KR101640258B1 - Anti-obesity composition comprising red grape extracts, green tea extracts, soybean extracts, and L-carnitine - Google Patents

Abstract

The present invention relates to an anti-obesity composition comprising as an active ingredient at least one selected from the group consisting of green tea extract and soybean extract, and L-carnitine as an active ingredient. The present invention relates to an anti-obesity composition containing weight loss, reduced blood lipid concentration, And has excellent anti-obesity effect as well as an effect of reducing liver lipid deposition and also improving fatty liver. Therefore, the anti-obesity composition of the present invention is expected to be able to prevent and treat obesity and fatty liver simultaneously by effectively acting on improving obesity, liver quality and liver damage.

Description

An anti-obesity composition comprising red grape extract, green tea extract, soybean extract and L-carnitine as active ingredients,

The present invention relates to an anti-obesity composition, and more particularly, to an anti-obesity composition containing at least one red and green grape extract selected from the group consisting of green tea extract and soybean extract and L-carnitine as an active ingredient. The present invention has an excellent anti-obesity effect such as weight loss, reduction of blood lipid concentration, decrease of body fat and decrease of blood leptin concentration, as well as an effect of reducing hepatic lipid deposition, and thus shows an excellent effect in improving obesity-related diseases.

Obesity is a phenomenon in which excess energy is accumulated in body fat due to an imbalance between the energy consumed by food and the energy consumed by physical activity. Generally, obesity means excessive fat tissue in the body. If such obesity persists for a long time, various metabolic diseases such as diabetes, hyperlipemia, heart disease, stroke, arteriosclerosis, fatty liver and adult diseases are induced. Due to excessive caloric intake and lack of exercise, the obesity population is rapidly increasing not only in developed countries but also in Korea, which is becoming a serious social problem.

Obesity is known to be the main cause of excess energy supply, which is caused by the accumulation of fat in the body by inducing an increase in fat cell size and number. In addition, genetic factors, environmental factors by Westernized diet, psychological factors, It is known that various causes such as abnormalities are acting.

There is a multidisciplinary study on the development of obesity drugs worldwide. Drugs for the treatment of obesity can be broadly divided into the inhibition of fat absorption, the promotion of fat decomposition and heat generation, the regulation of appetite and satiety, the inhibition of protein metabolism, and the emotional regulation associated with the ingestion of food. Representative anti-obesity agent is a rideoktil ^™ (Reductil ^™) to stimulate the sympathetic nervous system as Xenical ^™ (Xenical ^™) as the main ingredient of sibutramine in the oristat as a raw material suppresses fat absorption inhibiting appetite. However, Xenical ^™ has been reported to have adverse effects such as nausea, abdominal pain, vomiting, itching, and liver damage. Reductin ^™ has serious side effects such as headache, anorexia, insomnia and constipation as well as serious cardiovascular side effects There has been controversy such as the recent use standard being strengthened. In addition to pharmacotherapy through these obesity drugs, there are also dietary therapies to limit the intake of foods and exercises to increase energy consumption, psychotherapy, behavioral therapy, and surgical therapy.

The preferred method of treating obesity is to promote energy consumption through exercise and to treat obesity drugs with few side effects as the most safe and effective method. However, in the case of obesity treatment drugs, severe side effects such as the above examples of Xenical ^™ and Reductil ^™ have been reported, and there is no clear reliance on safety. Therefore, it is required to develop a substance which shows excellent efficacy of anti-obesity against the human body while ensuring 100% safety. Recently, various studies have been made on substances for treating obesity through in vivo fat burning / degradation mechanism and energy metabolism promotion mechanism, and in particular, functional foods based on a material capable of ensuring safety to human body And so on.

Accordingly, the inventors of the present invention have found that a composition containing at least one selected from the group consisting of green tea extract and soybean extract and the red grape extract and L-carnitine as an active ingredient is useful for weight loss, reduction of blood lipids concentration, Leptin concentration and decreased liver lipid deposition as well as an excellent anti-obesity effect such as reduction of leptin concentration. Thus, the present inventors have completed the present invention.

It is an object of the present invention to provide an anti-obesity composition comprising at least one selected from the group consisting of green tea extract and soybean extract and L-carnitine as an active ingredient.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating obesity or fatty liver comprising the above anti-obesity composition.

It is an object of the present invention to provide a food composition for preventing or improving obesity or fatty liver comprising the above anti-obesity composition.

In one aspect, the present invention relates to an anti-obesity composition comprising at least one and at least one red and green grape extract selected from the group consisting of green tea extract and soybean extract and L-carnitine as an active ingredient.

The present inventors have found that a composition comprising grape extract, green tea extract and L-carnitine, a composite composition comprising grape extract, soybean extract and L-carnitine, and a complex composition comprising grape extract, green tea extract, soybean extract and L-carnitine It was confirmed that the composition had an anti-obesity effect. In particular, the present inventors have found that a composition comprising red grape extract, green tea extract and L-carnitine, a composite composition comprising red grape extract, soybean extract and L-carnitine, and a composition comprising red grape extract, green tea extract, It was confirmed that the composite composition containing carnitine had an anti-obesity effect.

More specifically, the inventors of the present invention found that the combination of at least one selected from the group consisting of red grape extract, green tea extract, soybean extract and L-carnitine was mixed in various combinations, and as a result, the red grape extract, green tea extract, Carnitine (Example 1, treatment group 1) and a composite composition (Example 2, treatment group 2) containing red grape extract, green tea extract and L-carnitine, and red grape extract, soybean extract and L- (Experimental Example 1), blood lipid concentration reduction effect (Experimental Example 2), hepatic tissue and body fat reduction effect (Experimental Example 3), plasma The effect of reducing my glucose concentration, the effect of improving liver lipids, and the inhibitory effect on leptin secretion (Experimental Example 4). Particularly, the composition obtained by mixing all four substances showed excellent anti-obesity effect.

