KR101440488B1 - Composition for preventing and treating Marcrophage activation syndrom, Liver Cirrhosis or obesity comprising hypothemycin - Google Patents

Abstract

The present invention relates to a macrophage activation syndrome, a pharmaceutical composition for the prevention and treatment of liver cirrhosis or obesity, or a health food containing hypothemaic acid as an active ingredient. More particularly, The present invention relates to a pharmaceutical composition or health composition for preventing and treating macrophage activation syndrome, liver cirrhosis, or obesity, which is a disease induced by activated macrophages, such as hypothermia, because it inhibits TNF-α production and TNF- And can be usefully used as an active ingredient of foods.

Description

[0001] The present invention relates to a composition for preventing and treating macrophage activation syndrome, liver cirrhosis or obesity, which comprises hypophosphatemia as an active ingredient. [0002] The present invention relates to a composition for prevention and treatment of macrophage activation syndrome, liver cirrhosis or obesity comprising hypothemycin,

The present invention relates to a composition for preventing and treating macrophage activation syndrome, cirrhosis or obesity using hypothemycin.

The diseases associated with the activation of macrophages include macrophage activation syndrome, cirrhosis and obesity. Specifically, Macrophage activation syndrome (MAS) is a rheumatic disease with symptoms such as acute fever, liver spleen enlargement, lymphadenopathy, skin and mucosal hemorrhage, and hemocytopenia. Because of the excessive activation of macrophages, inappropriate interaction between macrophages and lymphocytes has been associated with an increase in various cytokines, such as TNF-α, IL-1α, IL-1β and IL-6, produced by macrophages and T cells do.

In addition, liver cirrhosis (liver cirrhosis) is a disease that normal hepatocytes are replaced with scar tissue to perform liver function, and in severe cases liver damage is very serious and liver transplantation is also necessary. Chronic liver injury caused by various causes commonly leads to liver fibrosis. When hepatic cells are damaged by various causes and Kupffer cells, which are macrophages in liver, are activated and secrete several cytokines, hepatic cells are activated to generate connective tissues. When the liver damage is sustained, the damaged liver cells are replaced with connective tissues, resulting in stromal repair, resulting in scarring due to accumulation of connective tissues in the liver tissue, liver damage due to hepatocyte damage, (Rojkind et al., Clinical Hepatology., 1983; Rubin et al., Essential pathology., Second, 339-41, 1995). Studies have shown that inhibition of macrophages, one of the cells that make up the immune system, can block the process of liver damage caused by cirrhosis. Such a study is expected to help develop new therapies for cirrhosis that have not yet been cured.

In addition, obesity is a disease associated with macrophages. Specifically, the expression of M2 macrophage markers is decreased in the adipose tissue of the obese model through the high fat diet, while the expression of M1 macrophage markers such as TNF-α is markedly increased. Thus, when the obesity progresses from lean adipose tissue to obese adipose tissue, most cell types are changed from ATM (adipose tissue macrphage) showing M2 phenotype to ATM showing M1 phenotype . In addition, TNF-α secreted from M1 macrophages has an effect of inducing insulin resistance. Thus, in addition to the numerical increase of macrophages in the obesity process, the hypothesis that the phenotype exchange between M1 and M2 is important for macrophage tissue inflammation and insulin resistance has been suggested and confirmed by subsequent studies (Lumeng, CN, JL Bodzin, and AR Saliel, J Clin Invest, 117 (1), 175-84, 2007).

As described above, studies have been made that diseases such as macrophage activation syndrome, cirrhosis and obesity are associated with macrophage activation, but hypophytes inhibit the production of TNF-? Secreted from macrophages, There is no evidence to date of treatment effects.

Therefore, the inventors of the present invention confirmed that an inhibitory effect on hypoxia-induced macrophage-mediated TNF-α production from phoma species (Phoma sp.), Which is one of the fungi, The present invention has been completed based on the findings that it can be effectively used as a therapeutic or preventive composition for macrophage activation syndrome, liver cirrhosis or obesity.

