KR20140057705A - A composition for histamine receptor antagonist comprising polycosanol as an effective ingredient - Google Patents

Abstract

The present invention provides new uses of polycosanol as a histamine receptor antagonist. The polycosanol is used as a natural anti-histamine agent which can be used for preventing or treating allergic rhinitis; inflammatory bowel disease; asthma; bronchitis; vomiting; stomach and duodenal ulcers; gastro-oesophageal reflux; sleep disorders; anxiety; and depression, and has an effect for reducing an increased hypnagogue time and increasing a sleep time. The polycosanol is a natural product derived from rice, sugar cane, wheat or sorghum, thereby has no side effects, which develop cognitive impairment, tolerance, or dependence, even for a long-term use.

Description

[0001] The present invention relates to a histamine receptor antagonist composition comprising policosanol as an active ingredient,

The present invention relates to a novel use of policosanol as a histamine receptor antagonist, and also relates to an allergic rhinitis comprising rice, rice bran or rice hull extract as an active ingredient; Inflammatory bowel disease; asthma; bronchitis; throw up; Gastric and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And pharmaceutical compositions or food compositions for the prevention or treatment of depression.

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

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

In Korea, there is not much interest in sleeping, and especially, there is no awareness of medical treatment or illness. On the other hand, according to statistics, about 15% of adults are known to need medication due to insomnia due to anxiety symptoms. Insomnia is caused by various factors such as stress, tension, and fear. Drugs include benzodiazepines Serotonin antagonists, etc. However, there is a serious problem in that cognitive impairment, tolerance, and dependence are formed when these drugs are used for a long period of time. In the United States, antihistamines and natural herbal products are used as non-prescription sleeping aids because of their low pharmacological side effects and dependence. In particular, antihistamines are antagonists to histamine receptors and are representative of cold medicines. It is the only sleeping pills that can be used.

Histamine [2- (4-imidazolyl) ethylamine] is one of the actinic neurotransmitters widely distributed throughout the body, for example, throughout the gastrointestinal tract [Burks 1994 in Johnson LR ed., Physiology of the Gastrointestinal Tract, Raven Press, NY, pp. 211-242]. Histamine has been implicated in gastric acid secretion, intestinal motility (Leurs et al., Br J. Pharmacol. 1991, 102, pp 179-185], vasomotor system response, intestinal inflammatory response and allergic response (Raithel et al., Int. Arch. Allergy Immunol. 1995, 108, 127-133) (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 of its actions in both the central nervous system and peripheral regions through the histamine receptors of the four families, the histamine H ₁ , H ₂ , H ₃ and H ₄ receptors. 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 gastroesophageal reflux, sedative in the brain and induction of sleep.

Policosanol is a long-chain aliphatic primary alcohol derived from sugarcane, rice bran, beeswax, wheat, or millet, and is mainly derived from the bottom layer of a cereal grains or an embryo. In addition, policosanol is a fruit outer shell (apple, It is obtained by saponifying wax extracted from other plants and then refining. In addition to octacosanol, policosanol contains tetracosanol (C24: 0), hexacosanol (C26: 0), heptacosanol (C27: 0) It also contains nonacosanol (C29: 0), triacontanol (C30: 0), dotriacontanol (C32: 0) and tetra triacontanol (C34: 0).

Policosanol has a good effect on the lipid composition in the blood, such as lowering the total cholesterol and LDL-cholesterol levels in the serum, reducing platelet coagulation, improving the exercise performance of patients with coronary artery disease, ≪ / RTI > However, the correlation between policosanol and histamine receptor antagonists, and furthermore, allergic rhinitis such as allergic rhinitis, asthma, diseases associated with gastric acid secretion, sleep, anxiety or depression have not been disclosed.

The present invention relates to histamine receptor antagonists, including allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Gastric and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And to identify ingredients derived from natural materials that can replace conventional drugs that have been used in the prevention or treatment of depression.

The present invention also aims to discover components derived from natural materials which can be used as a food composition for preventing or ameliorating sleep disorders, anxiety or depression.

