KR20190046411A - Composition comprising ezetimibe for preventing or treating immune disease or inflammatory disease - Google Patents

Abstract

The present invention relates to a pharmaceutical composition and a health functional food composition for preventing or treating immunological disease or inflammatory disease containing ezetimibe as an active component, which can induce Treg cell activity under a Th17 cell differentiation condition, thereby being able to effectively treat immunological disease or inflammatory disease.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating an immunological disease or an inflammatory disease comprising ezetimibe as an active ingredient,

The present invention relates to a pharmaceutical composition for preventing or treating an immunological disease or an inflammatory disease comprising ezetimibe as an active ingredient and a health functional food composition for preventing or ameliorating an immunological disease or inflammatory disease comprising ezetimibe as an active ingredient .

Although diseases caused by immune hyperresponsiveness are increasing worldwide, fundamental causes for the occurrence of these diseases have not been sufficiently elucidated. Currently, as a method of treating diseases due to an excessive immune response, immunosuppressive agents are administered alone or in combination to alleviate or reduce various symptoms caused by the diseases.

Immunosuppressants refer to various substances that are used to reduce or block the ability of a host to make antibodies (humoral immune response) or the ability to cause a cellular immune response to the action of an antigen. Such immunosuppressants can be used not only in organ transplantation fields but also in autoimmune diseases such as rheumatoid arthritis and rheumatoid arthritis, and skin hypersensitivity reactions such as atopy and allergy. Superior immunosuppressants should be able to control the imbalance of the immune response, ensure human safety, and have a low incidence of disease recurrence during long-term treatment.

There are currently used immunosuppressants such as cyclosporin A and FK506. These compounds are derived from natural materials having complex chemical structures, which are uneconomical due to high costs in terms of raw material supply and demand, and various side effects may be caused due to long-term administration Which is a risk. Therefore, there is a desperate need to develop a new immunosuppressive agent which can induce low toxicity and induce immunity and economical production.

On the other hand, there are T cells as one of the cell groups which plays a central role in the immune system as a bio-defense system for various pathogens. T cells are produced in the thymus of the human body, and undergo a series of differentiation processes, resulting in differentiation into T cells with inherent characteristics. The differentiated T cells are largely classified into type 1 (Th1) Auxiliary cells (Th2). Among these, Th1 cells are mainly involved in cell mediated immunity, Th2 cells are involved in humoral immunity, and in the immune system, these two cell populations maintain the balance of the immune system through mutual checks to prevent mutual activation with each other.

Therefore, most of the immune diseases are caused by the imbalance between these two immune cells. For example, when the activity of Th1 cells abnormally increases, autoimmune diseases may occur and the activity of Th2 cells abnormally increases It is known that immune diseases are caused by hypersensitivity reactions.

On the other hand, recent studies on the differentiation of Th1 cells have revealed the existence of a new group of immunoregulatory T cells (Tregs) capable of regulating the activity of Th1 cells, , Treg cells have the property of suppressing the function of abnormally activated immune cells and controlling the inflammatory reaction. Therefore, many studies are being conducted to treat immune diseases through the action of increasing Treg cell activity.

In addition, T17 cells are known to be formed through a process similar to the differentiation of Treg cells in the differentiation process of undifferentiated T cells. In other words, the differentiation of Treg cells and Th17 cells is commonly performed in the presence of TGF-β, whereas IL-6 is not required for Treg cells, while IL-6 is present along with TGF- To differentiate. In addition, differentiated Th17 cells are characterized by secretion of IL-17.

Th17 cells, unlike Treg cells, are involved in the forefront of the inflammatory response seen in immune diseases, thereby maximizing the signal of the inflammatory response and accelerating the progression of the disease. Therefore, in the case of autoimmune diseases that are not controlled by Treg cells among autoimmune diseases, the development of therapeutic agents for autoimmune diseases targeting the inhibition of Th17 cell activation has been greatly emphasized.

Immunosuppressants that block the signal transduction pathway in T cells are the most commonly used therapeutic agents for immune diseases. Such immunosuppressants are toxic, infectious, lymphoid, diabetes, tremor, headache, diarrhea, hypertension, nausea , And a disorder of renal function.

In addition to the method of treating immune diseases through the method of inhibiting the activation of T cells, a method of regulating the amount of cytokine secreted from the immune cells and a method of using the antibody targeting the cytokine secreted from the immune cells have been developed . However, this method has a problem in that it takes much time to actually apply to patients through clinical experiments, and that the method using antibody is too expensive in the process of antibody production.

