WO2014069837A1 - Histamine receptor antagonist composition containing gamma oryzanol as active ingredient - Google Patents

Histamine receptor antagonist composition containing gamma oryzanol as active ingredient Download PDF

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WO2014069837A1
WO2014069837A1 PCT/KR2013/009500 KR2013009500W WO2014069837A1 WO 2014069837 A1 WO2014069837 A1 WO 2014069837A1 KR 2013009500 W KR2013009500 W KR 2013009500W WO 2014069837 A1 WO2014069837 A1 WO 2014069837A1
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sleep
gamma oryzanol
mg
histamine receptor
oryzanol
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PCT/KR2013/009500
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French (fr)
Korean (ko)
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조승목
한대석
김인호
이창호
윤민석
양혜진
김지영
성재영
백남인
진영호
박지해
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한국식품연구원
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/575Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A23B - A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105Plant extracts, their artificial duplicates or their derivatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/88Liliopsida (monocotyledons)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES
    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The present invention provides a novel use of gamma oryzanol as a histamine receptor antagonist. Gamma oryzanol is used as a natural antihistamine and can be used for preventing or treating allergic rhinitis, inflammatory bowel diseases, asthma, bronchitis, vomiting, stomach and duodenal ulcer, gastoesophegal reflux diseases, sleep disturbance, anxiety, and depression, and has the advantages of further reducing sleep latency, increasing sleep time, and increasing non-REM sleep time. Gamma oryzanol is a natural product derived from rice bran and does not cause side effects such as cognitive impairment, resistance, or dependence even after long-term use.

Description

Histamine receptor antagonist composition of the gamma oryzanol as an active ingredient

The present invention relates to a novel use as histamine receptor antagonists of gamma oryzanol, and allergic rhinitis for rice, rice bran or rice husk extract as an active ingredient; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And a process for the prevention or treatment a pharmaceutical composition or food composition of the depression.

Sleep occupies a third of human life and is a very important element in the most fundamental and essential to maintaining healthy physiology and mental stability. Chronic lack of sleep and disorder exerts a negative effect on cardiovascular disease and high blood pressure, memory and learning, metabolism and body weight, immunity and resistance to cancer, diabetes, accidents, mood, the overall physical and mental health. Currently, there are 30% of the world's population experience insomnia, 10% have problems with sleep disturbance enough to suffer chronic and recent significant rise.

US National Sleep Association, according to a survey of the (National Sleep Foundation USA, 2008), which is about 50% of US adults experience at least one insomnia a week, not the 50% of Americans satisfied with their sleep that was not investigated. The recent go Insomnia and sleep disorders prevalence of domestic quickly close to the level of advanced countries the number of patients with sleep disorders treatment appeared in 1,000 people 50,000 years 2001 to 228,000 people in 2008 it was recently increased 8 years 4.5 times (NHIC, 2009 ).

In the case of a domestic situation did not yet mothamyeo interest in high water, which is recognized as a thought, especially handageona undergo medical treatment and disease formation. On the other hand, according to the statistics, and about 15% of adults have known that medication is necessary because insomnia caused by anxiety, insomnia cause by stress, tension, fear, etc. vary, and the benzodiazepine to treat drug benzodiazepine-based drugs and used about the effect of serotonin, etc. However, these drugs, however, there is a long-term failure (cognitive impairment), immunity, severe side effects that the dependency is a problem that the formation when using. Due to the lower of these pharmacological side effects or dependency in the United States have been used as antihistamine (antihistamine) and this natural herbal product nonprescription sleep aids, especially antihistamines are typical components of the cold medicines as antagonists for the histamine receptors, intake just purchased without a doctor's prescription there used to be the only sleeping pill that can do it.

Histamine [2- (4-imidazolyl) ethylamine] is a body, for example, one of the operating neurotransmitter which is widely distributed throughout the gastrointestinal tract [Burks 1994 in Johnson LR ed., Physiology of the Gastrointestinal Tract, Raven Press, NY, pp. 211-242]. Histamine gastric acid secretion, intestinal motility [see:. Leurs et al, Br J. Pharmacol. 1991, 102, pp 179-185], vasomotor responses, intestinal inflammatory responses and allergic reactions [see:. Raithel et al, Int. Arch. Allergy Immunol. 1995, 108, 127-133] and a variety of pathophysiological events (pathophysiological event) to adjust the Reference like:. Panula et al, Proc. Natl. Acad. Sci. USA 1984, 81, 2572-2576; Inagaki et al., J. Comp. Neurol 1988, 273, 283-300]. To date, histamine mediates all its action in all four families of histamine receptors, the histamine H 1, H 2, H 3 and H 4 receptors through the central nervous system and in peripheral regions. Histamine receptors and above in connection with the allergic and immune responses, gastric acid secretion, such as in the H 1, H 2, H 3 and H 4 receptor agonists alone or in combination, and allergic rhinitis, inflammatory bowel disease, asthma, bronchitis, vomiting duodenal ulcer or GERD, it is known is associated with relax (sedative), and sleep inducing that in the brain.