The present invention provides a pharmaceutical composition for inhibiting histamine receptor activity comprising policosanol as an active ingredient for achieving the first object.

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

In the pharmaceutical composition for inhibiting histamine receptor activity of the present invention, the prevention or treatment of the sleep disorder may be for reducing the onset time or for increasing the sleep duration.

In the pharmaceutical composition for inhibiting histamine receptor activity of the present invention, the policosanol may be a long chain primary alcohol having 24 to 36 carbon atoms.

In the pharmaceutical composition for inhibiting histamine receptor activity of the present invention, the policosanol is selected from tetracosanol, hexacosanol, heptacosanol, octacosanol, nonacosanol, triacontanol, tetrythiaconanol and tetracycline Any one or a mixture of two or more.

In the pharmaceutical composition for inhibiting histamine receptor activity of the present invention, the policosanol may contain at least 30% by weight of octacosanol.

In the pharmaceutical composition for inhibiting histamine receptor activity of the present invention, the policosanol may be extracted from rice bran, rice bran oil or rice hull.

The present invention provides a food composition for preventing or ameliorating sleep disorder, anxiety or depression through inhibition of histamine receptor activity comprising policosanol as an active ingredient for achieving the second object.

In the food composition for preventing or ameliorating the sleep disorder, anxiety or depression of the present invention, the prevention or improvement of the sleep disorder may be for the reduction of the onset time or the increase of the sleep duration.

In the food composition for preventing or ameliorating the sleep disorder, anxiety or depression of the present invention, the policosanol may be a long chain primary alcohol having 24 to 36 carbon atoms.

In a food composition for preventing or ameliorating sleep disorders, anxiety or depression according to the present invention, the policosanol is selected from the group consisting of tetracosanol, hexacosanol, heptacosanol, octacosanol, nonacosanol, triacontanol, ≪ / RTI > and mixtures thereof.

In the food composition for preventing or ameliorating the sleep disorder, anxiety or depression of the present invention, the policosanol may contain at least 30% by weight of octacosanol.

In the food composition for preventing or ameliorating the sleep disorder, anxiety or depression of the present invention, the policosanol may be extracted from rice bran, rice bran oil or rice hull.

Policosanol provides a reduction in facial time and an increase in sleep duration, which is almost the same level as conventionally known histamine H1 and H3 antagonist, poison sepin hydrochloride, and the effect of toxin hydrochloride, known in the art as a histamine receptor antagonist, The effect of policosanol on the sleeping effect is suppressed by the same mechanism that is completely inhibited by 2-pyridylethylamine dihydrochloride, which is an agonist, and it acts as a natural antihistamine agent. It originates from natural rice bran and the like, cognitive impairment), no side effects that result in resistance or dependence.

