피에 의한 부작용 중 하나인 수면장애를 방지할 뿐 아니라, 카페인 과다 복용에 의한 신경 과다 활성을 억제시킬 수 있다. 특히, 상기 레몬 추출물 및/또는 오렌지 추출물 은 커피에 첨가되거나 포함됨으로써 커피 본연의 맛을 변질시키지 않으며, 카페인과 경쟁적으로 작용함으로써 카페인에 의해 유발될 수 있는 불면 효과를 최소화할 수 있다.Coffee containing the lemon extract and/or orange extract of the present invention not only prevents sleep disturbance, which is one of the side effects caused by coffee, but also inhibits neurological hyperactivity caused by an overdose of caffeine. In particular, the lemon extract and/or orange extract do not alter the original taste of coffee by being added to or included in coffee, and by acting competitively with caffeine, the insomnia effect that may be caused by caffeine can be minimized.
본 발명의 레몬 추출물 및/또는 오렌지 추출물을 첨가할 수 있는 식품은 상기 커피 뿐 아니라 소세지, 육류, 빵, 초콜릿류, 스넥류, 캔디류, 과자류, 라면, 피자, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있다. 음료수로 제형화할 경우에 본 발명의 레몬 추출물 및/또는 오렌지 추출물 외에 첨가되는 액체 성분으로는 이에 한정되지는 않으나, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 모노사카라이드(예, 포도당, 과당 등), 디사카라이드(예, 말토오스, 수크로오스 등) 및 폴리사카라이드(예, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당), 및 자일리톨, 소르비톨, 에리스리톨 등의 당 알코올일 수 있다.Foods to which the lemon extract and/or orange extract of the present invention can be added include not only coffee but also sausage, meat, bread, chocolate, snacks, candy, confectionery, ramen, pizza, other noodles, gums, and dairy including ice cream. There are products, various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexes. When formulated as a beverage, the liquid component added in addition to the lemon extract and/or orange extract of the present invention is not limited thereto, but may contain various flavoring agents or natural carbohydrates, etc. as an additional component like a conventional beverage. . The natural carbohydrates described above are monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.) and polysaccharides (e.g., common sugars such as dextrin, cyclodextrin, etc.), and xylitol, sorbitol. And sugar alcohols such as erythritol.
상기 식품의 종류는 식품 첨가제일 수 있으며, 상기 식품 첨가제는 식품의 제조, 가공, 또는 보존을 위해 식품에 첨가, 혼합, 침윤 기타의 방법에 의해 사용되는 물질을 의미한다. 상기 식품 첨가제는 천연물과 합성품이 있으며, 기능과 용도에 따라 분류할 수 있다. 현재 한국에 식품첨가물로 허가되어 있는 품목은 화학적 합성품 370여종, 천연첨가물 50여종이며, 주로 용도에 따라 보존료, 살균제, 산화방지제, 착색료, 발색제, 표백제, 조미료, 감미료, 착향료, 팽창제, 강화제, 개량제, 유화제, 증점제(호료) 및 안정제, 피막제, 껌 기초제, 소포제, 용제, 이형제, 방충제, 품질개량제와 기타 식품제조용 첨가제 등으로 분류되어 쓰이고 있다. The type of food may be a food additive, and the food additive refers to a substance used by a method such as adding, mixing, infiltrating or adding to food for the preparation, processing, or preservation of food. The food additives include natural products and synthetic products, and can be classified according to functions and uses. Currently, 370 kinds of chemical synthetic products and 50 kinds of natural additives are approved as food additives in Korea. Depending on the purpose, preservatives, fungicides, antioxidants, coloring agents, coloring agents, bleaching agents, seasonings, sweeteners, flavoring agents, expanding agents, reinforcing agents, and improving agents , Emulsifiers, thickeners and stabilizers, coating agents, gum base agents, defoaming agents, solvents, release agents, insect repellents, quality improvers and other additives for food manufacturing.
상기 식품첨가제의 형태는 분말, 과립, 정제, 캡슐 또는 액상 형태를 포함할 수 있으며, 상기 형태에 제한되는 것은 아니다.The form of the food additive may include a powder, granule, tablet, capsule or liquid form, but is not limited thereto.
또한, 상기 식품의 종류는 구체적으로 건강기능식품일 수 있다. 상기 건강기능 식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 증진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 유기산, 보호성 콜로이드 점증제, pH 조절제, 안정화제, 보존제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 또한, 본 발명의 건강기능식품은 과일 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 단독으로 또는 조합으로 사용될 수 있으며, 이러한 첨가제의 비율은 조성물 전체 중량당 0.001 내지 50 중량부의 범위에서 선택되는 것이 일반적이다.In addition, the type of food may specifically be a health functional food. The health functional foods include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavors, coloring agents and enhancers (cheese, chocolate, etc.), pectic acid and its salts, organic acids, protective colloidal growth It may contain an agent, a pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated beverages, and the like. In addition, the health functional food of the present invention may contain pulp for the manufacture of fruit and vegetable beverages. These components may be used alone or in combination, and the proportion of these additives is generally selected in the range of 0.001 to 50 parts by weight per total weight of the composition.