The gamma oryzanol (gamma-oryzanol) are the triterpene alcohols obtained etc. rice bran, corn, barley used as a combination of ester compounds, maintain and keep-containing antioxidant in food, lowers the blood glucose (Korea Patent No. 0496019 No.), Blood lowering cholesterol (PHYTOTHERAPY RESEARCH 15, 277-289 (2001 )), menopausal symptoms, and mitigates symptoms such as abdominal pain, it has been reported to promote the growth of humans and animals. However, the correlation of gamma oryzanol and histamine receptor antagonists relations, and further allergy rhinitis, allergic diseases such as asthma, and not known about the correlation between disease, sleep, anxiety or depression associated with excessive acid secretion yet.

The present invention relates to a histamine receptor antagonist, allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And to discover the ingredients of natural origin that can replace existing drugs that have been used for the prevention or treatment of depression for the purpose.

In addition, the present invention aims to discover the ingredients of natural origin that can be used as a sleep disorder, anxiety or prevent or food composition for improvement of depression.

The present invention provides a histamine receptor inhibitory pharmaceutical composition comprising the gamma-oryzanol to the achievement of the first task as an active ingredient.

In the histamine receptor inhibitory pharmaceutical composition of the present invention, a pharmaceutical composition for the inhibition of histamine receptor activity is allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And it may be for the prevention or treatment of depression.

In the present invention the histamine receptor inhibitory pharmaceutical composition for the prophylaxis or treatment of a sleep disorder may be for a decrease in the elevation, time, an increase in sleep duration, or an increase in nonrem sleep.

In the histamine receptor inhibitory pharmaceutical composition of the present invention, the gamma oryzanol can be extracted from rice bran.

The present invention provides a sleep disorder, anxiety, or for preventing or food composition for improving depression through histamine receptor activity, including inhibition of gamma oryzanol, as an active ingredient for the achievement of the second task.

In the sleep disorder of the present invention, or preventing anxiety or food composition for improving depression, prevention or improvement of the sleep disorder may be for a decrease in the elevation, time, an increase in sleep duration, or an increase in nonrem sleep.

From sleep disorders, anxiety, or for preventing or food composition for improving depression of the present invention, the gamma oryzanol can be extracted from rice bran.

Gamma oryzanol provides a substantially increased effect of reduction in the same level of elevation of time and sleep duration and the dock sepin hydrochloride conventionally known a histamine H 1 antagonist, in particular all of the diazepam is nonrem sleep and REM sleep are used by conventional opiates as compared to the increase, gamma oryzanol is to increase only the surface of the water nonrem Alternatively it is possible to improve the quality of sleep, histamine receptor antagonists, prior art dock sepin hydrochloride histamine receptor agonist is 2-pyridyl ethylamine dihydrochloride effects known as by the inhibition of the surface effect of gamma oryzanol in a similar mechanism to that completely inhibited, side effects that act as a natural antihistamine and, as derived from the natural products of rice bran such that the even long-term use disorders (cognitive impairment), are resistant or dependence no.

Figure 1a in order to determine the type and amount of the histamine H 1 and H 3 receptor antagonist used as a positive control, pentobarbital sleeping dose (45 mg / kg, ip) venom sepin hydrochloride for elevation time of treated mice and a graph showing the effect of God Kone, Figure 1b is a graph showing a dock sepin hydrochloride and Kone god effect on the sleep time of pentobarbital sleeping dose (45 mg / kg, ip) administration of a mouse. The control group (0.5% CMC- brine 10 mL / kg), DH (10, 20, 30, 40 mg / kg) and CS (6.25, 12.5, 25, 50 mg / kg) oral administration (po) and after 45 minutes It was administered pentobarbital. Each graph shows the mean values ​​(means ± SEM, n = 10). * At p <0.05 compared to control, * means as compared with the control group p <that this is significantly different from 0.01 (Dunnet's test). C is control; DH is poison sepin hydrochloride; CS is the KONE God stands.

Figure 2a pentobarbital sleeping capacity is a graph showing the effect of rice bran origin single compound on elevation hours (45 mg / kg, ip) the administration of a mouse, Figure 2b pentobarbital sleep dose (45 mg / kg, the graph shows the effect of rice bran derived from single compounds on sleeping time of mice administered the ip). Each graph shows the mean values ​​(means ± SEM, n = 10). * At p <0.05 compared to control, * means as compared with the control group p <that this is significantly different from 0.01 (Dunnet's test). CON is the control group; DH is poison sepin hydrochloride; OZ gamma oryzanol; The OC oktakosanol; MA, myristic acid; SA is a stearic acid; PA is palmitic acid; OA is oleic acid; LA, linoleic acid; And LNA stands for linolenic acid.