FIG. 1A shows the effect of poisonic sterol hydrochloride on the facial time of mice treated with pentobarbital water (45 mg / kg, ip) dose and the concentration of horseradish peroxidase FIG. 1B is a graph showing the effect of poison sephin hydrochloride and conesine on the sleeping time of a mouse administered with pentobarbital water (45 mg / kg, ip). After 45 minutes of oral administration (po), control (0.5% CMC-saline 10 mL / kg), DH (10,20,30,40 mg / kg) and CS (6.25,12.5,25,50 mg / kg) Pentovaval was administered. Each graph represents the mean value (means ± SEM, n = 10). * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. C is the control; DH is a toxin sulphine hydrochloride; CS is the abbreviation of KONE.
FIG. 2A is a graph showing the effect of a single compound derived from rice bran on the surface time of a mouse administered with pentobarbital water surface dose (45 mg / kg, ip), FIG. 2B is a graph showing the effect of pentobarbital water surface dose (45 mg / kg, ip) on the sleeping time of mice treated with rice bran. Each graph represents the mean value (means ± SEM, n = 10). * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. CON is the control; DH is a toxin sulphine hydrochloride; OZ is gamma oryzanol; OC is octacosanol; MA is myristic acid; SA is stearic acid; PA is palmitic acid; OA is oleic acid; LA is linoleic acid; And LNA is abbreviation for linolenic acid.
Fig. 3 (a) is a graph showing the effect of octacosanol on the elevation time of mice administered with pentobarbital water surface dose (45 mg / kg, ip) Lt; RTI ID = 0.0 &gt; octacosanol < / RTI &gt; on the sleeping time of the administered mice. Pentobarbital was administered 45 minutes after oral administration (po) of control (0.5% CMC-saline 10 mL / kg), DH 30 mg / kg and octacosanol 10, 25, 50, 100 mg / . Each graph represents the mean value (means ± SEM, n = 10). * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. CON is the control; DH represents dorsepepin hydrochloride.
FIG. 4A is a graph showing the time taken for the administration of a histamine receptor agonist (PD) to octacosanol (OC) and an antagonist (DH) acting on histamine receptors. FIG. 4B shows the effect of octacosanol (OC) DH) of the histamine receptor agonist (PD). Control group (CON, 0.5% CMC-saline 10 mL / kg), OC (100 mg / kg) and DH (30 mg / kg) were orally administered 45 minutes before pentobarbital administration (hypnotic dosage 45 mg / kg). In addition, agonist PD was intraperitoneally injected (ip) 150 mg / kg 10 minutes before oral administration of OC and DH. * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. CON is the control; DH is a toxin sulphine hydrochloride; PD represents 2-pyridylethylamine dihydrochloride. ## indicates that there is a significant difference between the experimental groups at p <0.01 (Unpaired Student's t-test).
FIG. 5A is a graph showing the effect of policosanol on the time of face of a mouse administered with pentobarbital water surface dose (45 mg / kg, ip), and FIG. 3B is a graph showing the effect of pentobarbital water surface dose (45 mg / Lt; RTI ID = 0.0 &gt; policosanol < / RTI &gt; on the sleeping time of the administered mice. Pentobarbital was administered 45 minutes after oral administration (po) of control (0.5% CMC-saline 10 mL / kg), DH 30 mg / kg and policosanol 10, 25, 50, 100 mg / . Each graph represents the mean value (means ± SEM, n = 10). * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. CON is the control; DH represents dorsepepin hydrochloride.
Figure 6a shows the time of facialization due to administration of the histamine receptor agonist (PD) to policosanol (PC) and antagonist (DH) acting on the histamine receptor. Figure 4b shows the effect of policosanol (PC) DH) of the histamine receptor agonist (PD). Control group (CON, 0.5% CMC-saline 10 mL / kg), PC (100 mg / kg) and DH (30 mg / kg) were orally administered 45 minutes before pentobarbital administration (hypnotic dosage 45 mg / kg). In addition, agonist PD was intraperitoneally injected 150 mg / kg 10 minutes before oral administration of PC and DH. * Indicates p <0.05 compared to the control, ** indicates that there is a significant difference (Dunnet's test) at p <0.01 compared to the control. CON is the control; DH is a toxin sulphine hydrochloride; PD represents 2-pyridylethylamine dihydrochloride. ## indicates that there is a significant difference between the experimental groups at p <0.01 (Unpaired Student's t-test).

In the present invention, &quot; agonist &quot;, when not otherwise indicated, interacts with histamine receptors, i.e., the H ₁ receptor, the H ₂ receptor, the H ₃ receptor and the H ₄ receptor to activate the histamine receptor and inhibit the physiological or pharmacological &Quot; antagonist &quot; is a substance that competitively binds to a receptor at the same site as the agonist, does not activate the intracellular response initiated by the active form of the receptor, thereby inhibiting intracellular response by the agonist Of the material.

As histamine receptor antagonists, the present inventors have found that allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Gastric and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And to produce a natural composition highly effective for the prevention or treatment of depression. As a result, the present invention has been completed by confirming that policosanol acts as a histamine receptor antagonist, and in particular, has an effect of preventing or treating sleep disorders, anxiety or depression.