On the contrary, the extracts of green grape extract (Comparative Example 5, treatment group 8), green tea extract (Comparative Example 6, treatment group 9), soybean extract (Comparative Example 7, treatment group 10), and L- (Comparative Example 2, Treatment Group 5), the composite composition containing the red grape extract and the soybean extract (Comparative Example 3, treatment group 5), and the composite composition containing the red grape extract and the green tea extract (Comparative Example 4, Treatment Group 7), and Composite Composition Containing Green Grape Extract, Green Tea Extract and Soybean Extract (Comparative Example 1, Treatment Group 4), and Composite Composition Containing Red Grape Extract and L-Carnitine ) Had little effect on anti-obesity.

Thus, the inventors of the present invention have found that grape extract, green tea extract (and / or soybean extract), and L-lactic acid extract are superior to the single composition or the composite composition of the two materials, (Or / and soybean extract) and L-carnitine according to the present invention can be obtained by extracting grape extract, green tea extract (and / or green tea extract) and / or carnitine, And soybean extract), and L-carnitine, resulting in remarkably elevated anti-obesity effect even when contained at a low concentration.

The term " anti-obesity composition " in the present invention refers to a composition exhibiting an effect of at least one of weight loss, reduction of blood lipid concentration, reduction of liver tissue and body fat, decrease of plasma glucose concentration, improvement of liver lipid, and inhibition of leptin secretion, The anti-obesity composition can be used to ameliorate, prevent, or treat various metabolic diseases such as diabetes, hyperlipidemia, heart disease, stroke, arteriosclerosis, fatty liver, etc. derived from obesity-related diseases such as obesity and obesity.

In the present invention, 'grape extract' can be extracted from various organs of natural, hybrid, and variant plants and extracted from, for example, shells, seeds as well as plant tissue cultures. Various methods known in the art can be used to prepare grape extracts using various solvents and include purified water, methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, 1,3-butylene glycol, ethyl acetate, The solvent may be one or more selected from the group consisting of the solvents. The solvent may be extracted using 5 to 100% ethanol, and more preferably 70% ethanol. According to a specific embodiment of the present invention, red grape extract was obtained using 70% ethanol. Can be extracted according to various extraction methods such as cold extraction, heat extraction, ultrasonic extraction, and cold extraction as known in the art. The extraction method is not particularly limited, and extraction can be carried out at room temperature or with heating under conditions where the active ingredient is not destroyed or minimized. In addition, it may be dried according to various drying methods such as hot air drying, freeze drying, vacuum drying, etc., as is known in the art. Alternatively, commercially produced goods may be used.

In order to achieve the object of the present invention, the grape extract of the present invention is preferably red grape extract and preferably contains resveratrol as an active ingredient. More preferably, the grape extract contains 0.2 to 5% by weight of resveratrol. Resveratrol is a polyphenol substance contained in grape skin, grape seed, peanut and the like. Phytoalexin, an antibiotic made into a defense system when a plant is exposed to molds or pests, has been reported to have effects such as anticancer, antiviral, neuroprotection, anti-aging, and life extension. In particular, it has been reported that activation of intracellular SIRT1 and PGC-1α increases mitochondrial function and induces metabolic activity (Seung-Hoi Koo et al., 2006).

In the present invention, the 'green tea extract' can be extracted from various organs of natural, hybrid, and variant plants, and can be extracted from, for example, leaves and stems as well as plant tissue cultures. According to a specific embodiment of the present invention, Were used. The green tea extract may be prepared using various solvents by various methods known in the art. For example, the green tea extract may be prepared by washing, drying and pulverizing green tea; And the pulverized green tea is mixed with one or more solvents selected from the group consisting of purified water, methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, 1,3-butylene glycol, ethyl acetate and acetone And then extracting it by using a solvent. Can be extracted according to various extraction methods such as cold extraction, heat extraction, ultrasonic extraction, and cold extraction as known in the art. The extraction method is not particularly limited, and extraction can be carried out at room temperature or with heating under conditions where the active ingredient is not destroyed or minimized. In addition, it may be dried according to various drying methods such as hot air drying, freeze drying, vacuum drying, etc., as is known in the art. According to a specific embodiment of the present invention, green tea extract was obtained from green tea leaves using purified water. In addition, the green tea extract may be a commercially produced product.

The 'green tea' contains a large amount of catechin such as epicatechin, epicatechin galate, epigallocatechin, and epigallocatechin gallate (EGCG) It is a kind of phenol and is known to have strong antioxidant activity. Therefore, green tea containing catechin exhibits effects such as antioxidative action, anti-inflammatory action, as well as prevention of arteriosclerosis, cancer, and neurological diseases. In particular, the EGCG component of catechins is known to prevent the development of type 1 diabetes and to lower triglyceride and low-density lipoprotein (LDL) in the blood to prevent adult diseases such as hyperlipemia and arteriosclerosis.

In the present invention, the 'soybean extract' can be extracted from various organs of natural, hybrid, and variant plants and extracted from plant tissue cultures as well as embryos, for example. The soybean extract can be prepared using various solvents by various methods known in the art, and can be prepared by mixing purified water, methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, 1,3-butylene glycol, ethyl acetate, And one or more solvents selected from the group consisting of the above-mentioned solvents can be mixed and extracted. According to a specific embodiment of the present invention, soybean extract is obtained through hot water extraction using purified water. Can be extracted according to various extraction methods such as cold extraction, heat extraction, ultrasonic extraction, and cold extraction as known in the art. The extraction method is not particularly limited, and extraction can be carried out at room temperature or with heating under conditions where the active ingredient is not destroyed or minimized. In addition, it may be dried according to various drying methods such as hot air drying, freeze drying, vacuum drying, etc., as is known in the art. Alternatively, commercially produced goods may be used.

In order to achieve the object of the present invention, the soybean extract of the present invention preferably contains isoflavone as an active ingredient. More preferably, the soybean extract contains 0.2 to 10% by weight of isoflavone. The 'isoflavone' is a kind of soybean protein contained in soybean and has a structure similar to that of estrogen, which is a female hormone, and is known to activate its action by binding to an estrogen receptor in the body. It has also been reported that depression, osteoporosis, and other deficiencies of female hormones may alleviate the symptoms of menopausal symptoms.

