KR101368383B1 - Composition for prevention and treatment of obesity or metabolic diseases comprising deoxyshikonin - Google Patents

Abstract

The present invention relates to a pharmaceutical composition and a health functional food for preventing and treating obesity or lipid-related metabolic diseases containing deoxysiconin as an active ingredient. The deoxysiconin according to the present invention has an excellent effect of inhibiting adipocyte differentiation. Therefore, it can be used as a pharmaceutical composition and health functional food for the prevention and treatment of obesity or lipid-related metabolic diseases containing it as an active ingredient.

Description

COMPOSITION FOR PREVENTION AND TREATMENT OF OBESITY OR METABOLIC DISEASES COMPRISING DEOXYSHIKONIN}

The present invention relates to a pharmaceutical composition and health functional food for the prevention and treatment of obesity or lipid-related metabolic diseases containing deoxysiconin as an active ingredient.

In addition to the development of the industry, the shift to instant food consumption and meat-based eating has become a major cause of the increase in the obese population. Obesity is caused by adipocyte differentiation due to hormonal changes and disproportionate energy metabolism due to excessive fat intake. Adipogenesis in the body is caused by the differentiation of fat cells from preadipocytes. As a process of accumulation, mature adipocytes are differentiated from immature adipocytes, such as fibroblasts, and eventually form lipid droplets within the cells. As such, the accumulation of fat and excess energy during fat cell differentiation not only leads to obesity, but also causes various lipid-related metabolic diseases such as diabetes, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease, or the like. It is known to be a major cause of metabolic syndrome. Metabolic syndrome refers to a syndrome that is accompanied by risk factors such as hyperlipidemia, hypertension, abnormal glucose metabolism, and obesity. Recently, the Adult Treatment Program III (ATP III), established by the World Health Organization and the National Institute of Health's Cardiopulmonary Blood Research Institute, was officially named as metabolic syndrome or insulin resistance syndrome.

The differentiation process of adipocytes has been studied using cells such as 3T3-L1, and various transcription factors, particularly transcription factors known to be involved in localization, CAAT enhancer binding proteins (C / EBPs), It is known that PPARs (Peroxisome Proliferator Activated receptor) and ADD / SREBPs (Adipocyte determination and differentiation dependent factor1 / sterol response element binding proteins) are expressed over time and regulate the process (Bart A Jessen et al., Gene, 299, pp95-100, 2002; Darlington et al., J. Biol. Chem., 273, pp30057-30060, 1998; Brun RP et al., Curr. Opin. Cell. Biol., 8, pp826-832 , 1996). Given the stimulation of hormones such as isobutylmethylxanthin, dexamethasone and insulin (MDI), C / EBP β and δ are the first, transiently expressed, to initiate differentiation into adipocytes (Reusch J. E et al., Mol Cell Biol., 20, pp 1008-1020, 2000). This continues to lead to increased expression of C / EBPa and PPARγ (James M. N. et al., J. Nutr., 130, pp 3122S-3126S, 2000). PPARγ is a particularly important transcription factor for adipocyte differentiation, and is present in the promoters of various adipocyte genes after forming dimers with the retinoic acid X receptor protein (RXR). Binds to peroxisome proliferator response elements (PPRE) (Tontonoz PE et al., Genes Dev., 8, pp1224-1234, 1994;

Hwang, C. S et al., Cell Dev. Biol., 13, pp 873-877). The interaction of PPARγ with C / EBPa is critical for differentiation into mature adipocytes, which regulate the expression of adipocyte specific proteins and fat metabolizing enzymes, such as fatty acid binding protein aP2. In addition, ADD1 / SREBPs play an important role in fat metabolism, but are also known to be involved in the differentiation process. Expression of ADD1 / SREBP1c in immature adipocytes is believed to contribute to the activation of PPARγ (Rosen ED et al., Annu. Rev. Cell Dev. Biol., 16, pp 145-171, 2000; Osborn TF, J. Biol Chem., 275, pp 32379-32382, 2000). Only the differentiated fat cells synthesize fatty acids and store triglycerides.

Therefore, current research trends are focused on the discovery of substances that can inhibit metabolic processes related to adipocyte differentiation as a method for preventing or treating obesity or lipid-related metabolic diseases. For example, Korean Patent No. 10-0798004 has revealed the action of inhibiting adipocyte differentiation of a compound isolated from the gourd plant extract, and Korean Patent No. 10-0813222 shows the action of inhibiting adipocyte differentiation of herbal extracts. Revealed.