The present invention relates to a novel use of policosanol as a histamine receptor antagonist, an allergic rhinitis comprising rice, rice bran or rice hull extract as an active ingredient; Inflammatory bowel disease; asthma; bronchitis; throw up; Gastric and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And a pharmaceutical composition for the prevention or treatment of depression, an allergic rhinitis comprising administering to a subject a therapeutically effective amount of policosanol; Inflammatory bowel disease; asthma; bronchitis; throw up; Gastric and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And a method of preventing or treating depression.

In the present invention, improvement of sleep disorder, prevention or treatment may mean reduction of the time of the sleeping face and increase of the sleeping time.

In the following examples, policosanol exhibits approximately the same level of decrease in facial time and increase in sleep duration as conventionally known histamine H1 and the H3 antagonist, poison sepin hydrochloride. In addition, the sleep effect of policosanol is suppressed by the same mechanism that the sleep effect of toxin hydrochloride known as histamine receptor antagonist is completely inhibited by histamine receptor agonist 2-pyridylethylamine dihydrochloride , And acts as a natural antihistamine agent. Policosanol is therefore a histamine receptor antagonist; it is an allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Gastric and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And compositions for the prevention or treatment of depression, and is particularly useful as a composition for preventing or treating sleep disorders, anxiety or depression. Unlike conventional sleeping pills, policosanol is harmless to human body, which is approved as a food, and has not only side effects, but also has excellent induction effect on the surface and prolonged sleeping effect, so that it can be effectively used for preventing or treating sleep disorders, anxiety or depression . In the examples of the present invention, an experiment for anxiety or depression was not performed separately. However, for example, ingredients used for improvement, prevention, or treatment of sleep disorders, such as diazepam, , Prophylactic or therapeutic, as is well known to those skilled in the art.

In the present invention, the policosanol may be a mixture of long chain primary alcohols having 24 to 36 carbon atoms, which are usually derived from rice bran, sorghum, beeswax, wheat or sorghum, or a fraction of these long chain primary alcohols, It means all the separated and purified isolates. For example, policosanol may be any one or a mixture of two or more selected from among tetracosanol, hexacosanol, heptacosanol, octacosanol, nonacosanol, triacontanol, tetryriacontanol and tetratriacontanol. Of these, the octacosanol content is at least 30 wt%, preferably at least 50 wt%, more preferably at least 80 wt%, even more preferably at least 90 wt%. The policosanol may also be derived from rice bran, sorghum, beeswax, wheat or millet, preferably from rice bran or rice bran oil.

By the term &quot; comprising as an active ingredient &quot; is meant herein to include an amount sufficient to achieve the efficacy or activity of policosanol. In one embodiment of the invention, the policosanol in the composition of the present invention is administered in an amount of, for example, 0.001 mg / kg or more, preferably 0.1 mg / kg or more, more preferably 10 mg / kg or more, More preferably 100 mg / kg or more, still more preferably 250 mg / kg or more, and most preferably 0.1 g / kg or more. Since policosanol has no adverse effect on human body even when it is administered in an excessive amount as a natural product, the quantitative upper limit of policosanol contained in the composition of the present invention can be selected by a person skilled in the art within a suitable range.

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

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

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

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

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

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

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

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

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

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

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

The present invention provides a health functional food comprising a food composition for preventing or ameliorating sleep disorders, anxiety or depression comprising policosanol as an active ingredient. A health functional food is a food prepared by adding policosanol to a food material such as beverage, tea, spice, gum, confectionery, or by encapsulation, powdering, suspension, etc., Unlike ordinary drugs, there is no side effect that can occur when a drug is used for a long period of time using food as a raw material. The health functional food of the present invention thus obtained is very useful because it can be ingested routinely. The amount of policosanol to be added to such a health functional food can not be uniformly determined depending on the kind of the health functional food. However, it may be added within a range that does not impair the original taste of the food, To 50% by weight, preferably 0.1 to 20% by weight. In the case of health functional foods in the form of pills, granules, tablets or capsules, they may be added usually in the range of 0.1 to 100% by weight, preferably 0.5 to 80% by weight. In one embodiment, the health functional food of the present invention may be in the form of a pill, tablet, capsule or beverage.