The complex composition of the present invention is based on natural extracts such as grape extract, green tea extract, and soybean extract, and has safety, toxicity, and side effects, so that it can be taken for a long period of time. In addition, the composition may be used not only for humans but also for animals such as cattle, dogs, etc. where obesity-related diseases may occur.

In addition, in the present invention, carnitine can be isolated from natural materials and can be produced by chemical synthesis methods according to methods known in the art. Carnitine is one of the vitamin B complexes, and is an enzyme that acts to transfer fatty acids to mitochondria in the process of decomposition of fatty acids into energy. One of the two isomers of carnitine, L-carnitine, is called vitamin Bt. It has been reported that L-carnitine plays an important role in mitochondrial β-oxidation processes for energy production in various cells (Yano H. et al., Mol Cell Biochem, 2010), CPT- 1 enzyme.

The grape extract, green tea extract (and / or soybean extract), and L-carnitine in the composition according to the present invention can be contained at various weight ratios as long as they can cause synergistic action with each other.

Preferably, grape extract (a), green tea extract (b) and L-carnitine (c) can be contained in a ratio of a: b: c = 1 to 2: 1 to 1.2: 0.2 to 80% by weight of grape extract, 0.2 to 60% by weight of green tea extract, and 0.2 to 50% by weight of L-carnitine may be prepared. If it is contained in an amount of less than 0.2% by weight, it may be difficult to expect an anti-obesity effect in an amount less than the recommended minimum use amount. If the content is more than 80% by weight, 60% by weight and 50% by weight or more, The effect is not increased, and therefore, it may not be suitable for economic reasons or the like.

Preferably, the grape extract (a), the soybean extract (b1) and the L-carnitine (c) can be contained in a ratio of a: b1: c = 1 to 4: 1: 0.2 to 80% by weight of grape extract, 0.2 to 80% by weight of soybean extract, and 0.2 to 50% by weight of L-carnitine, respectively. If it is contained in an amount less than 0.2% by weight, it may be difficult to expect an anti-obesity effect in an amount less than the recommended minimum use amount. If the content is more than 80% by weight, 80% by weight and 50% by weight or more, The effect is not increased, and therefore, it may not be suitable for economic reasons or the like.

The composition containing the grape extract (a), the green tea extract (b), the soybean extract (b1) and the L-carnitine (c) is preferably a: b: b1: c = 1 to 4: 1 to 3, and 0.2 to 40 wt% of the grape extract, 0.2 to 30 wt% of the green tea extract, 0.2 to 30 wt% of the soybean extract, and L-carnitine Can be prepared to contain 0.2 to 40% by weight. If it is contained in an amount less than 0.2% by weight, it may be difficult to expect an anti-obesity effect in an amount less than the recommended minimum use amount. If the content is 40% by weight, 30% by weight, 30% The effect is not increased in direct proportion with respect to the market, and therefore may not be suitable for economic reasons.

According to a specific embodiment of the present invention, red grape extract, green tea extract, and L-carnitine were contained in the composition at a ratio of 1: 1: 1, and each was prepared so as to contain 33% by weight based on the total weight Example 2). In addition, the composition contained red grape extract, soybean extract, and L-carnitine in a ratio of 1: 1: 1, and each of the red grape extract, soybean extract and L-carnitine was contained in an amount of 33% by weight based on the total weight. Carnitine was added to the composition in an amount of 1: 1: 1: 1, and each composition contained 25% by weight based on the total weight of the composition (Example 1 ).

In addition, grape extract, green tea extract (and / or soybean extract) and L-carnitine in the composition according to the present invention may be contained in various ranges as long as they can cause synergistic action with each other. For example, the grape extract, green tea extract (or soybean extract) and L-carnitine may be contained in an amount of 0.6 to 100% by weight based on the total weight, but are not limited thereto. The grape extract, green tea extract, soybean extract and L-carnitine may be contained in an amount of 0.8 to 100% by weight based on the total weight, but are not limited thereto. According to a specific embodiment of the present invention, in Example 1, it was contained in an amount of 100% by weight based on the total weight, and in Example 2 and Example 3, it was contained in an amount of 99.9% by weight based on the total weight.

The anti-obesity composition according to the present invention exerts excellent effects on weight loss, reduction of blood lipid concentration, decrease of liver tissue and body fat, decrease of glucose concentration in plasma, improvement of liver lipid, and inhibition of leptin secretion, effective.

Accordingly, in another aspect, the present invention provides a pharmaceutical composition for preventing or treating obesity or fatty liver comprising said anti-obesity composition and a method for preventing or treating obesity or fatty liver by administering said anti-obesity composition.

The term " prophylactic " in the present invention refers to any action that inhibits or delays the onset of the obesity-related disease by the administration of the anti-obesity composition according to the present invention.

The term " treatment " in the present invention refers to any action that improves or alleviates symptoms of the obesity-related disease by administration of the anti-obesity composition according to the present invention.

The compositions according to the present invention may be formulated into pharmaceutical formulations using methods well known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. In the preparation of the formulations, it is preferred that the compositions according to the invention are mixed or diluted with the carrier or enclosed in a carrier in the form of a container.

Accordingly, the pharmaceutical composition of the present invention can be formulated in the form of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, aerosols, And can be used as formulations. Examples of carriers, excipients and diluents that can be included in the pharmaceutical 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. 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.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, Can be prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, Can be used.

Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and the suspending agent include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, injectable esters such as ethyl oleate, and the like.

In addition, the pharmaceutical composition of the present invention may further comprise a carrier, an excipient or a diluent. Examples of the carrier, excipient or diluent include lactose, textol, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Mineral such as propyl methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, silicon dioxide and the like can be used have.