Figure 3a pentobarbital sleeping capacity is a graph showing the effect of gamma oryzanol for elevation time of the mouse administered with (45 mg / kg, ip), Figure 3b pentobarbital sleep dose (45 mg / kg, ip) a a graph illustrating the effect of gamma-oryzanol to the sleep time of mice administered. The control group (0.5% CMC- brine 10 mL / kg), DH (30 mg / kg) and gamma oryzanol (10, 25, 50, 100 mg / kg) for oral administration (po) administered pentobarbital after 45 minutes It was. Each graph shows the mean values ​​(means ± SEM, n = 10). * At p <0.05 compared to control, * means as compared with the control group p <that this is significantly different from 0.01 (Dunnet's test). CON is the control group; DH denotes a dock sepin hydrochloride.

Figure 4a will showing the elevation time of the histamine receptor agonists (PD) administration for the antagonist (DH) acting on the gamma oryzanol (OZ) and histamine receptors, Figure 4b acting on the gamma oryzanol (OZ) and histamine receptor a graph showing sleeping time of the histamine receptor agonists (PD) administration for the antagonist (DH). Control group (CON, 0.5% CMC- brine 10 mL / kg), OC (100 mg / kg), the DH (30 mg / kg) administration of pentobarbital (hypnotic dosage 45 ㎎ / ㎏) 45 minutes before was orally administered. In addition, agonist PD was intraperitoneally injected in advance (ip) with 150 mg / kg administered orally 10 minutes before OZ and DH. * At p <0.05 compared to control, * means as compared with the control group p <that this is significantly different from 0.01 (Dunnet's test). CON is the control group; DH is poison sepin hydrochloride; PD denotes a 2-pyridyl ethylamine dihydrochloride. ## means that a significant difference between the p <group at 0.01 (Unpaired Student's t-test ).

Figure 5a is gamma oryzanol for gamma oryzanol (OZ, 200 mg / kg) graph, Figure 5b nonrem and REM sleep architecture in a C57BL / 6N mouse showing the effect of the elevation time in C57BL / 6N mice (OZ, 200 mg a graph showing the effect of / kg). Each graph shows the mean (± SEM, n = 8). * Is compared with the control means p <0.05 and that this is, significantly different (Dunnet's test). CON represents the control group, DPZ represents the diazepam used as the positive control, DPZ is treated with 6 mg / kg.

6 is a graph showing through histamine H 1 receptor-deficient mice and sleep mechanism of action the surface structure analysis of wild-C57B / 6 mouse gamma oryzanol (OZ, 200 mg / kg) using a type. The graph represents the mean value (± SEM, n = 8), * is compared with the control means p <0.05 and that this is, significantly different (Dunnet's test). CON is the control group; WT is the wild type C57B / 6 mice; H 1 KO represents a histamine H1 receptor-deficient mice.

Gamma oryzanol represents a substantially increased effect of reduction in the same level of elevation and time of sleep duration and the dock sepin hydrochloride conventionally known histamine H 1 and H 3 antagonist. Additionally, the effect of the surface of the water completely inhibited as oktakosanol a similar mechanism by which conventional histamine receptor antagonist effect of the sleep dock sepin hydrochloride, known as histamine receptor agonist 2-pyridyl ethylamine dihydrochloride (2-pyridylethylamine dihydrochloride) is suppressed and , it acts as a natural antihistamine. Therefore, gamma oryzanol is a histamine receptor antagonist, allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And it can be used as a preventive or active ingredients for the treatment of depression composition, particularly useful as sleep disorders, anxiety, or a composition for prevention or treatment of depression. Unlike conventional opiates gamma oryzanol can be used as a component harmless to the human body, which is approved as a food, so not only no side effects elevations induced effects and surface extending effect is excellent useful for the prevention or treatment of a sleep disorder, anxiety or depression have. In an embodiment of the present invention, experiments for anxiety or depression, although not performed separately, for example, as diazepam, the ingredients used for the improvement of sleep disorders, the prophylaxis or treatment is the improvement of anxiety or depression by changing the dose , can be used for the prevention or treatment it is well known to those skilled in the art.

"Agonist" in the present invention, if there is no other explanation histamine receptors, the H 1 receptor, H 2 receptor, the H 3 receptor and interacts with the H 4 receptor, and activate the histamine receptor, physiology or pharmacology of the receptor enemy a substance for initiating reaction characteristics, "antagonist" is but competitive binding to the receptor at the same site as agonists, do not activate the intracellular response initiated by the active form of the receptor, whereby the intracellular responses by agonists the means substances which can be suppressed.

The present inventors as histamine receptor antagonists, allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And is effective in the prevention or treatment of depression was tried to prepare a high natural composition. As a result, the gamma oryzanol, thereby completing the present invention by acting as histamine receptor antagonists and, in particular, identifying that there is a preventive or therapeutic efficacy of sleep disorders, anxiety or depression.