The invention also provides the use of policosanol for the manufacture of a medicament or food for the prevention, treatment or amelioration of sleep disorders, anxiety or depression. As mentioned above, policosanol may be used for the prevention, treatment or amelioration of sleep disorders, anxiety or depression.

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

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

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

The composition comprising policosanol as an active ingredient in the treatment method of the present invention can be administered orally in a usual manner via oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, percutaneous, topical, can do.

Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below. The present invention may, however, be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Is provided to fully convey the scope of the invention to those skilled in the art, and the invention is only defined by the scope of the claims.

Experimental animal

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

Pentobaby  Sleep induction experiment Pentobarbital - induced sleep test )

The pentobarbital sleep induction experiment was conducted within a certain time from 1 pm to 5 pm, and 10 mice (n = 10) per group were used after fasting for 24 hours before the experiment. All samples were prepared using 0.5% CMC-saline solution and administered orally (p.o.) to mice 45 minutes before pentobarbital administration. In the normal control group, 0.5% CMC-saline solution was treated at a concentration of 10 mL / kg.

(10, 20, 30, 40 mg / kg) and CS (6.25, 30 mg / kg) to determine the type and content of histamine H1 and H3 receptor antagonists to be used as positive control. 12.5, 25, 50 mg / kg) was orally administered (po) and after 45 minutes, pentobarbital was administered via intraperitoneal injection (ip). DH is Doxepin hydrochloride, and CS is Conesine. After the pentobarbital treatment, each individual was moved to a separate space to measure sleep latency and sleep duration. The time of the elevation was set as the elapsed time until the righting reflex was lost for more than 1 minute after the peritoneal injection of pentobarbital, and the sleeping time was set as the time until the regular reflection was restored again. Mice that did not show sleep behavior after 10 minutes of pentobarbital administration were excluded from the experiment.

The effect of the dose of venezepine hydrochloride and conesine on the time of face and sleeping time of mice administered with pentobarbital water (45 mg / kg, ip) was confirmed and shown in FIGS. 1A and 1B, respectively. As a result, the positive control group and the content thereof were set to 30 mg / kg of the toxin hydrochloride, and then applied to the experiment.

Experimental Example  1: Using a single compound derived from rice bran Pentobaby  Sleep induction experiment

The present inventors confirmed that the rice bran extract exhibited a sleeping effect by antagonizing the histamine receptor rather than the GABAA-benzodiazepine receptor binding. Therefore, in order to confirm whether the physiologically active substances contained in rice bran also exhibit a sleeping effect, Tobacco slope induction experiment was conducted.

Among the single compounds derived from rice bran, the sleep effects of gamma orizanol, octacosanol and fatty acids, which have not been previously known for their sleeping effects, were analyzed. After 45 minutes oral administration (po) of 50 mg / kg of fatty acids such as gamma orizanol, tricine, octacosanol and myristic acid, stearic acid, palmitic acid, oleic acid, linoleic acid and linolenic acid, pentobarbital was intraperitoneally injected ip ), And the surface time and the sleeping time of the mice were shown in Figs. 2A and 2B, respectively. 2A and 2B, OZ is gamma oruzanol; OC is octacosanol; MA is myristic acid; SA is stearic acid; PA is palmitic acid; OA is oleic acid; LA is linoleic acid; And LNA is abbreviation for linolenic acid.

From the results shown in FIG. 2A, it was confirmed that octacosanol, myristic acid, stearic acid and linolenic acid showed the same effect of reducing the facade time as that of the toxinsin hydrochloride, and that the effect of decreasing the facade time was also observed in the case of gamma oryzanol.

In addition, from the results of FIG. 2B, it was confirmed that gamma oruzanol, octacosanol, myristic acid, palmitic acid, and oleic acid showed the same sleeping time increasing effect as that of poisoned sephin hydrochloride, and stearic acid and linolenic acid also increased sleeping time Respectively.

From the above results, experiments were carried out to confirm the sleeping time reduction effect, sleeping time extension effect and sleep mechanism according to the contents of octacosanol and policosanol.