The dosage of the pharmaceutical composition according to the present invention should be a pharmaceutically effective amount. The term " pharmaceutically effective amount " as used herein means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will vary depending on the formulation method, , The sex of the patient, the age, the severity of the disease, the drug form, the route and time of administration, the excretion rate, the responsiveness, and the like. Effective amounts may vary depending on the route of treatment, the use of excipients, and the likelihood of use with other agents, as will be appreciated by those skilled in the art. For the desired effect, in the case of oral administration, generally 1 to 500 mg, preferably 50 to 100 mg per 1 kg body weight of the pharmaceutical composition according to the present invention can be administered, which is administered once to several times per day, Preferably 1 to 3 times, but the dosage and the number of times do not limit the scope of the present invention in any way.

The pharmaceutical composition of the present invention can be administered via various routes to mammals such as rats, mice, livestock, humans, and the like. All modes of administration are contemplated and may be administered, for example, by oral, parenteral, intravenous, intradermal, and subcutaneous injection.

In another aspect, the present invention provides a method of treating obesity or obesity comprising said anti-obesity composition,

There is provided a food composition for prevention or improvement of fatty liver.

The above food composition may be a functional food according to the purpose of the present invention. The above-mentioned 'functional food' is a food emphasizing the biological control function of food, and it is a food which functions and manifests itself for a specific purpose using physical, biochemical, It is a food added value. These functional food ingredients are designed and processed so that the body control functions related to the regulation of the body defense and the body rhythm, the prevention and recovery of the disease are sufficiently exhibited to the living body, and the food can be supplemented with food, a sweetener or a functional ingredient ≪ / RTI >

Examples of the food composition to which the anti-obesity composition according to the present invention can be added include various foods such as beverages, gums, tea, vitamin complexes, health supplements, etc. The beverage includes natural fruit juice, Fruit juice drinks, and vegetable drinks.

The food composition of the present invention can be prepared in the form of tablets, tablets, granules, powders, capsules, liquid solutions, rings and the like according to known production methods. According to a specific embodiment of the present invention, capsules were prepared in Examples 4 and 5, tablets in Examples 6 and 7, and drinks in Examples 8 and 9. However, Examples 4 and 5 are preparative examples for producing a conventional hard capsule containing a composition for dietary intake having an anti-obesity effect, and do not limit the formulations and raw materials of the present invention. Examples 6 and 7 are preparative examples for producing a conventional tablet containing a composition for dietary intake having an anti-obesity effect, and do not limit the formulations and raw materials of the present invention. Examples 8 and 9 are preparative examples for producing a conventional beverage containing a composition for dietary intake having an anti-obesity effect, and are not intended to limit the formulations and raw materials of the present invention.

In addition, the food composition of the present invention may further contain various conventional flavors, natural carbohydrates and the like. Flavors include natural flavors such as tau Martin and stevia extract, and synthetic flavors such as saccharin and aspartame. The above-mentioned natural carbohydrates may include polysaccharides such as disaccharides such as glucose, monosaccharide such as fructose, maltose, sucrose, dextrin, cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol . In general, the natural carbohydrate is preferably contained in a proportion of 1 to 20 g, preferably 5 to 12 g per 100 ml of the composition of the present invention. In addition, the food composition of the present invention may further contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring agents, heavy stabilizers (cheese, chocolate etc.), pectic acid and its salts, Salt, organic acids such as anhydrous citric acid, protective colloid thickener, pH adjusting agent, stabilizer, preservative, glycerin, alcohol, carbonating agent used in carbonated drinks, natural fruit juice, fruit juice etc. Lt; RTI ID = 0.0 > additive < / RTI > These additives may be used independently or in combination, and the ratio of the additives is not particularly limited, but may be appropriately selected in the range of 0 to 20 parts by weight, preferably 0.001 to 20 parts by weight, per 100 parts by weight of the composition .

In another embodiment, the anti-obesity composition according to the present invention may be used as a cosmetic composition or a quasi-drug composition for improving or preventing obesity or fatty liver.

In another aspect, the present invention provides an anti-obesity composition comprising resveratrol, green tea extract, and L-carnitine as an active ingredient.

In addition, in another aspect, the present invention provides an anti-obesity composition containing resveratrol, soybean extract, and L-carnitine as an active ingredient.

In another aspect, the present invention provides an anti-obesity composition comprising grape extract, isoflavone, and L-carnitine as an active ingredient.

Further, in another aspect, the present invention provides an anti-obesity composition containing resveratrol, isoflavone, and L-carnitine as an active ingredient.

In another aspect, the present invention provides an anti-obesity composition comprising resveratrol, soybean extract, green tea extract and L-carnitine as active ingredients.

In addition, in another aspect, the present invention provides an anti-obesity composition comprising resveratrol, isoflavone, green tea extract and L-carnitine as an active ingredient.

In another aspect, the present invention provides an anti-obesity composition comprising grape extract, isoflavone, green tea extract and L-carnitine as active ingredients.

The resveratrol and isoflavone may be separated from natural materials, for example, resveratrol may be isolated from the grape extract and isoflavone may be isolated from soybeans, or may be isolated by chemical methods known in the art Or may be produced by a synthetic method.

In another aspect, there is provided a pharmaceutical composition for preventing or treating obesity or fatty liver comprising the above anti-obesity composition.

In addition, in another aspect, there is provided a food composition, quasi-drug composition or cosmetic composition for improving or preventing obesity or fatty liver including the above anti-obesity composition.

It is expected that the anti-obesity composition of the present invention can effectively prevent obesity, liver damage and hepatic damage, thereby simultaneously preventing and treating obesity, metabolic diseases caused by obesity and fatty liver.

FIG. 1 is a graph showing the body weight of a mouse induced by obesity in a high fat diet after administering the complex for 8 weeks in order to confirm the weight loss effect of the anti-obesity composition according to the present invention.
FIG. 2 is a graph showing blood lipids concentration in blood after collecting the compound for 8 weeks in a mouse to examine the lipid-improving effect of the anti-obesity composition according to the present invention.
FIG. 3 is a graph showing weights of liver, epididymal fat, subcutaneous fat and visceral fat extracted after administration of a compound to a mouse for 8 weeks in order to confirm the effect of reducing the body fat of the anti-obesity composition according to the present invention.
FIG. 4 is a graph showing changes in blood biochemical indicators by the anti-obesity composition according to the present invention. After 8 weeks of high fat diet induced obesity, , Glucose, and leptin.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these examples and experimental examples are intended to illustrate the present invention, and the scope of the present invention is not limited to these examples.