상기 건강기능식품은 식품의 생체 조절 기능을 강조한 식품으로 물리적, 생화학적, 생물공학적인 방법을 이용하여 특정 목적에 작용 및 발현하도록 부가가치를 부여한 식품이다. 이러한 건강기능 식품의 성분은 생체 방어와 신체 리듬의 조절, 질환의 방지 및 회복에 관계하는 신체 조절 기능을 생체에 대하여 충분히 발휘하도록 설계하여 가공하게 되며, 식품으로 허용 가능한 식품 보조 첨가제, 감미료 또는 기능성 원료를 함유할 수 있다. The health functional food is a food that emphasizes the biological regulation function of food, and is a food that has added value to act and express it for a specific purpose using physical, biochemical, and bioengineering methods. The ingredients of these health functional foods are designed and processed to sufficiently exert the body's control functions related to the body defense, regulation of body rhythm, prevention and recovery of diseases to the living body, and food supplementary additives, sweeteners, or functional foods acceptable as foods. It may contain raw materials.
본 발명의 레몬 추출물 및/또는 오렌지 추출물을 건강기능식품(또는 건강기능 음료 첨가물)으로 사용할 경우, 상기 레몬 추출물 및/또는 오렌지 추출물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용하고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 상기 레몬 추출물 및/또는 오렌지 추출물의 혼합량은 그의 사용 목적(예방, 건강 또는 개선, 치료적 처치)에 따라 적합하게 결정될 수 있다. When the lemon extract and/or orange extract of the present invention is used as a health functional food (or a health functional beverage additive), the lemon extract and/or orange extract is added as it is or used with other foods or food ingredients, and a conventional method It can be used appropriately according to. The amount of the lemon extract and/or orange extract mixed may be appropriately determined according to the purpose of use (prevention, health or improvement, therapeutic treatment).
본 발명의 다른 일 측면은 레몬 추출물 및 오렌지 추출물 중 어느 하나 이상을 포함하는, 카페인에 의한 수면장애의 예방 또는 치료용 약학적 조성물에 관한 것이다. 구체적으로, 상기 수면장애는 카페인에 의한 불면증 또는 일주기리듬 수면장애(circadian rhythm sleep disorders)인 것일 수 있다. Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating sleep disorders caused by caffeine, comprising any one or more of a lemon extract and an orange extract. Specifically, the sleep disorder may be caffeine-induced insomnia or circadian rhythm sleep disorders.
“수면장애”, “불면증”, “일주기리듬 수면장애” 는 상기 설명한 바와 같다. “Sleep disorder”, “insomnia”, and “circadian rhythm sleep disorder” are as described above.
구체적으로, 상기 레몬 추출물은 레몬 과피 추출물일 수 있다.Specifically, the lemon extract may be a lemon peel extract.
또한 구체적으로, 상기 오렌지 추출물은 오렌지 과피 추출물일 수 있다.In addition, specifically, the orange extract may be an orange peel extract.
본 발명의 약학적 조성물은 투여를 위하여, 상기 본 발명의 레몬 추출물 및/또는 오렌지 추출물 외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier, excipient, or diluent in addition to the lemon extract and/or orange extract of the present invention for administration. The carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.
또한, 본 발명의 약학적 조성물은 어떠한 제형으로도 적용가능하며, 보다 구체적으로 경구용 제형일 수 있다. 비경구용 제형으로는 주사용, 도포용, 에어로졸 등의 스프레이 형일 수 있다. In addition, the pharmaceutical composition of the present invention can be applied in any dosage form, and more specifically, may be an oral dosage form. The parenteral formulation may be a spray type such as injection, application, or aerosol.
본 발명의 조성물은 카페인에 의한 과다한 신경활성을 진정시킴과 동시에 수면장애를 개선시키는 효과를 나타내며, 특히 단시간에서의 카페인의 신경 활성을 억제하는 효과를 넘어서 카페인의 지속적 작용까지도 억제할 수 있음에 따라, 카페인에 의해 유도된 신경 활성을 안정시킴과 함께 수면장애를 개선시키는 용도로 널리 활용될 수 있다.The composition of the present invention has the effect of pacifying excessive neuronal activity caused by caffeine and at the same time improving sleep disorders. In particular, as it can inhibit the continuous action of caffeine beyond the effect of inhibiting the neurological activity of caffeine in a short time. , It can be widely used for improving sleep disorders while stabilizing the nerve activity induced by caffeine.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be deduced from the configuration of the invention described in the detailed description or claims of the present invention.