The invention allergic rhinitis including a novel use as histamine receptor antagonists of gamma oryzanol, rice, rice bran or rice husk extract as an active ingredient; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And allergic rhinitis for the prevention or treatment a pharmaceutical composition of the depression, comprising administering a therapeutically effective amount of gamma oryzanol the target object; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And it provides a method of preventing or treating depression.

In the present invention, referred to the improvement of sleep disorders, treatment or prevention can mean a reduction in the elevation of time, an increase in the duration of sleep or increase of nonrem sleep.

In the present invention, the gamma oryzanol rice bran is to be obtained, etc., raw materials, purification method and the manufacturing method is not particularly limited, and may be used for commercial gamma oryzanol is marketed.

On the other hand, it is meant to include an amount sufficient to achieve the specification is the efficacy or the activity of gamma oryzanol, comprising as an active ingredient "in the term. In one embodiment of the invention, as in the composition of the present invention, gamma oryzanol, for example, more preferably, 0.001 mg / kg or more, preferably 0.1 mg / kg or more, more preferably 10 mg / kg or more, It is contained 100 mg / kg or more, more further preferably 250 mg / kg or more, and most preferably from 0.1 g / kg or more. Gamma-oryzanol is overdose and side effects are not a quantitative upper limit of the gamma oryzanol contained in the composition of the present invention to the human body as a natural product can be carried out by any person skilled in the art to select in the proper range.

The pharmaceutical compositions of this invention can be prepared using the adjuvants that are suitable as a pharmaceutical in addition to the active ingredient and a physiologically acceptable, in the adjuvant excipients, disintegrants, sweeteners, binders, coating agents, swelling agent, lubricant, and the like can be used lubricants or flavoring agents.

The pharmaceutical composition may include the above-described acceptable carrier in addition to the additional pharmaceutically active ingredient for administration to at least one and preferably formulated as pharmaceutical compositions.

Formulation form of the pharmaceutical composition may be a granule, powder, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops or injectable solutions and the like. For example, for a formulation in the form of tablets or capsules, the active ingredient may be combined with an acceptable inert carrier in an oral, non-toxic pharmaceutical, such as ethanol, glycerol, water. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, glucose or beta-natural sugars such as lactose, corn sweetener, acacia, natural and synthetic gums such as tracker kaenseu or sodium oleate, sodium stearate, magnesium stearate, sodium and the like benzoate, sodium acetate, sodium chloride. Disintegrants include, but are not limited to, include starch, methylcellulose, agar, bentonite knit, xanthan gum and the like.

As in an acceptable pharmaceutical carrier in compositions to be formulated as liquid solution, sterilized and as suitable for the living body, saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and of these components it may be used by mixing one or more ingredients may be added other conventional additives such as antioxidants, buffers, bacteriostatic agents, if necessary. It can also be added to the diluent, dispersant, surfactant, binder and lubricant additionally formulated into aqueous solutions, suspensions, injectable formulations, pills, capsules, granules or tablets, such as emulsions.

By further using the art disclosed by way of a suitable method to Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA can be preferably formulated according to each disease or component according to.

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

A suitable dose of the pharmaceutical composition of the invention may vary by the formulation method, administration method, patient's age, body weight, sex, diseased condition, food, administration time, administration route, excretion rate and response sensitivity and the like factors, a skilled physician will usually effective dose for the treatment or prevention of hope can readily determine and prescribe. According to a preferred embodiment of the invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-10 g / ㎏.

The pharmaceutical compositions of the present invention is prepared in unit dosage form by formulated, using carriers and / or excipients that are pharmaceutically acceptable according to a method that can be carried out to facilitate self having ordinary skill in the art the instant invention by or in the intergranular dose container can be made. The formulation is a solution of oil or aqueous medium, or a suspension or emulsion form and may be X, powders, granules, tablet or capsule, may further comprise a dispersion agent or a stabilizer.

The invention also provides a sleep disorder, anxiety, or for preventing or food composition for improving depression, including gamma oryzanol as an active ingredient.

Food composition according to the invention are formulated in the same way as the pharmaceutical composition can be used or added to various foods as a functional food. The food can be added to the composition of the present invention include, for example, beverages, alcoholic beverages, confectionery, diet bars, if dairy products, meat, chocolate, pizza, and other noodles, gum, ice cream, vitamin complex, health supplement foods and the like.

Food compositions of the present invention as well as the active ingredient as gamma oryzanol, may include a component that is typically added to when the food production, include, for example, proteins, carbohydrates, fats, nutrients, seasoning agents and flavoring agents. Examples of the above carbohydrate are monosaccharide, e.g., glucose, fructose and the like; Disaccharides, such as maltose and sucrose, oligosaccharides and the like; And a poly saccharide, such as dextrin, sugar alcohol such as a conventional sugar and xylitol, sorbitol, erythritol, such as cyclodextrins. As flavorings may be natural flavors [thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.]), and synthetic flavors (saccharin, aspartame, etc.). For example, in the case of the invention the food composition is made of drinks and beverages, there can further include a citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts, such as in addition to the gamma oryzanol of the present invention.