It is an object of the present invention to provide a pharmaceutical composition for preventing and treating macrophage activation syndrome, liver cirrhosis or obesity comprising hypothemycin as an active ingredient.

It is an object of the present invention to provide a food composition for preventing or ameliorating macrophage activation, cirrhosis or obesity, which comprises hypophytes as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing and treating macrophage activation syndrome comprising hypothemycin as an active ingredient.

In addition, the present invention provides a food composition for preventing and improving macrophage activation syndrome comprising hypothemacin as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing and improving liver cirrhosis comprising hypothemacin as an active ingredient.

In addition, the present invention provides a food composition for prevention and improvement of liver cirrhosis comprising hypothemacein as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing and treating obesity comprising hypothemacin as an active ingredient.

In addition, the present invention provides a food composition for prevention and improvement of obesity comprising hypothema icin as an active ingredient.

Since pretreatment of the hypothemycin of the present invention inhibits TNF-α production and TNF-α mRNA expression by the activated macrophages, the hypothemaic is inhibited by macrophages, which are induced by activated macrophages, The active ingredient of the pharmaceutical composition for prevention and treatment of any one disease selected from the group consisting of an active syndrome, cirrhosis and obesity, or a food composition for prevention and improvement.

Figure 1 is a graph showing cytotoxicity assessment of hypothemycin.
Figure 2 is a graph showing the inhibitory effect of hypothemaic on lipopolysaccharide-induced TNF-a production in RAW 264.7 cells.
Figure 3 is a graph showing the inhibitory effect of hypothemaic isoforms on the expression of lipopolysaccharide-induced TNF-a mRNA in RAW 264.7 cells.
Figure 4 is a graph showing the effect of lipopolysaccharide-induced nitric oxide (NO) production of hypothecia in RAW 264.7 cells.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing and treating macrophage activation syndrome comprising hypothemycin as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing and treating liver cirrhosis, which comprises hypothemacein as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for the prevention and treatment of obesity, which comprises hypothema icin as an active ingredient.

The hypothemaicin is a compound represented by the following general formula (1).

≪ Formula 1 >

The general chemical name of the compound is ((1aR, 3S, 4S, 9S, 15bR, Z) -3,4,12-trihydroxy- 14-methoxy-9-methyl-3,4,8,9-tetrahydro- [c] oxireno [2,3-e] [1] oxacyclotetradecine-5,11 (2H, 15bH) -dione).

The hypothemaic compound according to the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a hypothemic sine compound in an excess amount of an acid aqueous solution, and using this salt in a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile Followed by precipitation. It may also be prepared by evaporating a solvent or excess acid in this mixture and then drying or by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Hypothermic < / RTI > compounds according to the present invention include both their pharmaceutically acceptable salts, as well as their isomers or possible solvates or hydrates which may be prepared therefrom.

The hypothemic compounds according to the present invention may be those commercially available or synthesized using conventional synthetic methods known in the art of organic synthesis.

The hypothemaicin can inhibit TNF-a production by activated macrophages.

The hypothemaicin can inhibit TNF-a mRNA expression by activated macrophages.

Hypothermicin capable of inhibiting TNF-α production and TNF-α mRNA expression by the activated macrophages is preferably 1 μM to 100 μM, more preferably 1 μM to 50 μM, more preferably 3 μM to 50 μM μM is most preferable, but not limited thereto.

The activated macrophages may be activated by lipopolysaccharide (LPS), IFN-y, IL-4 or GM-CSF, and specifically activated by lipopolysaccharide, It is not limited.

In a specific example of the present invention, the mouse macrophage cell line RAW 264.7 (TIB-71, ATCC) cells were pretreated with a broad range of concentrations of 3, 10, 30, 100 and 300 nM for 1 hour The cells were cultured by treatment with phospholiposaccharide, and cytotoxicity was measured using a cell proliferation kit II (Roche Applied Science). As a result, it was confirmed that hypothema icin did not cause specific cytotoxicity up to 100 nM (Fig. 1) .

