KR20210098643A - Composition having antipyretic effect containing geraniin - Google Patents

Abstract

The present invention relates to an antipyretic composition comprising geraniin. Since geraniin of the present invention has excellent antipyretic efficacy on fever, geraniin is useful as a health functional food composition, a health food composition, and a feed additive composition for preventing or alleviating fever.

Description

Antipyretic composition containing geranine {Composition having antipyretic effect containing geraniin}

The present invention relates to a composition for antipyretic comprising geranine.

Heat production in the human body occurs in all biological processes that contribute to muscle movement, food assimilation, and basal metabolic rate. A constant body temperature is required in order to maintain normal functions of the human body, and when the body temperature control center is modulated due to various pathological causes, abnormal conditions such as fever occur.

An antipyretic drug is a drug that lowers the body temperature in a fever state.

Various mechanisms have been proposed for antipyretics and fever symptoms. Although some associations are found in relation to the antipyretic and analgesic effects and anti-inflammatory and analgesic effects, there are drugs that have little anti-inflammatory and analgesic action but have strong antipyretic action. Since there are excellent substances, it is judged that the above effects do not necessarily have a direct correlation with each other.

On the other hand, indomethacin is one of the representative antipyretic analgesics, and it is a noncorticosteroid drug, and when administered to humans and animals, serious problems including bleeding, ulceration, perforation, etc. It is known to cause gastric mucosa damage.

Therefore, there is a need for the development of a substance having excellent antipyretic action and little risk of such side effects or cytotoxicity.

Korean Patent Registration No. 10-1834872

It is an object of the present invention to provide a pharmaceutical composition for antipyretic, comprising geraniin.

Another object of the present invention is to provide a health functional food composition for preventing or improving fever containing geranine, a health food composition, and a composition for adding feed.

In order to achieve the above object,

The present invention provides a pharmaceutical composition for antipyretic comprising geraniin, an isomer, a derivative thereof, or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a health functional food composition, a health food composition, and a composition for adding feed, comprising geraniin, an isomer, derivative, or a food pharmaceutically acceptable salt thereof.

Since the geranine of the present invention has excellent antipyretic efficacy against fever, it may be useful as a pharmaceutical composition for antipyretic, a health functional food composition for preventing or improving fever, a health food composition, and a composition for adding feed.

1 is a graph showing the antipyretic effect of geraniin of the present invention and indomethacin (INN) as a positive control on fever caused by pyretics.

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition for antipyretic

The present invention provides a pharmaceutical composition for antipyretic comprising geraniin, an isomer, a derivative thereof, or a pharmaceutically acceptable salt thereof.

The term "antipyretic" or "pain suppression" refers to any action that improves or beneficially changes the body temperature or pain of an individual to a normal range. Antipyretic means lowering the body temperature in a fever state or not lowering the normal body temperature. Fever is a condition in which the body temperature rises above the normal range. In humans, when the oral body temperature is about 37.8°C or higher or the rectal body temperature is about 38.2°C, it can be said that there is a fever.

In the pharmaceutical composition according to the present invention, the composition may be used to suppress abnormal fever or to treat or prevent abnormal fever accompanying a disease. The abnormal fever means an abnormally high body temperature.

According to an embodiment of the present invention, the geranine may be a compound derived from dampalsu ( Elaeocarpus sylvestris ), but is not limited thereto, and geranine derived from other natural products or commercially obtained may be used.

For example, the geranine, dampalsu ( Elaeocarpus sylvestris ) by immersing in water, C1 to C4 alcohol, ethyl acetate, or a mixture thereof to obtain a dampalsu extract; and separating the geranine, an isomer, a derivative, or a pharmaceutically acceptable salt thereof from the Dampalsu extract.

In this case, the C1 to C4 alcohol may be ethanol, methanol, butanol, or a combination thereof. For example, the alcohol may be 30% (v/v) aqueous ethanol solution, 50% (v/v) aqueous ethanol solution, 70% (v/v) aqueous ethanol solution, or 100% (v/v) ethanol. The immersion may be performed at about 0°C to about 100°C, about 0°C to about 50°C, about 0°C to about 30°C, about 4°C, or room temperature. The immersion may be performed for about 1 minute to about 1 month. The Dampalsu extract includes an extract obtained by extracting from Dampalsu using a suitable solvent, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, or a crude or purified product thereof. The Dampalsu extract may be prepared using conventional extraction methods in the art, such as ultrasonic extraction, filtration, and reflux extraction.