The present invention provides a dietary supplement comprising a sleep disorder, anxiety, or a food composition for the prevention or amelioration of depression, including the gamma oryzanol as an active ingredient. Health as a food is, to produce the gamma-oryzanol as drinks, teas, spices, gums, added to the food material in confectioneries such, or encapsulated, powdered, suspensions, including food, to bring health specific effects if ingested them meaning one, unlike generic drugs to food as a raw material has the advantage of no side effects that can occur during long-term use of the drug. Thus, functional food of the present invention is obtained, it is extremely useful since it is possible to routinely ingested. The amount of gamma oryzanol in such dietary supplement is the subject and can not be unconditionally defined as dependent on the kind of health food, and the addition in a range that does not impair the food original taste, usually 0.01 with respect to the target food to 50% by weight it decided, preferably in the range of 0.1 to 20% by weight. In addition, a pill, a case of granules, tablet or capsule form of a dietary supplement there is it supposed to usually 0.1 to 100% by weight, preferably added in the range of 0.5 to 80% by weight. In an embodiment, the dietary supplement of the invention may be pills, tablets, capsules or in the form of drink.

The present invention also provides the use of gamma oryzanol for the manufacture of a medicament or food for the prevention of sleep disorders, anxiety or depression, treatment or improvement. Gamma oryzanol as described above may be used for the purposes of prevention, treatment or amelioration of a sleep disorder, anxiety or depression.

In another aspect, the present invention provides a sleep disorder, anxiety or prevention of depression, treatment or amelioration method comprising: administering an effective amount of gamma-oryzanol to the mammal.

As used herein, the term "mammal" means a mammal that is the subject of treatment, observation or experiment, preferably it refers to a human.

The term "effective amount" as used herein to mean the amount of active ingredient, or a pharmaceutical composition for inducing a researcher, veterinarian, medical doctor or other clinical jojikgye is thought by the animal or the biological or medical response in a human, which is the including the amount of inducing relief of symptoms of a disease or disorder. Effective amount and administration number of times for the active ingredient of the present invention will be varied according to the desired effect will be apparent to those skilled in the art. Therefore, the optimum dosage of to be administered may be readily determined by one skilled in the art, the type of disease, severity of the disease, the amount of the active ingredient and other ingredients contained in the composition, the type of formulation, and the age, body weight, general health state, it can be adjusted depending on the sex, diet, time of administration, route of administration and the ratio of composition, treatment period, a variety of factors, including the drug to be used simultaneously. In the prevention, treatment or amelioration method of the present invention, in the case of adults, it is desirable to administer a dose of gamma oryzanol once a day to several times during administration, 0.001 g / kg to about 10 g / kg.

Composition comprising the gamma oryzanol in the treatment method of the present invention as an active ingredient in oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, ocular conventional manner through the site or intradermal route It can be administered.

Methods of accomplishing the advantages and features of the present invention and reference to the embodiments that are described later in detail will be apparent. However, the invention is not limited to the embodiments set forth herein be embodied in many different forms, but the present embodiments are to complete the disclosure of the present invention, ordinary skill in the art will to those provided to indicate that the full scope of the invention, the present invention will only be defined by the appended claims.

Animals

ICR mice (18-22 g, male), and C57BL / 6N mice (28-30 g, male) are then adapted to a week breeding box for animals receiving pre-sale (main) core TEX were used in the experiments. Breeding of animals, the temperature 23 ± 1 ℃, humidity of 55 ± 5%, people-arm period - took place (people 9:00 AM 21:00), under the terms of illuminance 3000 Lux, were fed diets and negative freedom. All animals were maintained according to experiments using animals Korea Food Research Institute Animal Care Committee (KFRI-IACUC, Korea Food Research Institutional Animal Care and Use Committee) guidelines.

Pentobarbital induced sleep test (Pentobarbital-induced sleep test)

Pentobarbital sleep induction experiments were conducted within a period of time between 5:00 to 1:00 pm, it was used after fasting for 24 hours before the 10 mice (n = 10) per test group. All samples were produced using a 0.5% saline solution of CMC- pentobarbital administered orally administered to the mice (po) 45 minutes before. Normal control group was treated with 0.5% CMC- saline solution at a concentration of 10 mL / kg.