The RAW 264.7 cells were pretreated with hypothemaicin at 3, 10 and 30 nM for 1 hour, treated with Lipopolysaccharide (LPS), and the supernatant was applied to the RAW 264.7 cells using an ELISA kit (R & D systems INC.) (Fig. 2). As a result, it was confirmed that Hypothermia significantly inhibited the production of TNF-α at 3 μM, 10 μM and 30 μM (FIG. 2).

After RAW 264.7 cells were cultured, the RNA extracted from RAW 264.7 cells treated with lipopolysaccharide was pretreated with hypothemaicin. The amount of mRNA expressed by qRT-PCR was measured at 10 μM and 30 μM, lt; / RTI > mRNA expression (Fig. 3).

In addition, RAW 264.7 cells were cultured and RAW 264.7 cells treated with lipopolysaccharide after pretreatment with hypothemaicin did not inhibit the production of NO up to 30 μM, unlike the case of TNF-α ( 4).

Therefore, when pretreatment of hypothemaicin of the present invention is inhibited by activated macrophage-mediated TNF-α production and TNF-α mRNA expression, hypomesi is treated with macrophage activation syndrome , Liver cirrhosis, and obesity, or a food composition for prevention and improvement, which is useful as an active ingredient.

Hypothermia of the present invention can be administered parenterally at the time of clinical administration and can be used in the form of a general pharmaceutical preparation.

The hypothema of the present invention can be administered in various formulations of actual parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous agents, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the suspending agent. As a suppository base, witepsol, macrogol, tween 61, cacao paper, Liu ling, glycerogelatin and the like can be used.

Hypothermia of the present invention can be used in combination with various carriers permitted as pharmaceutical agents such as physiological saline or an organic solvent, and can be used in combination with carbohydrates such as glucose, sucrose or dextran, ascorbate Antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers can be used as pharmaceuticals.

The effective dose of hypothema in the present invention is 0.0001 to 100 mg / kg, preferably 0.01 to 10 mg / kg, and can be administered once to three times a day.

The total effective amount of hypothecia of the invention in the pharmaceutical composition of the present invention may be administered to the patient in a single dose by bolus or by infusion for a relatively short period of time, Multiple doses may be administered by a fractionated treatment protocol administered over a prolonged period of time. Since the concentration of the effective dose of the patient is determined in consideration of various factors such as the route of administration and the number of treatments as well as the age and health condition of the patient, in view of this point, Lt; RTI ID = 0.0 > pharmacological < / RTI >

In addition, the present invention provides a food composition for preventing and improving macrophage activation syndrome comprising hypothemacin as an active ingredient.

In addition, the present invention provides a food composition for prevention and improvement of liver cirrhosis comprising hypothemacein as an active ingredient.

In addition, the present invention provides a food composition for prevention and improvement of obesity comprising hypothema icin as an active ingredient.

The food composition may be a health food, but is not limited thereto.

The hypothemaicin is a compound represented by the following general formula (1).

≪ Formula 1 >

The general chemical name of the compound is ((1aR, 3S, 4S, 9S, 15bR, Z) -3,4,12-trihydroxy- 14-methoxy-9-methyl-3,4,8,9-tetrahydro- [c] oxireno [2,3-e] [1] oxacyclotetradecine-5,11 (2H, 15bH) -dione).

The kind of the food composition is not particularly limited. Examples of the foods to which the above substances can be added include dairy products including dairy products such as drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages, and vitamin complexes, all of which include health functional foods in a conventional sense.

Hypothermia of the present invention can be added directly to food or used together with other food or food ingredients, and can be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose (for prevention or improvement). Generally, the amount of hypothecia in the health functional food may be 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the 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 exceeding the above range.