[ Example  1] Preparation of the mixture

1-1. Manufacture of green tea extract

1 kg of dried green tea leaves and 23 to 30 kg of purified water were added to an extractor and then extracted at a temperature of about 60 to 70 ° C for about 3 hours. After the extraction was completed, green tea leaf and its suspension were removed through a filtration apparatus and spray dried to obtain about 250 g of powdery green tea extract.

1-2. Preparation of red grape extract

1 kg of dried red grape skin and 30 kg of 70% ethanol were put into an extractor and then extracted twice at a temperature of about 60 to 70 캜 for about 2 hours. The red grape skin and its suspension were removed through a filtration device and spray dried to obtain red grape extract in powder form. The red grape extract of the present invention contained resveratrol in an amount of 0.2 to 5% by weight.

1-3. Production of soybean extract

Five to 10 kg of purified water was added to 1 kg of soybean embryo and the mixture was stirred at 80 ° C for 2 hours. The thus obtained extract was filtered to remove residues and lyophilized to obtain a powdery soybean extract. The soybean extract contained isoflavones in an amount of 0.2 to 10% by weight.

1-4. Preparation of mixtures

L-carnitine was purchased from Lonza (Basel, Switzland), L-carnipure crystalline.

25% by weight of the red grape extract, green tea extract, soybean extract and L-carnitine were converted into 25% by weight of the green grape extract in terms of the content ratio (unit:% by weight) %, Soybean extract 25 wt%, and L-carnitine 25 wt%, to prepare a mixture.

[ Example  2] to [ Example  3], [ Comparative Example  1] to [ Comparative Example  8]

As shown in Table 1, the red grape extract, green tea extract, soybean extract and L-carnitine were prepared in the same manner as in Example 1 except that the content was changed.

Red grape extract
(weight%) Green tea extract
(weight%) Soybean extract
(weight%) L-carnitine
(weight%) Example 1 25 25 25 25 Example 2 33.3 33.3 0 33.3 Example 3 33.3 0 33.3 33.3 Comparative Example 1 33.3 33.3 33.3 0 Comparative Example 2 50 50 0 0 Comparative Example 3 50 0 50 0 Comparative Example 4 50 0 0 50 Comparative Example 5 100 0 0 0 Comparative Example 6 0 100 0 0 Comparative Example 7 0 0 100 0 Comparative Example 8 0 0 0 100

[ Experimental Example  1] mouse Red grapes  Extract, green tea extract, soybean extract and L- Carnitine  Confirm weight loss effect of complex

To investigate the effect of the composition of the present invention on lipid metabolism in an animal model of obesity induced by high fat diet, 100 male C57BL / 6 mice were experimented. Obesity was induced by 7 - week - old C57BL / 6 mice for 3 weeks in a high fat diet, and 7 rats were randomly allocated to each group. Each group received 600 mg of the mixture of Examples 1 to 3 and Comparative Examples 1 to 8 prepared in the ratio of Table 1 together with the control group 1 fed with the normal diet, the control group 2 fed with the high fat diet, (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11) were administered orally at a dose of 1 mg / day / kg. In the case of the treatment groups (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11), the mixture was administered to the mice using a feeding needle, And then administered orally. In the case of control group 2, only pure water was orally administered to set as a medium control group. Oral administration was performed at the same time every day for a total of 8 weeks over 6 days.

The feeds consumed by the animals were used during the refinement and quarantine period using a solid feed for the animals (Harlan, Polaris International, Inc.). During the administration and observation period, 60% of the total calories were consumed in the high fat diet 60% Kcal, Research Diets, supplier: Central laboratory animals) were used.

All animals were weighed twice a week immediately prior to administration and at the beginning of the administration and the change in body weight after the end of the 8-week administration was calculated and shown in Table 2 and FIG.

Classification Weight gain (%) Standard Deviation IR (%) Control 1 Normal feed 113.2 ± 5.8 Control group 2 High fat feed 148.4 ± 9.1 Treatment group 1 Example 1 115.8 ± 9.6 22.0 *** Treatment group 2 Example 2 117.5 ± 12.7 20.8 *** Treatment group 3 Example 3 125.2 ± 11.8 15.6 ** Treatment group 4 Comparative Example 1 134.5 ± 15.2 9.4 Treatment group 5 Comparative Example 2 131.9 ± 12.5 11.1 Treatment group 6 Comparative Example 3 133.5 ± 7.6 10.0 Treatment group 7 Comparative Example 4 132.4 ± 6.6 10.8 * Treatment group 8 Comparative Example 5 144.5 ± 8.3 2.6 Treatment group 9 Comparative Example 6 140.4 ± 11.3 5.4 Treatment group 10 Comparative Example 7 140.5 ± 10.4 5.3 Treatment group 11 Comparative Example 8 138.3 ± 8.9 6.8 *

* Significant (t-TEST): * p <0.05, ** p <0.01, *** p <0.001 vs control group 2

IR (%): Inhibition rate, 100 [(treated group / control group 2) * 100]

As shown in Table 2, the body weight of the high-fat diet control group 2 was significantly increased compared to that of the normal diet diet control group 1, indicating that dietary fat was effectively induced (p <0.05).

There was no difference in body weight between the groups before starting the experiment, since the obesity was induced in the high fat diet for 3 weeks before the start of the administration and then the equal weight was distributed among the 7 groups in each group. The weight loss effect and the inhibition rate were different according to each mixture.

Specifically, about 22.0% of the body weight reduction effect (p <0.001) was observed in the treatment group 1 (red grape extract + green tea extract + soybean extract + L-carnitine) Carnitine (2) (red grape extract + green tea extract + L-carnitine) and 3 (red grape extract + soybean extract + L-carnitine) And 15.6% (p <0.05), respectively.