In order to determine the type and amount of the histamine H 1 and H 3 receptor antagonist used as a positive control group, the control group (0.5% CMC- brine 10 mL / kg), DH ( 10, 20, 30, 40 mg / kg) , and CS ( orally (po) of 6.25, 12.5, 25, 50 mg / kg) and was administered pentobarbital after 45 minutes via intraperitoneal injection (ip). DH is a poison sepin hydrochloride (Doxepin hydrochloride), CS is the abbreviation of the new Kone (Conessine). After the treatment pentobarbital move the respective object in independent spaces elevation time (sleep latency) and sleep (sleep duration) were measured. Elevation time was set as the elapsed time until you lose at least 1 minute to specular (righting reflex) after intraperitoneal injection of pentobarbital, sleep duration was set at the time until you recover the specular reflection. Mice did not show behavioral sleep after 10 minutes after administration of pentobarbital were excluded from the experiment.

Check the pentobarbital sleeping capacity effect of poison sepin hydrochloride and Kone content god for elevation time and sleeping time (45 mg / kg, ip) the administration of a mouse, are shown in Figures 1a and 1b, respectively. The positive control result and the contents were applied to the test after the set to dock sepin hydrochloride 30 mg / kg.

Sleep Structure Analysis

C57BL / 6N mouse (28-30 g) of the electrode insertion operation was performed after one week adapted for measuring brain waves (Electro- encephalogram, EEG) and electromyogram also (Electromyogram, EMG). Mouse anesthetized with pentobarbital (50 mg / kg, ip) and were fixed in a stereotactic head crisis (stereotaxic instrument). After cutting the curd subcutaneous connective tissue was inserted Mouse EEG / EMG Headmount (Pinnacle Technology Inc, Oregon, USA) for the EEG and EMG measurement. It was then secured and sealed with dental cement for dental. Conduct disinfection of surgical and antibiotic treatment for three days was to prevent the inflammation caused by surgery, it kept the seven days recovery period. It was measured 4 days before administration of the 0.5% CMC-saline solution used in the control group orally (po) to adapt to the measurement environment was induced to conform to the experimental procedures by connecting the recording apparatus. EEG and EMG using the stabilized sample 5 minutes after oral administration and then PAL-8200 series (Pinnacle Technology Inc, Oregon, USA) was measured for 12 hours from 09:00 to 21:00. The EEG and EMG sampling rate is set to 200 Hz, and (epoch time: 10 s), EEG is 0.1-25 Hz, EMG was recorded data to set a filter area of ​​10-100 Hz. Surface structure analysis was performed by a fast Fourier transform (FFT) algorithm, was used SleepSign program (Ver. 3.0, Kissei Comtec, Nagono, Japan). The results are wake, REM sleep are shown, separated by:: (0.65-4 Hz non-rapid eye movement, delta band) (rapid eye movement, theta band 6-10 Hz), NREM sleep. Sleep latency (the elevation time) was set at the time of NREM sleep epoch s units 10 appears taken as more than 12 times in a row.

Experimental Example 1 Using rice bran origin single compound pentobarbital sleep induction experiments

In order to determine whether it refers to benzo by diazepin receptor antagonistic action for histamine receptors than the combination so bar confirming indicates the surface effect, the physiologically active substance contained in the rice bran also sleep effect - the inventors are rice bran extract GABA A pen was performed Toba slope sleep induction test.

From rice bran origin single compound analysis of the surface effect of conventional gamma oryzanol, and fatty acid oktakosanol sleep effects are not known. Gamma oryzanol, tri sour oktakosanol and myristic acid, stearic acid, palmitic acid, oleic acid, linoleic acid and fatty acids such as linolenic acid, 50 mg / kg for oral administration (po) and intraperitoneal pentobarbital after 45 minutes injection (ip ) by administration through, showing the elevation of time and sleeping time of mice was measured in Figures 2a and 2b, respectively. Figures 2a and 2b in Fig OZ is gamma oryzanol; The OC oktakosanol; MA, myristic acid; SA is a stearic acid; PA is palmitic acid; OA is oleic acid; LA, linoleic acid; And LNA stands for linolenic acid.

From the results of Fig. 2a oktakosanol, myristic acid, stearic acid and linolenic acid was confirmed to represent the Elevation time reducing effect equivalent to the dock sepin hydrochloride, it was confirmed that the elevation, time reduction effect even in the case of gamma oryzanol.

Also that this is a result of gamma oryzanol, oktakosanol, myristic acid, palmitic acid, was confirmed oleate refers to increasing sleep effect equivalent to the dock sepin hydrochloride, increased sleep time in the case of stearic acid and linolenic acid effects from Figure 2b It was OK.

Experiments to determine the gamma oryzanol is that this is a time effective to reduce the elevation and sleep time is extended from the result, and determine the elevation of time reduction and surface Late effects and sleep architecture, and sleep mechanism according to the content of gamma-oryzanol was performed.

Experimental Example 2: Using a gamma oryzanol pentobarbital sleep induction experiments

By gamma oryzanol (TOKYO CHEMICAL INDUSTRY, CO., LTD., 95%) for 10, 25, 50 and 100 mg / a concentration of kg after oral administration (po) pentobarbital (45 mg / kg, ip) the sleep inducing effects were analyzed.