The food composition containing the hypothemaic acid of the present invention as an active ingredient is not particularly limited to the other components other than those containing the fermentation product as an essential ingredient at the indicated ratio, and may contain various flavors or natural carbohydrates And may be contained as an additional component. 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, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

In addition to the above, the hypothema of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate etc.), pectic acid and its salts, And salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the hypothema of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the proportion of such additives is not so critical, it is common that the hypothema in the present invention is selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight.

Hereinafter, the present invention will be described in detail with reference to examples and preparation examples.

However, the following examples and preparative examples are merely illustrative of the present invention, and the present invention is not limited to the following examples and preparative examples.

Mouse macrophage line RAW  264.7 Cell culture

RAW 264.7 cells were cultured as follows.

Specifically, the cell line used in the present invention is a RAW 264.7 (TIB-71, ATCC) mouse macrophage cell line. For culturing the cells, 10% fetal bovine serum, 100 U / ml penicilin, Dulbecco ' s modified Eagle ' s medium (Invitrogen Life Tehchnologies) containing 100 [mu] g / ml streptomycin was used. All cells were cultured in an air / 5% CO ₂ incubator at 37 ° C in a humidified atmosphere at 95 ° C, and cells were maintained in subculture with fresh culture every 2-3 days.

Hypo theme  Cytotoxicity Assessment

In order to evaluate the cytotoxicity of the hypothetical strains, the following experiment was conducted.

Specifically, RAW 264.7 cells were plated at a concentration of 5 x 10 ⁵ cells / ml in a 96-well microplate (microplate) at 200 μl / well and cultured in Hypo-themeses (Enzo Life Sciences, Catalog #: ALX-380-116- M001) was pretreated for a period of 1 hour at a wide range of concentrations of 3, 10, 30, 100 and 300 nM and then treated with 200 ng / ml of lipopolysaccharide for 24 hours. The cytotoxicity was evaluated using a cell proliferation kit II (Roche Applied Science) and 1 mg / ml of sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (4-methoxy- nitro) benzene sulfonic acid hydrate and 0.0383 mg / ml N-methyldibenzopyrazine methyl sulfate were diluted to 50: 1 to make an XTT labeling mixture. After removing 50 μl of the culture solution, 50 μl of the XTT labeled mixture was added to each well, and the mixture was allowed to stand for 1 hour and absorbance was measured at 490 nm (reference wavelength, 650 nm).

As a result of confirming the degree of cytotoxicity induced by the hypothermia, it was confirmed that the hypothermia did not cause specific cytotoxicity up to 100 nM (Fig. 1).

Hypo theme Lipopolysaccharide  Judo TNF -α generation inhibitory effect measurement

In order to measure the inhibitory effect of hypophytes on TNF-α production by activated macrophages, the following experiment was carried out.

Specifically, RAW 264.7 cells cultured from <Example 1> were dispensed into a 96-well microplate at a concentration of 5 × 10 ⁵ cells / ml at 200 μl / well. After stabilization, hypothemaicin was added at 3, 10 and 30 nM For 1 hour, treated with Lipopolysaccharide (LPS) for 6 hours, and the supernatant was used for TNF-a measurement. Measurement of TNF- [alpha] was performed using an ELISA kit (R & D systems INC.) According to the manufacturer's recommended method. Hypothermia was purchased from Enzo Life Sciences (Catalog #: ALX-380-116-M001).

As a result, the production of TNF-α was significantly increased when RAW 264.7 cells were activated, whereas the production of TNF-α at 3 μM, 10 μM and 30 μM, which did not induce cytotoxicity, (Fig. 2).

Hypo theme Lipopolysaccharide  Judo TNF -α mRNA  Measurement of inhibition of expression

In order to measure the inhibitory effect of TNF-α mRNA expression by activated macrophages of hypophytic mycin, the following experiment was carried out.