However, in the case of treatment group 4 (red grape extract + green tea extract + soybean extract) and treatment group 5, 6, and 7 in which two substances were mixed in combination of three substances among the four substances, each ingredient was administered alone There was no significant difference except for treatment group 7, but the tendency was confirmed only in the treatment group 8, 9, 10 and 11. In addition, no significant weight loss effect was observed in the treatment groups 8, 9, 10, and 11 administered with only a single substance (p> 0.05).

From these experimental results, it was confirmed that when the four components of red grape extract, green tea extract, soybean extract and L-carnitine were all mixed, there was a synergistic effect between the components, so that it was possible to effectively suppress the weight gain by the high fat diet Respectively. In addition, the combination of three components of red grape extract, green tea extract or soybean extract in L-carnitine showed an increased inhibitory effect on obesity, and compared with treatment group 3 in which soybean extract was mixed, green tea extract was mixed The effect was better in one treatment group 2. On the other hand, the combination of treatment group 4 did not show elevated anti-obesity efficacy. This indicated that specific synergistic effects may occur when red grape extracts interacted with green tea extract (and / or soybean extract) and L-carnitine in a complex manner.

As a result of the combination of four substances with a low effective range as a single substance, it was found that the best combination of four substances (red grape extract + green tea extract + soybean extract + L-carnitine) Which was a synergistic effect due to the synergistic action of each substance. In addition, the combination of red grape extract + green tea extract (or soybean extract) + L-carnitine showed excellent weight loss among the three compounded compounds, which is also synergistic Showed that elevated efficacy could be demonstrated.

[ Experimental Example  2] Red grapes  Extract, green tea extract, soybean extract and L- Carnitine  Reduction of blood lipid levels by complex

The blood of Experimental Example 1 was collected from the mice before the start of administration and after the administration of the mice for 8 weeks. TG, cholesyterol (TC), and LDL (low density) were measured by using a measurement kit (Youngdong Pharma). The blood was collected by centrifugation and heparinized. lipoprotein-cholesterol (LDL-c) levels were measured. The results are shown in Table 3 and FIG. 2, and the values of the respective lipid indicators measured in the blood before the start of administration were expressed in terms of 100.

Classification TG TC LDL-c Average Standard Deviation Average Standard Deviation Average Standard Deviation Control 1 Normal feed 56.3 ± 11 106 ± 27.8 9 ± 2.1 Control group 2 High fat feed 69 ± 8.5 175 ± 11.7 11.7 ± 3.7 Treatment group 1 Example 1 22.4 ** ± 9.2 117.5 ** ± 20.4 5.7 * ± 3.0 Treatment group 2 Example 2 34.5 * ± 6.9 134.5 ± 8.2 7.5 * ± 2.9 Treatment group 3 Example 3 45.7 * ± 4.1 133.4 ± 23.8 6.9 * ± 2.4 Treatment group 4 Comparative Example 1 57.5 ± 3.5 168.5 ± 15.4 10.5 ± 1.1 Treatment group 5 Comparative Example 2 55.8 ± 14.1 159.8 ± 18.5 12.5 ± 3.2 Treatment group 6 Comparative Example 3 62.4 ± 12.4 186.4 ± 20.7 10.2 ± 2.2 Treatment group 7 Comparative Example 4 69.2 ± 12.3 179.8 ± 13.8 11.6 ± 1.2 Treatment group 8 Comparative Example 5 63.5 ± 5.7 168.9 ± 10.4 12.8 ± 1.8 Treatment group 9 Comparative Example 6 65.3 ± 2.3 183 ± 26.7 13.6 ± 2.6 Treatment group 10 Comparative Example 7 59.8 ± 6.7 179.5 ± 30.8 11.2 ± 4.8 Treatment group 11 Comparative Example 8 69.7 ± 10.6 185.7 ± 17.9 11.4 ± 3.8

* Significant (t-TEST): * p <0.05, ** p <0.01, *** p <0.001 vs control group 2

IR (%): Inhibition rate, 100 [(treated group / control group 2) * 100]

As a result of the experiment, it was confirmed that the levels of TG, TC and LDL-c in the treated group 1 (red grape extract + green tea extract + soybean extract + L-carnitine) (P <0.05). Specifically, the TG level was 67.5%, the TC level was 32.8%, and the LDL-c level was 51.3% in comparison with the control group 2, which was fed with high-fat diets. The effect was confirmed. In the case of treatment group 2 (red grape extract + green tea extract + L-carnitine) and treatment group 3 (red grape extract + soybean extract + L-carnitine) among three compounded substances, serum TG and LDL-c values (P <0.05), and only a tendency of decrease of TC in the blood was detected (p> 0.05). TG levels in the treated group 2 (red grape extract + green tea extract + L-carnitine) mixed with green tea extract were reduced by 50% as compared with the control group 2, and treated with soybean extract 3 (red grape extract + soybean Extract + L-carnitine) showed an inhibition rate of 41% in the blood LDL-c level.

Treated group 5 (red grape extract + green tea extract), treated group 6 (red grape extract + soybean extract), treated group 7 (red grape extract + green tea extract + soybean extract) Carnitine), treated group 8 (red grape extract), treated group 9 (green tea extract), treated group 10 (soybean extract), treated group 11 (L-carnitine) There was no improvement in blood lipids.

As a result of the above experimental results, it was found that when four substances (red grape extract, green tea extract, soybean extract, L-carnitine) showing little or no effect as a single substance were mixed at a low concentration, And ascending efficacy. The combination of all four substances showed the best blood lipid-lowering effect. When the red grape extract was mixed with green tea extract (or soybean extract) and L-carnitine, the serum TG, LDL- c improvement.

[ Experimental Example  3] Red grapes  Extract, green tea extract, soybean extract and L- Carnitine  Body fat reduction by complex

After the end of the 8-week administration, the mouse of Experimental Example 1 was autopsied and examined for liver tissue, epididymal adipose tissue, subcutaneous adipose tissue, mesentric adipose tissue, perirenal adipose tissue ) Tissues were weighed and weighed. The extracted tissues were washed with physiological saline, and the weight was measured by removing moisture. The average of each treatment group was calculated and shown in Table 4 and FIG.