The method may further include fractionating the Dampalsu extract with water, C1 to C4 alcohol, or a combination thereof. The Dampalsu extract may be fractionated with water, ethanol, methanol, butanol, ethyl acetate, hexane, or a combination thereof.

The method includes isolating geranine, an isomer, derivative, or pharmaceutically acceptable salt thereof from the Dampalsu extract.

The method may further include performing concentration, centrifugation, filtration, adsorption, or chromatography on the Dampalsu extract.

Geranine of the present invention may exhibit an excellent antipyretic effect that significantly reduces body temperature rise compared to Dampalsu extract or a fraction thereof.

The term "isomer" refers to a compound in which the molecular formula is the same, but the connection method or spatial arrangement of constituent atoms in the bonsai is not the same. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomer may be a diasteromer or an enantiomer. Enantiomers refer to isomers that do not overlap their mirror images, such as the relationship between the left and right hands, and are also called optical isomers. Enantiomers are divided into R (Rectus: clockwise) and S (sinister: counterclockwise) when 4 or more substituents differ from each other at the chiral central carbon. Diastereomers refer to stereoisomers that are not in a mirror image relationship, and can be divided into cis-trans isomers due to the spatial arrangement of atoms.

The term "derivative" refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms.

The term "salt" refers to an addition salt of an inorganic, organic, or metal salt of a compound. The salt may be a pharmaceutically acceptable salt. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salt is formate, acetate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoro Acetate, benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonic acid, embonate, glutamate, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, or aspartate. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.

In the pharmaceutical composition according to the present invention, the geraniin, an isomer, a derivative, or a pharmaceutically acceptable salt thereof is 0.001 to 99.9% by weight based on the total weight of the composition, the pharmaceutical composition can be

In addition, the effective dosage for the human body of the geranine, isomer, derivative, or pharmaceutically acceptable salt thereof of the present invention may vary depending on the patient's age, weight, sex, dosage form, health status and disease degree, and in general to about 0.001 to 100 mg/kg/day, and preferably 0.01 to 35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and once a day at regular time intervals according to the judgment of a doctor or pharmacist It may be administered in several divided doses.

The pharmaceutical composition according to the present invention may be formulated for oral administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, intradermal administration, or topical administration.

The geranine of the present invention, its isomer, derivative, or pharmaceutically acceptable salt may be administered in various oral and parenteral formulations during clinical administration, and when formulated, commonly used fillers, extenders, binders, It is prepared using a diluent or excipient such as a wetting agent, a disintegrant, and a surfactant.

Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention with at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.

The pharmaceutical composition may further include a carrier, excipient or diluent. Carriers, excipients, or diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.

In addition, the pharmaceutical composition may further include a known active ingredient having antipyretic activity.

Health functional food composition, health food composition and feed additive composition

In addition, the present invention provides a health functional food composition, a health food composition, and a composition for adding feed, comprising geraniin, an isomer, derivative, or a food pharmaceutically acceptable salt thereof.

The term "health functional food" as used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful in the human body. Here, the term 'functionality' refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be prepared by a method commonly used in the ordinary technical field, and at the time of the preparation, it can be prepared by adding raw materials and components commonly added in the conventional technical field. In addition, the dosage form of the health functional food may also be manufactured without limitation as long as it is a dosage form recognized as a health functional food. The health functional food composition of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur when taking the drug for a long period of time using food as a raw material, and has excellent portability, The health functional food of the present invention can be ingested as an adjuvant to enhance the effect of a therapeutic agent for metabolic diseases.

The health functional food composition or health food composition according to the present invention contains the geranine, an isomer, a derivative or a pharmaceutically acceptable salt thereof for the purpose of preventing or improving related diseases through antipyretic, analgesic and anti-inflammatory activity. , can be added to health functional foods such as beverages or health foods.

There is no particular limitation on the type of the food. Examples of foods to which geranine, isomers, derivatives, or pharmaceutically acceptable salts thereof according to the present invention can be added include drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, Ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, etc.