도 1은 7일령의 수컷 백서의 해마 절편 준비 과정을 보여주는 사진이다. (a)는 백서의 뇌 전체를 적출하는 과정을 보여주는 사진이며, (b)는 적출한 뇌로부터 해마 조직을 적출하는 과정을 보여주는 사진이며, (c)는 적출한 해마를 절편 후 인서트(insert)와 6-웰 플레이트(6-well plate)에 넣는 과정을 보여주는 사진이다.1 is a photograph showing the preparation process of a hippocampal section of a 7-day-old male white paper. (a) is a picture showing the process of extracting the entire brain of a white paper, (b) is a picture showing the process of extracting the hippocampal tissue from the extracted brain, and (c) is a picture of the extracted hippocampus after sectioning and inserting it. And 6-well plate (6-well plate) is a picture showing the process of putting.
도 2는 해마 절편의 MEA 셋팅 과정을 보여주는 사진이다. (a)는 MEA 하나의 탐침을 확대한 사진이며, (b)는 해마가 올려진 MEA에 증폭기(amplifier)가 연결된 사진이며, (c)는 해마 절편을 MEA에 올려놓은 사진이며, (d)는 어레이(array)에 위치한 각 해마의 영역을 표시한 사진이다. 2 is a photograph showing the MEA setting process of a hippocampal section. (a) is an enlarged picture of one probe of the MEA, (b) is a picture of an amplifier connected to the MEA on which the hippocampus is placed, (c) is a picture of a hippocampal slice placed on the MEA, and (d) Is a photograph showing the area of each hippocampus located in an array.
도 3은 마이크로일렉트로드 어레이(MEA) 실험 프로토콜(A) 및 band pass filter를 이용한 스파이크 검출 과정(B)을 나타낸 것이다.3 shows a microelectrode array (MEA) experimental protocol (A) and a spike detection process (B) using a band pass filter.
도 4는 레몬 추출물 처리시 카페인에 의한 신경 활성이 완화된 것을 확인한 결과를 나타낸 것이다(a: 카페인 단독 처리 및 카페인 및 레몬 추출물 처리시 워싱 전 신경 활성 비교, b: 카페인 단독 처리 및 카페인 및 레몬 추출물 처리시 워싱 후 신경 활성 비교)Figure 4 shows the results confirming that the nerve activity by caffeine was alleviated during the lemon extract treatment (a: comparison of nerve activity before washing when caffeine alone treatment and caffeine and lemon extract treatment, b: caffeine alone treatment and caffeine and lemon extract Comparison of nerve activity after washing during treatment)
도 5는 레몬 추출물 처리시 저-수준 스파이크(Low-level spike, lls) 및 고-수준 스파이크(high-level spike, hls) 검출 결과를 나타낸 것이다(a: 저-수준 스파이크(Low-level spike, lls) 검출 결과, b: 고-수준 스파이크(high-level spike, hls) 검출 결과)Figure 5 shows the results of detection of low-level spikes (lls) and high-level spikes (hls) during lemon extract treatment (a: low-level spike, lls) detection result, b: high-level spike (hls) detection result)
도 6은 오렌지 추출물 처리시 카페인에 의한 신경 활성이 완화된 것을 확인한 결과를 나타낸 것이다(a: 카페인 단독 처리 및 카페인 및 오렌지 추출물 처리시 워싱 전 신경 활성 비교, b: 카페인 단독 처리 및 카페인 및 오렌지 추출물 처리시 워싱 후 신경 활성 비교)Figure 6 shows the results confirming that the nerve activity by caffeine was alleviated when orange extract treatment (a: caffeine alone treatment and caffeine and orange extract treatment before washing nerve activity comparison, b: caffeine alone treatment and caffeine and orange extract Comparison of nerve activity after washing during treatment)
도 7은 오렌지 추출물 처리시 저-수준 스파이크(Low-level spike, lls) 및 고-수준 스파이크(high-level spike, hls) 검출 결과를 나타낸 것이다(a: 저-수준 스파이크(Low-level spike, lls) 검출 결과, b: 고-수준 스파이크(high-level spike, hls) 검출 결과)7 shows the results of detection of low-level spikes (lls) and high-level spikes (hls) when orange extract is treated (a: low-level spikes, lls) detection result, b: high-level spike (hls) detection result)
도 8은 레몬 및 오렌지 혼합 추출물 처리시 카페인에 의한 신경 활성이 완화된 것을 확인한 결과를 나타낸 것이다(a: 카페인 단독 처리시 워싱 전 후 신경 활성 비교, b: 레몬 및 오렌지 혼합 추출물 처리시 워싱 전 신경 활성 비교, c: 레몬 및 오렌지 혼합 추출물 처리시 워싱 후 신경 활성 비교)8 shows the results confirming that the nerve activity by caffeine was alleviated when the lemon and orange mixture extract was treated (a: comparison of nerve activity before and after washing when caffeine alone was treated, b: nerve before washing when treated with a lemon and orange mixture extract Activity comparison, c: Comparison of nerve activity after washing when treated with lemon and orange mixture extract)
도 9는 레몬 및 오렌지 혼합 추출물 처리시 저-수준 스파이크(Low-level spike, lls) 및 고-수준 스파이크(high-level spike, hls) 검출 결과를 나타낸 것이다(a: 저-수준 스파이크(Low-level spike, lls) 검출 결과, b: 고-수준 스파이크(high-level spike, hls) 검출 결과)9 shows the result of detection of a low-level spike (lls) and a high-level spike (hls) when the lemon and orange mixed extract is treated (a: low-level spike (Low- level spike, lls) detection result, b: high-level spike (hls) detection result)
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited by the following examples.