Classification Liver (g) Epididymis fat (g) Avoid
Fat (g) guts
Fat (g) Control 1 Normal feed 1071.1 ± 160.9 478.5 + - 208.5 438.3 + 164.9 132.2 ± 78.6 Control group 2 High fat feed 1643.6 ± 330.6 2688.2 ± 379.5 3512.4 + - 848.4 1151 ± 147.1 Treatment group 1 Example 1 1045.8 ± 123.4
*** 1856.2 ± 152.6
** 2556.2 ± 568.4
* 985.1 ± 51.5
* Treatment group 2 Example 2 1063.5 ± 186.5
** 2213.5 ± 295.3
* 2956.5 + - 315.6 951.2 + - 126.5
* Treatment group 3 Example 3 1246.5 ± 200.7
* 1956.7 ± 165.9
** 2965.4 ± 485.9 1015.1 + - 46.5
* Treatment group 4 Comparative Example 1 1486 ± 180.7 2456.9 ± 201.1 3365.7 ± 102.4 1190.6 ± 75.4 Treatment group 5 Comparative Example 2 1356.4 ± 300.4 2568.2 ± 300.4 3265.6 ± 235.1 1265.4 ± 95.1 Treatment group 6 Comparative Example 3 1548.9 ± 358.1 2246.4 ± 264.0 3025.5 + 265.7 1156.5 ± 115.3 Treatment group 7 Comparative Example 4 1514.6 ± 112.5 2653.2 ± 325.4 3459.2 ± 112.1 1200.4 ± 132.2 Treatment group 8 Comparative Example 5 1653.7 ± 52.6 2689.5 ± 296.6 3326.4 + 346.2 1321.1 + - 95.1 Treatment group 9 Comparative Example 6 1698.2 ± 135.4 2756.4 ± 125.5 3259.8 ± 118.5 1256.2 ± 86.2 Treatment group 10 Comparative Example 7 1594.5 ± 267.5 2698.4 +/- 295.3 3568.9 + - 124.6 1145.8 ± 153.2 Treatment group 11 Comparative Example 8 1602.5 + - 382.2 2956.8 ± 185.3 3425.1 + - 132.4 1065.9 ± 56.1

* Significant (t-TEST): * p <0.05, ** p <0.01, *** p <0.001 vs control group 2

IR (%): Inhibition rate, 100 [(treated group / control group 2) * 100]

As shown in Table 4, in the treatment group 1 (red grape extract + green tea extract + soybean extract + L-carnitine) containing all four substances, liver tissue, epididymal fat, subcutaneous fat and visceral fat (P <0.05), respectively. Specifically, liver weight showed 36.4% inhibition rate of fat accumulation, 30.9% of epididymal fat, 27.2% of subcutaneous fat and 14.4% of visceral fat compared to control group 2.

In the case of treatment group 2 (red grape extract + green tea extract + L-carnitine) and treated group 3 (red grape extract + soybean extract + L-carnitine) among the three substances, liver tissue, epididymal fat and visceral fat Was significantly reduced. Treatment group 2 containing green tea extract was more effective in reducing liver and visceral fat. Treatment group 3 containing soybean extract showed excellent inhibitory effect on epididymal fat accumulation. (Red grape extract + green tea extract), treated group 6 (red grape extract + soybean extract + green soybean extract) treated group 4 (red grape extract + green tea extract + soybean extract) (Green tea extract), treatment group 10 (soybean extract), treatment group 11 (green tea extract), treatment group 7 (red grape extract + L-carnitine) L-carnitine) showed no significant weight loss.

 As a result of the experiment, it was verified that the elevated efficacy was obtained when the four substances having a small concentration of the effect were mixed singly as in the results of Examples 1 and 2 described above. In addition, it was confirmed that the combination of the red grape extract and one of the green tea extract or the soybean extract in L-carnitine effectively acts to reduce liver tissue and body fat.

[ Experimental Example  4] Red grapes  Extract, green tea extract, soybean extract and L- Carnitine  Measurement of blood biochemical changes by complex treatment

Blood was collected from all the mice of Experimental Example 1 by orbital blood collection at the end of the administration. The collected blood was centrifuged after heparin treatment and plasma was obtained. Using the automatic biochemical analyzer (AU400, Olympus, Japan), GOT (aspartate aminotransferase (AST), GPT Alanine aminotransferase (ALT) was measured. In addition, plasma levels of Leptin, which inhibits food intake and increases energy expenditure by hormones produced by obesity genes of adipocytes, were measured using a kit using the principle of enzyme-linked immunosolvent assay (ELISA).

Glucose concentration in plasma was significantly increased in control group 2 fed high fat diets and significantly decreased in treatment group 1 (red grape extract + green tea extract + soybean extract + L-carnitine) mixed with all four substances . In plasma GOT and GPT values, significant decrease was observed in the combination of the four substances (treatment group 1) and the treatment groups 2 and 3 of the combination of the three substances. Particularly, the excellent effect of inhibiting the GPT level by about 45% in the treated group 2 (red grape extract + green tea extract + L-carnitine) was confirmed (p <0.05).

Leptin levels in plasma were significantly increased by high fat diet (p <0.05), and leptin secretion in treated group 2 (red grape extract + green tea extract + L-carnitine) (P <0.05), respectively. Specifically, the secretion of leptin was inhibited by about 33.7% in the treatment group 2, and the results are shown in Fig.

[ Example  4] to [ Example  5] Capsule  Produce

Carnitine (Example 4) or green grape extract, green tea extract, soybean extract, and L-carnitine (Example 5) as main components and an excipient commonly used in hard capsules Silicon dioxide and magnesium stearate were used to prepare hard capsules in the combinations and contents shown in Table 5. [

ingredient Example 4 Example 5 Compounding ratio (% by weight) Content (mg) Compounding ratio (% by weight) Content (mg) Red grape extract 32.0 160.0 24.5 122.5 Green tea extract 33.0 165.0 24.5 122.5 L-carnitine 33.0 165.0 24.5 122.5 Soybean extract - - 24.5 122.5 Silicon dioxide 1.0 5.0 1.0 5.0 Magnesium stearate 1.0 5.0 1.0 5.0 Sum 100 500 100 500

As shown in Table 5, a mixture of red grape extract, green tea extract, and L-carnitine or red grape extract, green tea extract, soybean extract, and L-carnitine and excipient were uniformly agitated and granulated. This was injected into a hard capsule machine to prepare a conventional hard capsule.