The health food and health functional food composition according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the geranine, an isomer, a derivative thereof, or a pharmaceutically acceptable salt thereof according to the present invention may be appropriately determined depending on the purpose of its use (for prevention or improvement). In general, the amount of geranine, an isomer, derivative or a pharmaceutically acceptable salt thereof in health food and health functional food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for health maintenance or health control, the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

The health food and health functional food composition of the present invention is not particularly limited in other ingredients except for containing geranine according to the present invention, an isomer, derivative, or a food pharmaceutically acceptable salt thereof according to the present invention as an essential ingredient in the indicated ratio. It may contain various flavoring agents or natural carbohydrates as additional ingredients, such as beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 g of the nutraceutical composition of the present invention.

In addition to the above, the health food and health functional food composition containing geranine, an isomer, derivative or a pharmaceutically acceptable salt thereof according to the present invention are various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and natural flavorants. Used in flavoring agents, colorants and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonated beverages It may contain a carbonation agent and the like. In addition, the health food and health functional food composition of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage.

These components may be used independently or in combination. The proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.

The composition for addition to feed according to the present invention may further include known additives that can be added to improve antipyretic or pain suppression activity depending on the formulation. The composition for addition to the feed may be in the form of a highly concentrated solution, powder or granules.

The composition for addition to the feed may further include any protein-containing organic flour commonly used to meet the dietary needs of animals. The composition for addition to the feed may be used by adding it to animal feed by immersion, spraying, or mixing.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.

<Example 1> Preparation of geranine

After obtaining and drying domestic Dampalsu ( Elaeocarpus sylvestris ) from Jeju Island, 50% ethanol was added to 100 kg of Dampalsu fruit powder, stirred at 70~80℃ for 3 hours, and the extract was cooled to 50℃ or less. Then, the first filtration was carried out, and the second filtration was carried out. The extract, which had undergone secondary filtration, was concentrated at 45° C. or lower, lyophilized at -180 to 190° C., and then packaged. After 50 g of the Dampalsu extract was suspended in 2 L of distilled water, the fractions were sequentially fractionated into equal amounts of n-hexane (Hx), dichloromethane (MC), ethyl acetate (EA) and n-butanol (BuOH), respectively, and then concentrated under reduced pressure to obtain butanol fractions. got

The obtained butanol fraction was eluted with 20-100% MeOH using ODS (ODS column chromatography, 5×50 cm), and a fraction eluted with 60% MeOH was obtained. This fraction was eluted with 65% MeOH using ODS column chromatography, and then prep HPLC was performed to obtain a geranine compound.

Geranine obtained by the above method was used in the following examples.

<Example 2> Confirmation of the effect of inhibiting body temperature increase of geranine

In the high fever animal model, the antipyretic effect of geraniin prepared by the method of Example 1 was confirmed.

Specifically, Sprague-Dawley (SD) rats and BALB/c nude mouse (Nara-Biotec, Korea) used in the experiment were used after acclimatization to the breeding room environment for one week. The breeding room temperature was maintained at 25±1℃ and humidity at 50-60%. After allowing the light-dark cycle to be adjusted to a 12-hour cycle, solid feed and water were supplied without restriction. Animal experiments were performed according to the principles of the guidelines provided by the Animal Experimentation Ethics Committee of Kyunghee University.

A body temperature increase-inducing substance (Pyretics; Sigma, USA) was dissolved in saline at 2.5 mg/kg and administered intraperitoneally to the experimental animals to induce fever. The experimental group was divided into 5 groups of 5 animals each. Geranine (5, 10, 20 mg/kg) or a positive control group (indomethacin, 100 mg/kg) was orally administered 30 minutes before fever induction. The rectal body temperature was measured before inducing fever (0h) and 6 hours after induction (6h), and it is shown in FIG. 1 .

In the group administered with the pyretics, body temperature increased 6 hours after administration compared to before administration. However, it was confirmed that all of the groups pretreated with geranine suppressed the increase in body temperature in a concentration-dependent manner. From these results, it was confirmed that geranine had excellent antipyretic efficacy in suppressing fever.

<Formulation Example 1> Preparation of pharmaceutical formulations

<1-1> Preparation of powder

geranine 2 g

lactose 1 g

After mixing the above ingredients, the powder was prepared by filling in an airtight cloth.

<1-2> Preparation of tablets

geranine 100 mg

corn starch 100 mg

lactose 100 mg

magnesium stearate 2 mg

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

<1-3> Preparation of capsules

geranine 100 mg

corn starch 100 mg

lactose 100 mg

magnesium stearate 2 mg

After mixing the above ingredients, the capsules were prepared by filling in gelatin capsules according to a conventional manufacturing method of capsules.