제조예 1. 레몬 과피 추출물의 제조Preparation Example 1. Preparation of lemon peel extract
레몬 과피(Gio Herb Co., Yangju, Korea) 100 g에 10배(w/v)의 증류수를 가하여 121℃에서 40분간 열수추출하였다. 추출액은 Whatman No. 1 필터 페이퍼 (Whatman International Ltd., Maidstone, UK)를 이용하여 여과하였으며, 걸러진 추출액은 농축기(Eyela Co., Tokyo, Japan)를 이용하여 40 ℃에서 5시간 동안 농축시켰다. 농축된 추출액은 동결건조기(Ilsin Bio Co., Yangju., Korea)로 -70 ℃, 5 mTorr에서 7일간 동결건조 시킨 후 글라인더(Ilsin Bio Co., Yangju., Korea)로 분쇄하여 실험에 이용하였다. 위의 과정을 통해 레몬 과피를 열수추출 하였을 때 수율은 9.8% 이다.10 times (w/v) of distilled water was added to 100 g of lemon peel (Gio Herb Co., Yangju, Korea), followed by hot water extraction at 121°C for 40 minutes. The extract is Whatman No. 1 Filtered using filter paper (Whatman International Ltd., Maidstone, UK), the filtered extract was concentrated for 5 hours at 40 ℃ using a concentrator (Eyela Co., Tokyo, Japan). The concentrated extract was freeze-dried for 7 days at -70°C and 5 mTorr with a freeze dryer (Ilsin Bio Co., Yangju., Korea), then pulverized with a grinder (Ilsin Bio Co., Yangju., Korea) for experiments. Was used. When the lemon peel is extracted with hot water through the above process, the yield is 9.8%.
[규칙 제91조에 의한 정정 13.01.2021]　
Figure WO-DOC-TABLE-1
 [Amendment 13.01.2021 under Rule 91]
Figure WO-DOC-TABLE-1
제조예 2. 오렌지 과피 추출물의 제조 오렌지 과피(Gio Herb Co., Yangju, Korea) 100 g에 10배(w/v)의 증류수를 가하여 121℃에서 40분간 열수추출하였다. 추출액은 Whatman No. 1 필터 페이퍼 (Whatman International Ltd., Maidstone, UK)를 이용하여 여과하였으며, 걸러진 추출액은 농축기(Eyela Co., Tokyo, Japan)를 이용하여 40 ℃에서 5시간 동안 농축시켰다. 농축된 추출액은 동결건조기(Ilsin Bio Co., Yangju., Korea)로 -70 ℃, 5 mTorr에서 7일간 동결건조 시킨 후 글라인더(Ilsin Bio Co., Yangju., Korea)로 분쇄하여 실험에 이용하였다. 위의 과정을 통해 오렌지 과피를 열수추출 하였을 때 수율은 9.8% 이다. Preparation Example 2. Preparation of orange peel extract 100 g of orange peel (Gio Herb Co., Yangju, Korea) was added 10 times (w/v) of distilled water, followed by hot water extraction at 121° C. for 40 minutes. The extract is Whatman No. 1 Filtered using filter paper (Whatman International Ltd., Maidstone, UK), and the filtered extract was concentrated at 40°C for 5 hours using a concentrator (Eyela Co., Tokyo, Japan). The concentrated extract was lyophilized for 7 days at -70°C and 5 mTorr with a freeze dryer (Ilsin Bio Co., Yangju., Korea), then pulverized with a grinder (Ilsin Bio Co., Yangju., Korea) for experiments. Was used. When the orange peel is extracted with hot water through the above process, the yield is 9.8%.
[규칙 제91조에 의한 정정 13.01.2021]　
Figure WO-DOC-TABLE-2
 [Amendment 13.01.2021 under Rule 91]
Figure WO-DOC-TABLE-2
실험예 3. 레몬 과피 및 오렌지 과피 혼합 추출물 제조 상기 제조예 1 및 2에서 제조된 레몬 과피 추출물 및 오렌지 과피 추출물을 1: 1 비율로 혼합하여 혼합 추출물을 제조하였다. Experimental Example 3. Preparation of lemon peel and orange peel mixed extract The lemon peel extract and orange peel extract prepared in Preparation Examples 1 and 2 were mixed in a ratio of 1: 1 to prepare a mixed extract.