[ Example  6] to [ Example  7] Preparation of tablets

Carnitine (Example 6) or red grape extract, green tea extract, soybean extract, and L-carnitine (Example 7) as main components, and an excipient such as lactose The tablets were prepared in the combination and contents shown in Table 6 using powders, crystalline cellulose, magnesium stearate and hydroxypropyl methyl cellulose (HPMC).

ingredient Example 6 Example 7 Compounding ratio (% by weight) Content (mg) Compounding ratio (% by weight) Content (mg) Red grape extract 20.0 100.0 15.0 75.0 Green tea extract 20.0 100.0 15.0 75.0 L-carnitine 20.0 100.0 15.0 75.0 Soybean extract - - 15.0 75.0 Lactose powder 18.0 90.0 18.0 90.0 Crystalline cellulose 20.0 100.0 20.0 100.0 Magnesium stearate 1.0 5.0 1.0 5.0 HPMC 1.0 5.0 1.0 5.0 Sum 100 500 100 500

As shown in Table 6, a mixture of red grape extract, green tea extract, and L-carnitine or red grape extract, green tea extract, soybean extract, and L-carnitine and excipient were uniformly agitated and granulated. This was injected into a tablet machine to produce a tablet of a passbook.

[ Example  8] to [ Example  9] Beverage Manufacturing

(Example 8) or green grape extract, green tea extract, soybean extract, and L-carnitine (Example 9) as main components and a natural carbohydrate The beverages were prepared in the combination and contents shown in Table 7 using fructose, anhydrous citric acid, vitamin C and purified water, which are food supplementary additives.

ingredient Example 8 Example 9 Compounding ratio (% by weight) Compounding ratio (% by weight) Red grape extract 1.4 1.05 Green tea extract 1.4 1.05 L-carnitine 1.4 1.05 Soybean extract - 1.05 Crystalline fructose 10.0 10.0 Anhydrous citric acid 0.4 0.4 Vitamin C 0.1 0.1 Purified water 85.3 85.3 Sum 100.0 100.0

As shown in Table 7, a mixture of red grape extract, green tea extract, and L-carnitine or red grape extract, green tea extract, soybean extract, and L-carnitine and excipients were homogeneously mixed using a high-speed stirrer, And the mixture was uniformly mixed. Then, the mixture was pasteurized and put into bottles or cans to prepare beverages.

Claims (23)

An antioxidant composition containing at least one or more grape extract and L-carnitine selected from the group consisting of green tea extract and soybean extract as active ingredients.
The anti-obesity composition according to claim 1, wherein the red grape extract contains resveratrol.
The anti-obesity composition according to claim 1, wherein the soybean extract contains isoflavones.
The antifoulant composition according to claim 1, wherein the green tea extract is extracted from green tea leaves.
The anti-obesity composition according to claim 1, wherein the extraction solvent of the green tea extract is purified water.
The anti-obesity composition according to claim 1, wherein the red grape extract is extracted from red grape skin.
The anti-obesity composition according to claim 1, wherein the extraction solvent of the red grape extract is ethanol.
The anti-obesity composition according to claim 1, wherein the soybean extract is extracted from a soybean embryo.
The anti-obesity composition according to claim 1, wherein the extraction solvent of the soybean extract is purified water.
The anti-obesity composition according to claim 1, which comprises the red grape extract: green tea extract: L-carnitine in a weight ratio of 1-2: 1 to 1.2: 1.
The anti-obesity composition according to claim 1, which comprises the red grape extract: soybean extract: L-carnitine in a weight ratio of 1: 4: 1: 1 to 3.
The anti-obesity composition according to claim 1, which comprises the red grape extract: green tea extract: soybean extract: L-carnitine in a weight ratio of 1: 4: 1 to 1.2: 1:
The anti-obesity composition according to claim 1, wherein the composition contains 0.2 to 80% by weight of grape extract, 0.2 to 60% by weight of green tea extract and 0.2 to 50% by weight of L-carnitine based on the total weight of the composition .
The anti-obesity composition according to claim 1, wherein the composition contains 0.2 to 80% by weight of grape extract, 0.2 to 80% by weight of soybean extract and 0.2 to 50% by weight of L-carnitine, .
The method according to claim 1, wherein 0.2 to 40 wt% of red grape extract, 0.2 to 30 wt% of green tea extract, 0.2 to 30 wt% of soybean extract, and 0.2 to 40 wt% of L- Lt; RTI ID = 0.0 &gt; anti-obesity &lt; / RTI &gt;
The anti-obesity composition according to claim 1, wherein the green tea extract or soybean extract, red grape extract and L-carnitine are contained in an amount of 0.6 to 100% by weight based on the total weight of the composition.
The anti-obesity composition according to claim 1, wherein the green tea extract, soybean extract, red grape extract and L-carnitine are contained in an amount of 0.8 to 100% by weight based on the total weight of the composition.
18. A pharmaceutical composition for preventing or treating obesity or fatty liver comprising the anti-obesity composition of any one of claims 1 to 17.
The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, aerosols and injection solutions A pharmaceutical composition.
19. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is administered by any route selected from the group consisting of oral, intravenous, intramuscular and subcutaneous injection.
18. An obesity or fatty liver improvement food composition comprising the anti-obesity composition of any one of claims 1 to 17.
22. The food composition according to claim 21, wherein the food composition is any one selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and rings.
The food composition according to claim 21, wherein the food composition further comprises at least one selected from the group consisting of a flavoring agent, a natural carbohydrate, a pharmaceutically acceptable food-aid additive, a carrier, an excipient and a diluent .

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