Experimental Example  2: Octacosanol  Used Pentobaby  Sleep induction experiment

Pentavaval (45 mg / kg, ip) was orally administered (po) to octacosanol (Sigma-Aldrich, St. Louis, MO, USA, purity 99%) at 10, 25, 50 and 100 mg / Induced sleep induction.

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

In addition, as shown in FIG. 3B, the sleeping time tended to increase with the addition of octacosanol, and the sleeping time was significantly increased at the concentration of 50 mg / kg ( p <0.05) ( P <0.05), which is equivalent to the dose of 30 mg / kg of poisoned sephrin hydrochloride.

Experimental Example  3: Octacosanol  Sleep mechanism

The effect of the histamine receptor antagonist on the sleep-inducing effect is inhibited by histamine receptor agonists. In this experiment, the mechanism of action of octacosanol was confirmed by using an antagonist (Doxepin hydrochloride, DH) and an agonist (2-pyridylethylamine dihydrochloride, PD) acting on the histamine receptor.

To investigate the effect of 2-pyridylethyleneamine dihydrochloride (PD), a histamine receptor agonist, on the sleep-inducing effect of octacosanol, octacosanol 100 mg / kg and antagonist DH 30 mg / kg were administered by hypnotic dosage 45 mg / kg) was administered orally for 45 minutes. The efficacy of PD was 150 mg / kg, and the sleep latency and sleep duration were measured by intraperitoneal injection 10 minutes before the oral administration of OC or DH.

As a result of the experiment, as shown in FIGS. 4A and 4B, the sleep effect of DH, an antagonist of the histamine receptor, was completely inhibited by PD, which is an agonist. In addition, octacosanol (OC) was inhibited by PD, a histamine receptor agonist, as well as DH.

In the above results, it was confirmed that octacosanol has a sleeping effect by antagonizing the histamine receptor.

Experimental Example  4: Policosanol  Used Pentobaby  Sleep induction experiment

Octacosanol was a long-chain primary alcohol with 28 carbon atoms. In order to determine whether policosanol other than octacosanol or octacosanol-containing policosanol showed similar sleep effects to octacosanol, we conducted a sleep induction experiment using policosanol.

Policosanol is a product of GNC (General Nutrition Corporation, Pittsburgh, Pa.), And its content is 10 mg of policosanol per capsule.

In Experimental Example 2, oral administration (p.o.) at 10, 25, 50 and 100 mg / kg was performed using policosanol instead of octacosanol, and the effect of pentobarbital (45 mg / kg, i.p.

As a result, as shown in FIG. 5A, the incidence time decreased with increasing the content of policosanol, and the incidence time decreased significantly at the concentration of 25 mg / kg or higher ( p <0.05) .

In addition, as shown in FIG. 5B, as the addition amount of policosanol increased, the sleeping time tended to increase. At a concentration of 100 mg / kg, a significant increase in sleeping time was observed at a level equivalent to 30 mg / kg of poisoned hydrochloride ( p &Lt; 0.05).

From the above results, policosanol was also judged to exhibit similar or equivalent sleep effects to octacosanol.

Experimental Example  5: Policosanol  Sleep mechanism

The sleeping action mechanism of policosanol was confirmed in the same manner as in Experimental Example 3.

As shown in FIG. 5A and FIG. 5B, the effect of policosanol (TC) was suppressed by PD, which is a histamine receptor agonist, as well as DH of OC and OC of FIGS. 3A and 3B.

In the above results, policosanol was found to exhibit sleep effects by antagonizing histamine receptors.

Hereinafter, formulation examples of the composition containing octacanol or policosanol of the present invention will be described, but the present invention is not intended to be limited thereto but is specifically explained.

Formulation example  One. Sanje  Produce

20 mg of octacosanol of Experimental Example 2

Lactose 100 mg

Talc 10 mg

The above components are mixed and filled in airtight bags to prepare powders.