실험예 1. 신경활성 측정Experimental Example 1. Measurement of nerve activity
1-1. 해마 조직 절편 배양(Hippocampal organotypic slice culture, HOSC)1-1. Hippocampal organotypic slice culture (HOSC)
박막을 사용하여 뇌 해마의 절편을 organotypic 배양하는 하는 방법은 이미 일반적으로 많이 사용하는 방법을 사용하였다. 구체적으로, 뇌 해마는 5일령에서 7일령 사이의 Sprague Dawley 흰 어린 쥐(Orientbio Co., Seungnam, Korea)로부터 적출하였고 조직 박절기를 이용하여 350μm 두께로 절편내었다(Mickle Laboratory Engineering Co., UK). 5조각에서 6조각을 0.4μm 구멍을 갖고 있는 박막 insert (Millicell-CM; Millipore, MA) 안에 배치한 후, 6-웰 플레이트(SPL Life Sciences Co., Korea)에 넣고 36°C 로 5% CO2(Dong-A Co., Seoul, Korea)를 유지하는 배양기에서 배양하였다. 배양액(MEM; Welgene, Gyeongsan, South Korea), 20mM HEPES (Sigma, St. Louis, Mo, USA), 25% Hank's balanced salt solution(HBSS; Welgene, Gyeongsan, South Korea), 6 g/L D-glucose(Sigma, St. Louis, Mo, USA), 1mM L-glutamine(Sigma, St. Louis, Mo, USA), 25% horse serum(Welgene, Gyeongsan, South Korea) 과 1% penicillin-streptomycin(Gibco BRL, USA), pH=7.1)은 이틀에 한번 씩 갈아주었고 배양 기간은 12~14일이며 이후 실험에 사용하였다(도 1).The method of organotypic culturing of the brain hippocampus slices using a thin film has already used a commonly used method. Specifically, the cerebral hippocampus was excised from Sprague Dawley white young rats (Orientbio Co., Seungnam, Korea) between 5 and 7 days old, and sliced to a thickness of 350 μm using a tissue slicer (Mickle Laboratory Engineering Co., UK). After placing 5 to 6 pieces in a thin film insert (Millicell-CM; Millipore, MA) with a 0.4 μm hole, put it in a 6-well plate (SPL Life Sciences Co., Korea) and 5% CO at 36°C. 2 (Dong-A Co., Seoul, Korea) was cultured in an incubator maintained. Culture solution (MEM; Welgene, Gyeongsan, South Korea), 20mM HEPES (Sigma, St. Louis, Mo, USA), 25% Hank's balanced salt solution (HBSS; Welgene, Gyeongsan, South Korea), 6 g/L D-glucose (Sigma, St. Louis, Mo, USA), 1mM L-glutamine (Sigma, St. Louis, Mo, USA), 25% horse serum (Welgene, Gyeongsan, South Korea) and 1% penicillin-streptomycin (Gibco BRL, USA), pH=7.1) was changed once every two days, and the culture period was 12 to 14 days, which was used in subsequent experiments (FIG. 1).
1-2. MEA 탐침으로 배양된 뇌해마 조직의 이동1-2. Migration of cerebral hippocampal tissue cultured with MEA probes
핀을 이용하여 배양된 뇌해마 절편을 배양 박막 insert로부터 조심스럽게 분리한 후, 0.01% 폴리에틸렌이민(polyethylenimine, Sigma, St. Louis, Mo, USA)으로 코팅된 직경 10 μm, 간격 100 μm인 8x8 마이크로일렉트로드 어레이(microelectrode array, MEA; Multi Channel Systems, Germany)에 올려놓았다. 절편은 멸균된 인공 척수용액(aCSF; 114 mM NaCl, 26 mM NaHCO3, 10 mM glucose, 3 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 20 mM HEPES, pH=7.4, Sigma, Louis, Mo, USA)에서 15 분 동안 5% CO2 및 95% O2 혼합가스 (Dong-A Co., Seoul, Korea)를 주입하며 33 °C를 유지한 상태로 안정화시켰다. 이후에 뇌 해마를 포함한 MEA를 MEA1060(Multi Channel Systems Inc., Reutlingen, Germany) 증폭장치에 장착하고, MEA 속 인공 척수용액은 Ag/AgCl 으로 접지를 시켰다. 이후에 실험하는 동안은 5% CO2 및 95% O2 혼합가스를 투입시킨 인공 척수 용액을 3 mL/min의 속도로 관류시켰으며, MEA와 인공 척수 용액은 33°C로 유지하였다(도 2).After carefully separating the cerebral hippocampal section cultured using a pin from the culture thin film insert, it was coated with 0.01% polyethyleneimine (polyethylenimine, Sigma, St. Louis, Mo, USA). Electrode array (MEA; Multi Channel Systems, Germany). Sections are sterile artificial spinal cord solution (aCSF; 114 mM NaCl, 26 mM NaHCO 3 , 10 mM glucose, 3 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 20 mM HEPES, pH=7.4, Sigma, Louis, Mo , USA) 5% CO 2 and 95% O 2 mixed gas (Dong-A Co., Seoul, Korea) was injected for 15 minutes and stabilized at 33 °C. After that, the MEA including the brain hippocampus was mounted on the amplification device of MEA1060 (Multi Channel Systems Inc., Reutlingen, Germany), and the artificial spinal cord solution in the MEA was grounded with Ag/AgCl. During the subsequent experiment, an artificial spinal cord solution into which a 5% CO 2 and 95% O 2 mixed gas was added was perfused at a rate of 3 mL/min, and the MEA and the artificial spinal cord solution were maintained at 33°C (Fig. 2). ).