Meanwhile, siconin and its derivatives deoxyshikonin, acetylshikonin, acetylshikonin, isobutylshikonin, dimethylacrylshikonin, acetylshikonin, and isovaleryl siconin (isovalerylshikonin), hydroxyisovalerylshikonin, etc., are used in prescriptions for the purpose of anti-inflammatory, detoxification, and antipyretic. It is used externally and is recently used as a cosmetic raw material and high-quality natural dyes. It has also been found that siconin and deoxysiconin are fat-soluble pigments and are effective in removing lipid oxides. Due to the functionalities of the above-mentioned siconin derivatives having various physiological activities, many studies have been conducted on mass production of siconin derivatives through tissue culture, and antioxidant activity of skin extracts containing siconin and its derivatives is improved. There is also disclosed a patent (Korean Patent No. 10-0923974) regarding a method for enhancing various physiological activities such as tyrosinase inhibitory activity which is involved in and elastanase enzyme activity which is involved in wrinkle improvement.

Therefore, the present inventors continued to study the substances effective for obesity or lipid-related metabolic diseases, and completed the present invention by finding that deoxysiconin inhibits the differentiation of hormone-induced adipocytes.

An object of the present invention to provide a pharmaceutical composition and health functional food for the prevention and treatment of obesity or lipid-related metabolic diseases containing deoxyshikonin as an active ingredient that is effective in inhibiting adipocyte differentiation. have.

In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention and treatment of obesity or lipid-related metabolic diseases containing deoxyshikonin as an active ingredient. The metabolic disease may be, for example, diabetes mellitus, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease or metabolic syndrome in which the disorders occur simultaneously, and the composition may be in capsule, tablet, granule, powder or beverage form. Is possible. The present invention also provides a pharmaceutical composition for the prevention and treatment of obesity or lipid-related metabolic diseases, characterized in that the deoxysikonin inhibits the differentiation of adipocytes.

Furthermore, the present invention provides a dietary supplement for the prevention and symptom relief of obesity or lipid-related metabolic diseases, which contains deoxysiconin as an active ingredient. The metabolic disease may be, for example, diabetes, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease, or metabolic syndrome in which the above diseases occur simultaneously. In another aspect, the present invention provides a health functional food for the prevention and symptom relief of obesity or lipid-related metabolic diseases characterized in that the deoxysikonin inhibits the differentiation of fat cells.

The composition of the present invention, the deoxysiconin relative to the total weight of the composition 0.1 to 50% by weight. The composition comprising the deoxysiconin of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols or the like, oral preparations, suppositories or sterilized injection solutions according to a conventional method have. More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, water Can be prepared by mixing sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to commonly used diluents such as water and liquid paraffin . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

The present invention may vary depending on the age, sex and weight of the patient, but in general, an amount of 0.01 to 500 mg / kg, preferably 0.1 to 100 mg / kg, may be administered once to several times a day. . In addition, the dosage may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like by various routes. All modes of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection. The deoxysiconin of the present invention has little toxicity and side effects, and therefore can be used with confidence even for prolonged administration for prophylactic purposes.

The present invention provides a health functional food comprising the deoxysiconin and a food supplement acceptable food supplement, there are various foods, for example, beverages, gum, tea, vitamin complexes, health supplements, etc. It can be used in the form of a pill, powder, granule, acupuncture, tablet, capsule or beverage. At this time, the amount of the deoxysiconin in the food or beverage can generally be added to 0.01 to 15% by weight of the total food weight in the case of the health food composition of the present invention, 0.02 to 100 ml based on 100 ml for the health beverage composition 10 g, preferably 0.3 to 1 g.

Food additives as defined herein include food additives customary in the art, such as flavorings, flavors, colorants, fillers, stabilizers, and the like. The health beverage composition according to the present invention is an essential ingredient in the ratio indicated, and there is no particular limitation on the ingredients added in addition to the deoxysiconin, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have. Examples of the natural carbohydrate include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrins; And sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and its Salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

As described above, since deoxyshikonin according to the present invention is excellent in inhibiting adipocyte differentiation, the pharmaceutical composition and health function for the prevention and treatment of obesity or lipid-related metabolic diseases containing it as an active ingredient Can be used as food.

1 is a graph measuring lipid content when treated with deoxysikonin and not treated with hormone-induced differentiated adipocytes.

Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example

Example  One. Deoxysiconin ( Deoxyshikonin ) Screening of Sample

In order to investigate the prophylactic and therapeutic effects of obesity and lipid-related metabolic diseases, over 500 libraries were screened for 320 species, and the same procedure was repeated for 12 species and finally three compounds were selected. . One of them, Deoxyshikonin (Enzo life science, USA) is dissolved in dimethyl sulfoxide (DMSO) at a concentration of 2 mg / ㎖ to make a high concentration solution, and diluted in the culture medium so that the DMSO content of 20 ㎍ / ㎖ Cells were treated.