Specifically, RAW 264.7 cells were cultured in a 6-well tissue culture plate at a concentration of 5 × 10 ⁵ cells / ml for RNA acquisition, and experiments were conducted according to each experimental condition. After the incubation, the cells were washed with PBS stored at 4 ° C and collected using a scraper. The cells were collected by centrifugation at 1,200 rpm and 4 ° C for 2 minutes to obtain a pellet. Total RNA was extracted using the RNeasy Plus Mini Kit (Qiagen, Valencia, Calif.) According to the manufacturer's instructions. RNAs dissolved in DEPC-DW were measured for absorbance at A260 / 280 ratio (Versa Max Microplate Reader, Molecular Devices) to determine purity and concentration. The qRT-PCR method was used to confirm the expression level of the transcribed mRNA. The same amount of RNA was synthesized by using oligo (dt) ₁₅ primer and then tested using the Power SYBR Green PCR Master Mix (Applied Biosystems) reagent and the 7500 Fast real-time PCR system (Applied Biosystems) . For gene amplification, the sample was heated at 50 캜 for 20 seconds at 95 캜 for 10 minutes, and then repeated 45 times at 95 캜 for 15 seconds at 56 캜 for 30 seconds at 72 캜 for 1 minute. The results were expressed as the amplification ratio of the experimental group to naive using the △ ΔCt method. The sequences of the primers used in the experiments are as follows. Mouse TNF-α: sense sequence 5'-CCT GTA GCC CAC GTC GTA GC-3 ', antisense sequence 5'-TTG ACC TCA GCG CTG AGT TG-3; Mouse β-actin: sense sequence 5'-TGG AAT CCT GTGGCA TCC ATG AAA C-3 ', antisense sequence 5'-TAA AAC GCA GCT CAG TAA CAG TCC G-3'.

As a result, the expression of TNF-α mRNA was significantly increased when RAW 264.7 cells were activated, whereas the expression of TNF-α mRNA at 10 μM and 30 μM, which did not induce cytotoxicity, Statistically significant inhibition (Fig. 3).

Hypo theme Lipopolysaccharide  Induced nitric oxide ( nitric oxide ; NO Measuring the Effect of Generation

In order to measure the effect of lipopolysaccharide-induced hypoxia-induced nitric oxide (NO) production, the following experiment was carried out.

Specifically, RAW 264.7 cells were subcultured to a concentration of 5 x 10 ⁵ cells / ml in a 96-well microplate at 200 μl / well. After stabilization, hypothemaicin was pretreated with 3, 10 and 30 nM for 1 hour, The saccharide was treated for 24 hours. To the new 96-well microplate was added 50 μl of the culture solution and an equal amount of a grease reagent (2% (v / v) phosphoric acid containing 1% sulfanilamide and 0.1% naphthylethylenediamide in DW) at room temperature Absorbance was measured at 540 nm.

As a result, when RAW 264.7 cells were activated, NO production was greatly increased as in the case of TNF-α. However, unlike TNF-α, the pretreatment of hypothemaicin did not inhibit the production of NO up to 30 μM (Fig. 4).

The preparation examples for the composition of the present invention are illustrated below.

< Manufacturing example  1> Preparation of pharmaceutical preparations

<1-1> Sanje  Produce

20 mg &lt; RTI ID = 0.0 &gt;

20 mg of lactose

After mixing the above components, the mixture was packed in an airtight container to prepare a powder.

<1-2> Preparation of tablets

10 mg of the hypothecae of the present invention

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

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

&Lt; 1-3 > Preparation of capsules

10 mg of the hypothecae of the present invention

3 mg of crystalline cellulose

Lactose 14.8 mg

Magnesium stearate 0.2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<1-4> Liquid  Produce

20 mg &lt; RTI ID = 0.0 &gt;

10 g per isomer

5 g mannitol

Purified water quantity

Each component was added to purified water in accordance with the usual 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 adjusted to 100 ml with purified water, And sterilized to prepare a liquid preparation.

<1-5> Preparation of Injection

10 [mu] g / ml of the hypothesis of the present invention

Diluted hydrochloric acid BP until pH 7.6

Sodium chloride up to 1 ml for injection

The hypothecicin of the present invention was dissolved in a suitable volume of sodium chloride BP and the pH of the resulting solution was adjusted to 7.6 with dilute hydrochloric acid BP and the volume was adjusted using main sodium chloride BP and mixed well . The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed in an upper lattice of air by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and an injection solution was prepared.