*1-3. 레몬 과피 추출물의 신경 활성 측정 * 1-3. Measurement of nerve activity of lemon peel extract
안정화가 끝난 해마 조직을 3 분 동안 기록하였으며, 이후 1 mM의 카페인(Sigma, St. Louis, Mo, USA)이 포함된 인공 뇌척수액 또는 1mM 카페인 및 분석샘플(레몬 과피 추출물100 μg/ml, 200 μg/ml, 400 μg/ml)이 포함된 인공 뇌척수액을 각각 20 분 동안 동일한 조건으로 관류한 후 3분 기록하였고, 다시 인공 뇌척수액만으로 20 분간 워싱한 후 3분을 기록하여 총 9 분간의 데이터를 얻었다. Stabilized hippocampal tissue was recorded for 3 minutes, and then artificial cerebrospinal fluid containing 1 mM caffeine (Sigma, St. Louis, Mo, USA) or 1 mM caffeine and analysis samples (lemon peel extract 100 μg/ml, 200 μg) /ml, 400 μg/ml) were perfused under the same conditions for 20 minutes each, and then recorded for 3 minutes.After washing for 20 minutes with artificial cerebrospinal fluid alone, 3 minutes were recorded to obtain data for a total of 9 minutes. .
해마조직이 있는 MEA는 총 60개 채널을 통해 각 채널 당 25kHz의 sampling 속도로 데이터를 읽어내며, MC_Rack 및 MC_Data Tool (Multi Channel Systems, GmbH) 소프트웨어를 이용하여 컴퓨터를 통해 기록된다. 기록된 전체 신호들 중 의미있는 스파이크(spike)를 추출하기 위해 4단계의 band pass filter를 이용하였으며, 식은 아래와 같다.MEA with hippocampal tissue reads data at a sampling rate of 25 kHz for each channel through a total of 60 channels, and is recorded through a computer using MC_Rack and MC_Data Tool (Multi Channel Systems, GmbH) software. A band pass filter of 4 steps was used to extract meaningful spikes from all recorded signals, and the equation is as follows.
[식 1][Equation 1]
[규칙 제91조에 의한 정정 13.01.2021]　
Figure WO-DOC-MATHS-1
[Amendment 13.01.2021 under Rule 91]
Figure WO-DOC-MATHS-1
상기 식에서 X는 노이즈(noise)에 대한 실효값(RMS)을 나타내며, ĸ는 각 각의 임계값(threshold)을 결정하는 인자이다. 여기서는 총 3개의 인자로 임계값을 구성하였다(0.6, 1 및 3). ĸ값이 0.6이상인 경우 의미있는 스파이크(spike)로 하였으며, 이 때의 임계값은 -21.63 μV 이다. 이 과정은 60개 전 채널(channel)을 대상으로 MATLAB(Mathworks Inc., Natick, Massachusetts, USA) 프로그램을 이용하여 수행하였다(도 3). In the above equation, X represents an effective value (RMS) for noise, and ĸ is a factor that determines each threshold. Here, the threshold was composed of a total of 3 factors (0.6, 1 and 3). If the ĸ value is more than 0.6, it is set as a meaningful spike, and the threshold at this time is -21.63 μV. This process was performed using a MATLAB (Mathworks Inc., Natick, Massachusetts, USA) program for all 60 channels (FIG. 3).
이때, 스파이크(spike) 간 동기화 등에 의해 합종이 일어나는 현상을 구분하여 뇌의 생리활성을 살펴보기 위하여 저-수준 스파이크(Low-level spike, lls) 및 고-수준 스파이크(high-level spike, hls)를 구분하여 측정하였다. At this time, low-level spikes (lls) and high-level spikes (hls) in order to examine the physiological activity of the brain by classifying the phenomenon in which hybridization occurs due to synchronization between spikes, etc. Was measured separately.
그 결과, 레몬 과피 추출물(LP)의 카페인에 의한 신경 활성 완화 효과를 하기 표 3에 나타내었다.As a result, the effect of alleviating nerve activity by caffeine of lemon peel extract (LP) is shown in Table 3 below.