Example  2. Deoxysiconin  Inhibitory Activity of Adipocyte Differentiation

Hormone mixture (10 μg / ml insulin, 0.5 mM 3-isobutyl-1-methylxanthine, and 1 μg / ml dexamethasone) into adipocyte progenitor 3T3-L1 cells (purchased from the American Tissue Culture Collection, USA) Was treated by mixing in a culture medium and then cultured for two days, 10 μg / ml of insulin was mixed in the culture medium, and then cultured for two days, and finally, the culture medium was treated with two days to induce adipocyte differentiation.

The deoxysiconin sample obtained in the above preparation was treated at a concentration of 10 μM from the initial stage of induction of adipocyte differentiation, and then the inhibitory activity of adipocyte differentiation was compared with the control without deoxysiconin sample. After staining with Oil Red O (ORO) was observed under a microscope and the lipid content was measured quantitatively confirmed the degree of inhibition of adipocyte differentiation (see Fig. 1).

As a result, as shown in FIG. 1, when the deoxysiconin sample was treated, the lipid content was reduced, indicating that the inhibitory activity of adipocyte differentiation was effectively inhibited.

Examples of formulations for the composition of the present invention are illustrated below. However, the following formulation examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following formulation examples.

Formulation example  One: Sanje  Produce

Deoxysiconin 300 mg

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

Deoxysiconin 50 mg

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

Deoxysiconin 50 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 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 injection

Deoxysiconin 50 mg

Sterile sterilized water for injection

pH adjuster

(2 ml) per 1 ampoule according to the usual injection preparation method.

Formulation example  5: Liquid  Produce

Deoxysiconin 100 mg

10 g of isomerized sugar

5 g of mannitol

Purified water

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.

Formulation example  6: Manufacture of health food

Deoxysiconin 1000 mg

Vitamin mixture proper amount

70 μg 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 0.5mg

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.

Formulation example  7: Manufacture of health drinks

Deoxysiconin 1000 mg

Citric acid 1000 mg

100 g oligosaccharides

Plum concentrate 2 g

1 g of taurine

Add 900 ml of purified water

After mixing the above components according to a conventional healthy beverage production method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 l container, sealed sterilization and then refrigerated and stored in the present invention For the preparation of healthy beverage compositions.

Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.

While the present invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. You will know. In addition, many modifications may be made to adapt a particular situation and material to the teachings of the invention without departing from the essential scope thereof. Accordingly, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention be construed as including all embodiments falling within the scope of the appended claims.

Claims (8)

Obesity containing deoxyshikonin as an active ingredient, or at least one obesity selected from the group consisting of diabetes mellitus, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease and metabolic syndrome in which these diseases occur simultaneously Pharmaceutical composition for the prevention or treatment of lipid-related metabolic diseases caused by. delete The method of claim 1,
One or more selected from the group consisting of obesity, diabetes, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease and metabolic syndrome in which the diseases occur simultaneously, characterized in the form of capsules, tablets, granules, powders or beverages Pharmaceutical composition for the prevention or treatment of lipid-related metabolic diseases caused by obesity. The method of claim 1,
Obesity characterized by inhibiting the differentiation of adipocytes or diabetes mellitus, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease and at least one obesity selected from the group consisting of metabolic syndrome in which these diseases occur simultaneously Pharmaceutical compositions for the prevention or treatment of lipid-related metabolic diseases. Lipids caused by obesity, which contains deoxysiconin as an active ingredient, or one or more obesity selected from the group consisting of diabetes, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease and metabolic syndrome in which these diseases occur simultaneously Functional foods for the prevention or alleviation of symptoms related metabolic diseases. delete 6. The method of claim 5,
One or more selected from the group consisting of obesity, diabetes, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease and metabolic syndrome in which the diseases occur simultaneously, characterized in the form of capsules, tablets, granules, powders or beverages Health functional food for the prevention or symptom relief of lipid-related metabolic diseases caused by obesity. 6. The method of claim 5,
Obesity characterized by inhibiting the differentiation of adipocytes or diabetes mellitus, hyperlipidemia, fatty liver, arteriosclerosis, hypertension, cardiovascular disease and at least one obesity selected from the group consisting of metabolic syndrome in which these diseases occur simultaneously Health functional food for the prevention or symptom relief of lipid related metabolic diseases.

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