As a result, as can be seen in Figure 3a, the more the content of the gamma oryzanol increase showed a tendency to decrease in elevation, time, showed significantly reduced the elevation h at 25 mg / kg or more levels (p <0.01 ).

Also it was born tend to sleep increase appeared the more the addition amount of oktakosanol increased, as shown in Figure 3b, showed a significant increase of the sleeping time in the 25 mg / kg concentration (p <0.05), 100 mg / kg concentration in the dock sepin hydrochloride 30 mg / kg and significant increase of the sleeping time was equal level (p <0.05).

Experimental Example 3: effect of sleep mechanisms of gamma oryzanol

Sleep inducing effects of the histamine receptor antagonist is inhibiting the effect by a histamine receptor agonist. In the present experimental example was using the antagonist (Doxepin hydrochloride, DH) and agonists (2-pyridylethylamine dihydrochloride, PD) acting on these histamine receptors determine the mechanism of action of gamma oryzanol.

Histamine receptor agonist 2-pyridyl ethylene amine dihydrochloride (PD) is gamma oryzanol 100 mg / kg In order to examine the effects of the sleep inducing effect of oktakosanol, DH antagonists are 30 mg / kg pentobarbital administration (hypnotic dosage was administered orally 45 ㎎ / ㎏) 45 minutes before, agonist PD is in advance intraperitoneal injection of 150 mg / kg OZ, DH orally administered 10 minutes before to measure the elevation, time (sleep latency) and sleep (sleep duration) .

The experimental results, as can be seen in Figures 4a and 4b, the surface effect of the antagonists of the histamine receptors DH was completely inhibited by the agonist PD. In addition, gamma oryzanol (OZ), the effect was inhibited as in the DH by the histamine receptor agonist in PD.

In the above results, gamma oryzanol was identified to represent a surface effect by the antagonistic action on histamine receptors.

Experimental Example 4: surface structure analysis using a gamma oryzanol

Gamma oryzanol (OZ) 200 mg / kg, diazepam (DZP) 6 mg / kg after the oral administration are shown in Figure 5a the elevation time. The average elevation time of normal control group was 39.9 minutes was the elevation of the gamma oryzanol time was shortened by about 25.7 minutes to 14.2 minutes. The elevation time of diazepam used as the positive control than was reduced from about 12.6 minutes.

The nonrem and REM sleep time in C57BL / 6N mice are shown in Fig. 5b by analysis. Nonrem sleep in gamma oryzanol administration group was approximately 2-fold increase of 111 minutes compared to normal control group, REM sleep was about 3.4 min decreased. In contrast diazepam group used as the positive control group was nonrem sleep yieoteuna about 1.8 times increase of 112 minutes compared to the normal control group similarly to the gamma oryzanol group, REM sleep is rather was noticed an increase significantly compared to the normal control group by about 8.2 minutes. This shows that compared to the diazepam used as the conventional opiates that are likely to gamma oryzanol rather improve the quality of sleep.

Experimental Example 6: histamine H 1 mechanism sleep action of gamma oryzanol Using receptor deficient mice

Gamma oryzanol (OZ) the surface structure analysis was carried out by using the sleep mechanism of action of histamine H 1 receptor-deficient mice, and C57B / 6 wild-type mice to see the. Experimental results, in the wild-type C57B / 6 mice were confirmed that it was a gamma oryzanol (OZ, 200 mg / kg) is nonrem sleep in group about 2.4 times increase in 79 minutes as compared to normal control group As can be seen in Fig. However, histamine H 1 receptor-deficient mice in the sleep promoting effects were not similar to the OZ group and normal control group. In the above results, gamma oryzanol was identified to represent a surface effect by the antagonistic action on histamine receptors.

To be described a preparation example of a composition containing gamma-oryzanol to the present invention to, is only intended to describe in detail the invention is not intended to limit it.

Preparation of Formulation 1. Powder

Gamma oryzanol in Experimental Example 2 20 mg

Lactose 100 mg

Talc 10 mg

By mixing the above components and filled in airtight to prepare a powder.

Preparation of Formulation Example 2 Tablets

Gamma oryzanol in Experimental Example 2 10 mg

100 mg Corn starch

Lactose 100 mg

2 mg of magnesium stearate

After mixing the ingredients of the tablets prepared according to the method of manufacturing the appointed other conventional purification.

Formulation Example 3. Preparation of capsules

Gamma oryzanol in Experimental Example 2 10 mg

Crystalline cellulose 3 mg

Lactose 14.8 mg

Magnesium stearate 0.2 mg

According to a conventional capsule production method of mixing the components above and filled in a gelatin capsule to prepare a capsule.