[규칙 제91조에 의한 정정 13.01.2021]　
Figure WO-DOC-TABLE-3
 [Amendment 13.01.2021 under Rule 91]
Figure WO-DOC-TABLE-3
구체적으로, 카페인을 처리한 경우 신경 활성이 증가되었으며, 카페인을 처리한 후 워싱하더라도 카페인의 작용이 지속되어 신경 활성이 200% 이상 증가되었다. 반면 카페인 및 레몬 과피 추출물을 함께 처리한 경우 카페인만 처리한 경우에 비해 신경 활성 정도가 현저히 감소되었으며, 카페인 단독 처리시와 달리 워싱한 후에도 신경 활성의 지속적 증가가 나타나지 않음에 따라 신경 활성의 유의적 증가 없이 유지되는 것을 확인하였다(도 4).또한, 스파이크 수준(level)에 따라 pre로 정규화하여, 레몬 추출물 농도 100 μg/ml, 200 μg/ml, 400 μg/ml에서 측정한 결과를 하기 표 4에 나타내었다.Specifically, when caffeine was treated, nerve activity was increased, and even after washing after caffeine treatment, the action of caffeine continued to increase nerve activity by 200% or more. On the other hand, when caffeine and lemon peel extract were treated together, the degree of neuronal activity was significantly reduced compared to caffeine-only treatment, and the neuronal activity was not significantly increased even after washing, unlike caffeine alone treatment. It was confirmed that it was maintained without an increase (FIG. 4). In addition, by normalizing to pre according to the spike level, the results measured at 100 μg/ml, 200 μg/ml, and 400 μg/ml lemon extract concentration are shown in the following table. It is shown in 4.
[규칙 제91조에 의한 정정 13.01.2021]　
Figure WO-DOC-TABLE-4
 [Amendment 13.01.2021 under Rule 91]
Figure WO-DOC-TABLE-4
신경의 공진화로 인한 신경 활동의 활성화를 저-수준 스파이크 및 고-수준 스파이크에서 모두 살펴본 결과, 살펴본 결과 레몬 과피 추출물이 카페인 신경 활성화를 완화시키는데 효능이 있음을 확인하였다(도 5).1-4. 오렌지 과피 추출물의 신경 활성 측정As a result of examining activation of neural activity due to neural co-evolution in both low-level spikes and high-level spikes, it was confirmed that lemon peel extract is effective in alleviating caffeine nerve activation (FIG. 5). . Measurement of nerve activity of orange peel extract
신경 활성 측정방법은 상기 1-3의 방법과 동일하며, 분석샘플로는 레몬 과피 추출물 대신에 오렌지 과피 추출물 100 μg/ml, 200 μg/ml, 400 μg/ml를 사용하였다.The nerve activity measurement method is the same as the method of 1-3 above, and as an analysis sample, 100 μg/ml, 200 μg/ml, and 400 μg/ml of orange peel extract were used instead of lemon peel extract.
그 결과, 오렌지 과피 추출물(OP)의 카페인에 의한 신경 활성 완화 효과를 하기 표 5에 나타내었다.As a result, the effect of alleviating nerve activity by caffeine of the orange peel extract (OP) is shown in Table 5 below.
[규칙 제91조에 의한 정정 13.01.2021]　
Figure WO-DOC-TABLE-5
 [Amendment 13.01.2021 under Rule 91]
Figure WO-DOC-TABLE-5
구체적으로, 카페인 및 오렌지 과피 추출물을 함께 처리한 경우 카페인만 처리한 경우에 비해 신경 활성 정도가 현저히 감소하였으며, 워싱한 후에는 카페인만 처리한 경우에는 카페인의 작용이 지속되어 신경 활성이 200%이상 증가한 결과와 반대로, 오렌지 과피 추출물의 농도 의존적으로 신경 활성 정도가 감소됨을 확인하였다(도 6).또한, 스파이크 수준(level)에 따라 오렌지 추출물 농도 100 μg/ml, 200 μg/ml, 400 μg/ml에서 측정한 결과를 하기 표 6에 나타내었다.Specifically, when caffeine and orange peel extract were treated together, the degree of neuronal activity was significantly reduced compared to when caffeine was treated, and after washing, caffeine-only treatment continued the action of caffeine, resulting in more than 200% neuronal activity. Contrary to the increased result, it was confirmed that the degree of nerve activity was decreased depending on the concentration of the orange peel extract (FIG. 6). In addition, the orange extract concentration 100 μg/ml, 200 μg/ml, 400 μg/ depending on the spike level. The results measured in ml are shown in Table 6 below.
[규칙 제91조에 의한 정정 13.01.2021]　
Figure WO-DOC-TABLE-6
 [Amendment 13.01.2021 under Rule 91]
Figure WO-DOC-TABLE-6
그 결과, 저-농도 스파이크 및 고-농도 스파이크 모두에서 오렌지 과피 추출물이 카페인 신경 활성화를 완화시킴을 확인하였다(도 7).1-5 레몬 과피 및 오렌지 과피 혼합 추출물의 신경 활성 측정 As a result, it was confirmed that the orange peel extract alleviates caffeine nerve activation in both the low-concentration spike and the high-concentration spike (FIG. 7). 1-5 Measurement of Neurological Activity of Lemon Peel and Orange Peel Mixed Extract
신경 활성 측정방법은 상기 1-3의 방법과 동일하며, 분석샘플로는 레몬 과피 및 오렌지 과피 혼합 추출물 200 μg/ml를 사용하였다.The method for measuring nerve activity was the same as the method of 1-3 above, and 200 μg/ml of a mixed extract of lemon peel and orange peel was used as the analysis sample.