Formulation example  2. Preparation of tablets

10 mg of octacosanol of Experimental Example 2

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

Formulation example  3. Preparation of capsules

10 mg of octacosanol of Experimental Example 2

Crystalline cellulose 3 mg

Lactose 14.8 mg

Magnesium stearate 0.2 mg

The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

Formulation example  4. Preparation of injections

10 mg of octacosanol of Experimental Example 2

180 mg mannitol

Sterile sterilized water for injection 2974 mg

Na ₂ HPO _{4 ,} 12H ₂ O 26 mg

It is prepared by the above-mentioned component content per ampoule according to the usual injection preparation method.

Formulation example  5. Liquid  Produce

20 mg of octacosanol of Experimental Example 2

10 g per isomer

5 g mannitol

Purified water quantity

Each component was added to purified water in accordance with the conventional liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water and adjusted to 100 as a whole. To prepare a liquid agent.

Formulation example  6. Manufacture of health functional foods

1000 mg of policosanol in Experimental Example 4

Vitamin mixture quantity

70 [mu] g of vitamin A acetate

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

0.15 mg of vitamin B2

Vitamin B6 0.5 mg

0.2 [mu] g vitamin B12

Vitamin C 10 mg

Biotin 10 μg

Nicotinic acid amide 1.7 mg

50 ㎍ of folic acid

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a component suitable for a health functional food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above components may be mixed , Granules may be prepared and used in the manufacture of a health functional food composition according to a conventional method.

Formulation example  7. Manufacture of functional beverages

1000 mg of policosanol in Experimental Example 4

Citric acid 1,000 mg

100 g of oligosaccharide

Plum concentrate 2 g

Taurine 1 g

Purified water was added to the flask to obtain a total of 900 mL

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The solution thus prepared was filtered and sterilized in a sterilized 2 L container, It is used in the production of the functional beverage composition of the invention.

Although the composition ratio is a mixture of the components suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preferences such as the demand level, the demanding country, and the intended use.

Claims (13)

A pharmaceutical composition for inhibiting histamine receptor activity comprising policosanol as an active ingredient. The pharmaceutical composition for inhibiting histamine receptor activity according to claim 1, wherein the pharmaceutical composition comprises allergic rhinitis; Inflammatory bowel disease; asthma; bronchitis; throw up; Gastric and duodenal ulcers; Gastroesophageal reflux; Sleep disorders; unrest; And a pharmaceutical composition for inhibiting histamine receptor activity, which is for the prevention or treatment of depression. 3. The method of claim 2,
Wherein the prevention or treatment of the sleep disorder is for reducing the onset time or for increasing the sleep duration. The method according to claim 1,
Wherein the policosanol is a long chain primary alcohol having 24 to 36 carbon atoms. 5. The method of claim 4,
Wherein the policosanol is any one or a mixture of two or more selected from tetracosanol, hexacosanol, heptacosanol, octacosanol, nonacosanol, triacontanol, tetrythiaconanol, and tetratriacontanol. A pharmaceutical composition for inhibiting activity. 6. The method of claim 5,
Wherein the policosanol comprises at least 30% by weight of octacosanol. The method according to claim 1,
Wherein the policosanol is extracted from rice bran, rice bran oil or rice hull. A food composition for preventing or ameliorating sleep disorder, anxiety or depression through inhibition of histamine receptor activity comprising policosanol as an active ingredient. 9. The method of claim 8,
Wherein the prevention or amelioration of the sleep disorder is for a reduction in the onset time or an increase in the sleep duration. 9. The method of claim 8,
Wherein the policosanol is a long chain primary alcohol having 24 to 36 carbon atoms. 11. The method of claim 10,
Wherein the policosanol is any one or a mixture of two or more selected from tetraconol, hexacosanol, heptacosanol, octacosanol, nonacosanol, triacontanol, tetra triacontanol and tetra triacontanol. , Anxiety or depression. 12. The method of claim 11,
Wherein the policosanol comprises at least 30% by weight of octacosanol. 9. The method of claim 8,
Wherein the policosanol is extracted from rice bran, rice bran oil or rice husk.

Images