Preparation of Formulation Example 4 Injection

Gamma oryzanol in Experimental Example 2 10 mg

Mannitol 180 mg

Injectable sterile distilled water 2974 mg

Na 2 HPO 4, 12H 2 O 26 mg

According to the conventional method for preparing injections are prepared as components the amount of the per ampoule.

Preparation Example 5. Preparation of solutions

Gamma oryzanol in Experimental Example 2 20 mg

10 g per isomerization

Mannitol 5 g

Purified water q.s.

Each dissolved the components were added an appropriate amount of lemon flavor from the following mixture of the above components, and then purified water to the mixture and then adjusting the whole was added to purified water to total 100 and filled in a brown bottle sterilized in purified water according to the conventional method for preparing liquid preparation and thereby producing a solution.

Preparation Example 6. Preparation of health food

Gamma oryzanol in Experimental Example 4 1,000 mg

Vitamin mixture proper quantity

Vitamin A acetate 70 ㎍

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

Vitamin B12 0.2 ㎍

Vitamin C 10 mg

Biotin 10 ㎍

1.7 mg nicotinamide

Folic Acid 50 ㎍

Calcium pantothenate 0.5 mg

Mineral mixture suitable amount

Ferrous sulfate 1.75 mg

0.82 mg zinc oxide

25.3 mg Magnesium carbonate

No. 1 15 mg potassium phosphate

No. 2 55 mg Calcium Phosphate

Potassium citrate 90 mg

100 mg calcium carbonate

24.8 mg Magnesium chloride

The composition ratio of the vitamin and mineral mixtures are however the composition mixed to conduct relatively dietary preferred suitable ingredient in foods for example, and also mubang carried transform the mixing ratio optionally, mixing the above components according to conventional health food preparation method and then, to prepare a granule, it can be used to manufacture dietary supplement composition according to a conventional method.

Preparation Example 7. Preparation of Functional Beverage

Gamma oryzanol in Experimental Example 4 1,000 mg

Citric acid 1,000 mg

Oligosaccharide 100 g

Japanese apricot concentrate 2 g

Taurine 1 g

It was added to purified water Total 900 mL

A mixture of components of the in accordance with a conventional health beverage preparation method, and then, approximately one was heated and stirred at 85 ℃ for a time, after sterilization and sealed obtained in 2 L vessel and filtered to sterilize the created solution is stored in a refrigerator, and then the It is used in a functional beverage composition of the invention produced.

The composition is also relatively mubang but suitable components for beverages to the preferred embodiment of mixing the composition, according to regional and national symbols such demand layer, a demand country, use purpose modified the mixing ratio optionally performed.

The present invention is gamma oryzanol a may be used for histamine receptor inhibitory pharmaceutical composition prepared comprising as an active ingredient, and gamma oryzanol the surface of the water through the histamine receptor activity inhibition comprising as an active component failure, the prevention of anxiety or depression, or for improvement it may be used in a food composition prepared.

Claims (7)

  1. Histamine receptor inhibitory pharmaceutical composition comprising the gamma oryzanol as an active ingredient.
  2. The method of claim 1, wherein the histamine receptor inhibitory pharmaceutical composition for allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Stomach and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And the histamine receptor inhibitory pharmaceutical composition, characterized in that for the prevention or treatment of depression.
  3. 3. The method of claim 2,
    The prevention or treatment of sleep disorders are the histamine receptor inhibitory pharmaceutical composition, characterized in that for a reduction in the elevation of time, an increase in sleep duration, or an increase in non-REM sleep.
  4. According to claim 1,
    The gamma oryzanol is a pharmaceutical composition for inhibiting the histamine receptor activity, characterized in that the extracted from rice bran.
  5. Gamma oryzanol a sleep disorder by inhibiting the histamine receptor activity comprising as an active ingredient, anxiety, or preventing or improving the food composition of the depression.
  6. 6. The method of claim 5,
    The prevention of sleep disturbances or improvement of the decrease elevation, time, sleep disorders, anxiety, or food composition for the prevention or amelioration of depression, characterized in that for an increase in growth or non-REM sleep duration.
  7. The method of claim 8,
    The Gamma oryzanol is a sleep disorder characterized that extracted from rice bran, anxiety or food composition for the prevention or amelioration of depression.
PCT/KR2013/009500 2012-10-30 2013-10-24 Histamine receptor antagonist composition containing gamma oryzanol as active ingredient WO2014069837A1 (en)

Priority Applications (2)

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WO (1) WO2014069837A1 (en)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Gamma oryzanol for treating menopausal disorder(Embryo bud of rice)", 18 January 2012 (2012-01-18), Retrieved from the Internet <URL:http://parksa.net/148554662> *
CICERO, A. F. ET AL.: "Rice Bran Oil and y-Oryzanol in the Treatment of Hyperlipoproteinaemias and Other Conditions", PHYTOTHERAPY RESEARCH, vol. 15, 2001, pages 277 - 289 *

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