Therefore, it is urgent to develop a therapeutic agent and a treatment method for a new immune disease which has no side effects and is inexpensive and excellent in therapeutic effect.

Korean Patent Publication No. 10-2005-0073440

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating an immunological disease or an inflammatory disease comprising ezetimibe as an active ingredient.

It is still another object of the present invention to provide a health functional food composition for preventing or ameliorating an immune disease or an inflammatory disease comprising ezetimibe as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating an immunological disease or inflammatory disease comprising ezetimibe as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating an immunological disease or inflammatory disease comprising ezetimibe as an active ingredient.

The composition according to the present invention contains Ezetimibe as an active ingredient and can induce Treg cell activity under the condition of Th17 cell differentiation, thus effectively treating immunological diseases or inflammatory diseases.

FIG. 1 shows the results of evaluating the effect of regulating regulatory T cell expression by ezetimibe in one embodiment of the present invention.
Figure 2 shows the results of evaluation of inhibition of arthritis by ezetimibe in an ankylosing spondylitis model in one embodiment of the present invention.
FIG. 3 shows the results of evaluating the inhibitory effect of ezetimibe on uveitis in an ankylosing spondylitis model in an embodiment of the present invention.
FIG. 4 shows the results of evaluating the effect of inhibiting small intestinal tissue destruction by ezetimibe in an ankylosing spondylitis model in one embodiment of the present invention.
FIG. 5 shows the results of evaluating the effect of inhibiting the activity of inflammatory cytokine IL-1 beta in small intestine by ezetimibe in an ankylosing spondylitis model according to an embodiment of the present invention.
FIG. 6 shows the results of evaluating the effect of inhibiting the activity of inflammatory cytokine IL-17 in the small intestine by ezetimibe in an ankylosing spondylitis model in one embodiment of the present invention.
FIG. 7 is an X-ray photographic image showing the result of evaluation of reduction of spinal stenosis by ezetimibe in an ankylosing spondylitis model in one embodiment of the present invention.
FIG. 8 is an image of a result of staining for evaluating the destruction inhibition effect of spinal tissue by ezetimibe in an ankylosing spondylitis model according to an embodiment of the present invention.
9 is a graph illustrating the effect of the ezetimibe in inflammatory bowel disease in an embodiment of the present invention.
FIG. 10 is a graph showing the effect of regulating inflammatory cytokine activity by ezetimibe in normal PBMC in one embodiment of the present invention.
FIG. 11 is a graph showing the effect of modulating inflammatory cytokine activity by ezetimibe in inflammatory PBMC in an embodiment of the present invention. FIG.
12 shows the mitigation effect of ankylosing spondylitis caused by combination of ezetimibe and metformin in one embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the following description, detailed description of known techniques well known to those skilled in the art may be omitted. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear. Also, terminologies used herein are terms used to properly represent preferred embodiments of the present invention, which may vary depending on the user, intent of the operator, or custom in the field to which the present invention belongs.

Therefore, the definition of these terms should be based on the contents throughout this specification. Throughout the specification, when an element is referred to as " comprising ", it means that it can include other elements as well, without excluding other elements unless specifically stated otherwise.

The present invention provides a pharmaceutical composition for preventing or treating an immunological disease or an inflammatory disease comprising ezetimibe as an active ingredient.

The above-mentioned ezetimibe has been mainly used as a lipid lowering agent for suppressing the absorption of cholesterol in the small intestine and has the following structure.

The above-mentioned ezetimibe can induce Treg cell activity under the condition of Th17 cell differentiation, and is effective for the prevention or treatment of immune or inflammatory diseases, for example, ankylosing spondylitis, uveitis, psoriasis, multiple sclerosis, conjunctivitis, atherosclerosis, Inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, Behcet's disease, autoimmune hemodilution, autoimmune myocarditis, atopic dermatitis, asthma, primary cirrhosis, dermatomyositis, Goodpie's syndrome, autoimmune meningitis, Sjogren's syndrome, Dyslipidemia, epididymitis, glomerulonephritis, Graves' disease, Gilanvales syndrome, Hashimoto's disease, hemolytic anemia, multiple sclerosis, multiple sclerosis, multiple sclerosis, Scleroderma, myasthenia gravis, pemphigus vulgaris, psoriasis, sarcoidosis, scleroderma, spondylarthrosis, malignant anemia, But are not limited to, one or more diseases selected from the group consisting of inflammatory bowel disease, mitochondrial related syndrome, and inflammatory bowel disease.