그 결과, 레몬 과피 및 오렌지 과피 혼합 추출물의 카페인에 의한 신경 활성 완화 효과가 우수함을 확인하였다. 구체적으로 카페인만 처리한 경우 워싱하더라도 신경 활성이 200% 이상 지속되었으나, 레몬 과피 및 오렌지 과피 혼합 추출물을 처리한 경우 신경 활성 정도가 현저히 감소하였으며, 워싱 후에도 신경 활성 완화 효과가 지속됨을 확인하였다(도 8). 또한, 저-농도 스파이크 및 고-농도 스파이크 모두에서 레몬 및 오렌지 과피 혼합 추출물이 카페인 신경 활성화를 완화시킴을 확인하였다(도 9).As a result, it was confirmed that the extract of a mixture of lemon peel and orange peel has an excellent effect on alleviating nerve activity by caffeine. Specifically, when only caffeine was treated, nerve activity continued to be more than 200% even after washing, but when treated with a lemon peel and orange peel extract, the degree of nerve activity was significantly reduced, and it was confirmed that the nerve activity alleviating effect persisted after washing (Fig. 8). In addition, it was confirmed that the mixed extract of lemon and orange peel alleviates caffeine nerve activation in both the low-concentration spike and the high-concentration spike (FIG. 9).
상기 결과를 통해 레몬 과피 및/또는 오렌지 과피 추출물은 카페인으로 인한 신경 활성의 완화 효능이 뛰어남을 알 수 있다. From the above results, it can be seen that the lemon peel and/or orange peel extract has an excellent efficacy in alleviating nerve activity caused by caffeine.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that other specific forms can be easily modified without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative and non-limiting in all respects. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as being distributed may also be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the claims to be described later, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims (10)

  1. 레몬(Citrus limon) 추출물 및 오렌지(Citrus sinensis) 추출물 중 어느 하나 이상을 포함하는, 카페인에 의한 수면장애 예방 또는 개선용 식품 조성물.Lemon (Citrus limon) extract and orange (Citrus sinensis) containing any one or more of the extract, a food composition for preventing or improving sleep disorders caused by caffeine.
  2. 제1항에 있어서,The method of claim 1,
    상기 레몬 추출물은 레몬의 과피 추출물인 것을 포함하는, 식품 조성물.The lemon extract is a food composition comprising that of a lemon peel extract.
  3. 제1항에 있어서,The method of claim 1,
    상기 오렌지 추출물은 오렌지 과피 추출물인 것을 포함하는, 식품 조성물.The orange extract is a food composition comprising that of an orange peel extract.
  4. 제1항에 있어서,The method of claim 1,
    상기 추출물은 물, 알코올, 에틸아세테이트, 아세톤, 핵산, 디클로로메탄 또는 이들의 혼합 용매로 추출된 식품 조성물.The extract is a food composition extracted with water, alcohol, ethyl acetate, acetone, nucleic acid, dichloromethane, or a mixed solvent thereof.
  5. 제1항에 있어서,The method of claim 1,
    상기 수면장애는 카페인에 의한 불면증 또는 일주기리듬 수면장애(circadianrhythm sleep disorders)인 것인, 식품 조성물.The sleep disorder is caffeine-induced insomnia or circadianrhythm sleep disorders.
  6. 제1항에 있어서,The method of claim 1,
    상기 식품 조성물은 커피인 것인, 식품 조성물.The food composition is that of coffee, food composition.
  7. 제1항에 있어서,The method of claim 1,
    상기 식품 조성물은 식품 첨가제인 것인, 식품 조성물.The food composition will be a food additive, food composition.
  8. 레몬 추출물 및 오렌지 추출물 중 어느 하나 이상을 포함하는, 카페인에 의한 수면장애 예방 및 치료용 약학적 조성물.A pharmaceutical composition for preventing and treating sleep disorders caused by caffeine, comprising any one or more of a lemon extract and an orange extract.
  9. 제8항에 있어서,The method of claim 8,
    상기 레몬 추출물은 레몬의 과피 추출물인 것을 포함하는, 수면장애 예방 및치료용 약학적 조성물.The lemon extract is a pharmaceutical composition for preventing and treating sleep disorders, comprising that of a lemon peel extract.
  10. 제8항에 있어서,The method of claim 8,
    상기 오렌지 추출물은 오렌지 과피 추출물인 것을 포함하는, 수면장애 예방및 치료용 약학적 조성물.The orange extract is a pharmaceutical composition for preventing and treating sleep disorders, comprising that of an orange peel extract.
PCT/KR2020/014626 2019-10-25 2020-10-24 Composition for ameliorating sleep disorders caused by caffeine, containing lemon and orange extracts WO2021080393A1 (en)

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