&Lt; 1-6 >

1 g &lt; RTI ID = 0.0 &gt;

Lactose 1.5 g

Glycerin 1 g

0.5 g of xylitol

After mixing the above components, they were prepared so as to be 4 g per one ring according to a conventional method.

<1-7> Preparation of granules

150 mg of the hypothecae of the present invention

Soybean extract 50 mg

200 mg of glucose

600 mg of starch

After mixing the above components, 100 mg of 30% ethanol was added and the mixture was dried at 60 캜 to form granules, which were then filled in a capsule.

< Manufacturing example  2> Manufacturing of food

Foods containing the hypothecaicin of the present invention were prepared as follows.

<2-1> Production of flour food

0.5 to 5.0 parts by weight of the hypothecae of the present invention are added to flour and bread, cake, cookies, crackers and noodles are prepared by using the mixture to produce health food for the prevention and treatment of macrophage activation syndrome, liver cirrhosis and obesity Respectively.

<2-2> Dairy products ( dairy products )

5 to 10 parts by weight of the hypothecae of the present invention were added to milk and various dairy products such as butter and ice cream were prepared using the milk.

<2-3> Solar  Produce

Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh.

Black soybeans, black sesame seeds, and perilla seeds were steamed and dried by a conventional method, and then they were prepared into powder having a particle size of 60 mesh by a pulverizer.

The hypothemaicin of the present invention was concentrated under reduced pressure in a vacuum concentrator, dried by spraying and drying with a hot air drier, and pulverized to a size of 60 mesh with a pulverizer to obtain a dried powder.

The grains, seeds, and dried powders of the present invention were prepared in the following proportions.

(30 parts by weight of brown rice, 15 parts by weight of yulmu, 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 seeds)

Hypothermia (3 parts by weight) of the present invention,

(0.5 parts by weight), and

Rhubarb (0.5 parts by weight).

<2-4> Production of health supplement

100 mg of the hypothema of the present invention

Vitamin mixture quantity

70 [mu] g of vitamin A acetate

Vitamin E 1.0 mg

0.13 mg vitamin B1

0.15 mg of vitamin B2

0.5 mg vitamin B6

0.2 [mu] g vitamin B12

10 mg vitamin C

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

15 mg of potassium phosphate monobasic

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

100 mg of calcium carbonate

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

< Manufacturing example  3> Health drink  Produce

100 mg of the hypothema of the present invention

       Citric acid 100 mg

       100 mg of oligosaccharide

       2 mg of plum concentrate

       100 mg taurine

       Purified water was added to 500 ml

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the resulting solution was filtered to obtain a sterilized 1 liter container, sealed sterilized, It is used in the production of the health 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.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims. And can be used in the manufacture of an ointment which can be applied thinly to human body according to its effect, which is included in the purpose and scope of the present invention as defined in the appended claims.

Claims (9)

A pharmaceutical composition for preventing and treating liver cirrhosis comprising hypothemycin as an active ingredient.
[Claim 2] The pharmaceutical composition for preventing and treating cirrhosis according to claim 1, wherein the hypothema is represented by the following formula (1).
&Lt; Formula 1 >

The pharmaceutical composition for preventing and treating cirrhosis according to claim 1, wherein the hypomacic acid inhibits TNF-α production by activated macrophages.
The pharmaceutical composition for the prevention and treatment of cirrhosis according to claim 1, wherein the hypomacic acid inhibits TNF-α mRNA expression by activated macrophages.
delete delete The composition for prevention and improvement of cirrhosis of the present invention, which contains hypo-theme as an active ingredient.
A pharmaceutical composition for the prevention and treatment of obesity, which comprises hypophosphatemia as an active ingredient.
A food composition for prevention and improvement of obesity, which comprises hypophosphatemia as an active ingredient.

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