<1-4> Preparation of injection solution

geranine 10 μg/ml

dilute hydrochloric acid BP until pH 3.5

Sodium Chloride BP for Injection up to 1 ml

The geranine according to the present invention was dissolved in an appropriate volume of sodium chloride BP for injection, and the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, the volume was adjusted with sodium chloride BP for injection and thoroughly mixed. . The solution was filled in a 5 ml Type I ampoule made of clear glass, sealed under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120° C. for 15 minutes or more to prepare an injection solution.

<Formulation Example 2> Manufacture of health functional food and health food

<2-1> Manufacture of health functional food

geranine 100 mg

vitamin mixture appropriate amount

vitamin A acetate 70 μg

vitamin E 1.0 mg

vitamin B1 0.13 mg

vitamin B2 0.15 mg

vitamin B6 0.5 mg

vitamin B12 0.2 μg

vitamin C 10 mg

biotin 10 μg

Nicotinamide 1.7 mg

folic acid 50 μg

Calcium Pantothenate 0.5 mg

mineral mixture appropriate amount

ferrous sulfate 1.75 mg

zinc oxide 0.82 mg

magnesium carbonate 25.3 mg

monobasic potassium phosphate 15 mg

Dibasic Calcium Phosphate 55 mg

Potassium Citrate 90 mg

calcium carbonate 100 mg

magnesium chloride 24.8 mg

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

<2-2> Manufacture of health functional beverages

geranine 100 mg

citric acid 100 mg

oligosaccharide 100 mg

Plum Concentrate 2 mg

Taurine 100 mg

Purified water is added to 500 mL

After mixing the above ingredients according to a conventional health drink manufacturing method, after stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in one sterilized container, sealed and sterilized, and then refrigerated. used in the manufacture of health beverage compositions of Although the composition ratio is a composition that is relatively suitable for a beverage of preference in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demand class, demand country, and use purpose.

<2-3> Production of dairy products

0.01-1 parts by weight of the geranine of the present invention was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.

<2-4> Manufacture of wire type

Brown rice, barley, glutinous rice, and barley radish were pregelatinized by a known method and dried, and then roasted and prepared as a powder having a particle size of 60 mesh with a grinder. Black soybeans, black sesame, and perilla were also steamed and dried by a known method, and then roasted and prepared into powder having a particle size of 60 mesh with a grinder. It was prepared by mixing the dry powder of grains and seeds prepared above and the geranine of the present invention in the following ratio.

Grains (34 parts by weight of brown rice, 19 parts by weight of barley, 20 parts by weight of barley),

Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame),

geranine (2 parts by weight),

Reishi (1.5 parts by weight), and

Rehmannia (1.5 parts by weight).

So far, the present invention has been looked at with respect to preferred embodiments thereof. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than in the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (9)

A pharmaceutical composition for antipyretic, comprising geraniin, an isomer, derivative, or pharmaceutically acceptable salt thereof. According to claim 1,
The geraniin, an isomer, a derivative, or a pharmaceutically acceptable salt thereof is characterized in that it comprises 0.001 to 99.9% by weight based on the total weight of the composition, the pharmaceutical composition. According to claim 1,
The pharmaceutical composition is characterized in that it is formulated for oral administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, intradermal administration, or topical administration. A health functional food composition for preventing or improving fever, comprising geraniin, an isomer thereof, a derivative, or a food pharmaceutically acceptable salt. 5. The method of claim 4,
The health functional food is a health functional food composition, characterized in that the food in the form of tablets, capsules, pills or liquids. A health food composition for preventing or improving fever, comprising geraniin, isomers, derivatives thereof, or food pharmaceutically acceptable salts. 7. The method of claim 6,
The health food is selected from various drinks, meat, sausages, bread, candy, snacks, noodles, ice cream, dairy products, soups, ionic beverages, beverages, alcoholic beverages, gum, tea and vitamin complexes, health food composition . Geranin (geraniin), an isomer thereof, a derivative, or a composition for adding a feed for preventing or improving fever comprising a food pharmaceutically acceptable salt. 9. The method of claim 8,
The composition for addition to feed is a highly concentrated liquid, powder or granule form, characterized in that the composition for addition to feed.

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