The ezetimibe may be included at a throughput of 0.1 to 1000 mg / kg / day, preferably at a throughput of 0.1 to 100 mg / kg / day, more preferably at a throughput of 0.1 to 10 mg / kg / day However, the present invention is not limited to this, so long as it is intended to achieve the purpose of preventing or treating an immune disease or an inflammatory disease.

Further, the composition may further include metformin in ezetimibe and may be used in combination.

Can be included at a throughput of 0.5 to 5000 mg / day /, preferably at a throughput of 0.5 to 500 mg / kg / day, more preferably at a throughput of 0.5 to 50 mg / kg / day, But the present invention is not limited thereto so long as it achieves the object of prevention or treatment of immunological disease or inflammatory disease by combination treatment of metformin.

The term " treatment " of the present invention means, unless otherwise stated, reversing, alleviating, inhibiting the progress of, or preventing the disease or condition to which the term applies, And the term " treatment " as used herein refers to an act of treating. Accordingly, the treatment or therapies for immune diseases such as rheumatoid arthritis, graft rejection disease and the like in mammals may include one or more of the following:

(1) inhibiting the growth of the immune system, i.e., inhibiting its development;

(2) preventing the spread of immune diseases, i.e., preventing metastasis;

(3) relieving immune diseases;

(4) preventing recurrence of immune disorders; And

(5) palliating symptoms of immune disorders

The pharmaceutical composition of the present invention may further comprise an adjuvant. Such adjuvants may be used without limitation as long as they are known in the art, but may include, for example, Freund's complete or incomplete adjuvant to increase its immunity.

The pharmaceutical composition according to the present invention can be prepared by incorporating the active ingredient into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers for use in the pharmaceutical compositions of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition of the present invention can 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 .

In the case of formulation, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like which are usually used. Solid formulations 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, sucrose, lactose, gelatin And the like. 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, and syrups. In addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweetening agents, fragrances and preservatives . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Propellants, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used. As the base of suppositories, witepsol, tween 61, cacao paper, laurin, and glycerogelatin can be used.

The pharmaceutical composition according to the present invention can be administered to the individual by various routes. All modes of administration may be expected, for example, by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.

The dosage of the pharmaceutical composition according to the present invention is selected in consideration of the age, weight, sex, physical condition, etc. of the individual. It is obvious that the concentration of the active ingredient contained in the pharmaceutical composition may be variously selected depending on the subject, and it is preferably contained in the pharmaceutical composition at a concentration of 0.01 to 5,000 占 퐂 / ml. If the concentration is less than 0.01 μg / ml, the pharmaceutical activity may not be exhibited. If the concentration is more than 5,000 μg / ml, it may be toxic to the human body.

The present invention also provides a health functional food composition for preventing or ameliorating an immunological disease or inflammatory disease comprising ezetimibe as an active ingredient.

In addition to containing the active ingredient ezetimibe, the food composition may contain various flavors or natural carbohydrates as an additional ingredient, such as a conventional food composition.

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. The above-described flavors can be advantageously used as natural flavorings (tau martin), stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.).

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

In addition, the food composition may contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid, Salts of alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

The health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and circles.

In the present invention, the term "health functional food" refers to a food prepared and processed by using raw materials or ingredients having useful functions in accordance with Law No. 6727 on Health Functional Foods, and the nutritional control on the structure and function of the human body Or for the purpose of obtaining a beneficial effect for health use such as physiological action.

The health functional foods of the present invention may contain conventional food additives and, unless otherwise specified, whether or not they are suitable as food additives are classified according to the General Rules for Food Additives approved by the Food and Drug Administration, Standards and standards.

Examples of the food items included in the above food additives include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as persimmon extract, licorice extract, crystalline cellulose, high color pigment and guar gum; L-glutamic acid sodium preparations, noodle-added alkalis, preservative preparations, tar coloring preparations and the like.

For example, the health functional food in the form of tablets may be prepared by granulating a mixture obtained by mixing the effective ingredient of the present invention, ezetimibe, with an excipient, a binder, a disintegrant, and other additives in a usual manner, Or the mixture can be directly compression molded. In addition, the health functional food of the tablet form may contain a mating agent or the like if necessary.

The hard capsule of the capsule-type health functional food can be prepared by filling a normal hard capsule with a mixture of the active ingredient of the present invention, ezetimibe, with an additive such as an excipient. The soft capsule may contain ezetimibe as an excipient And filling the mixture with a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.

The ring-shaped health functional food can be prepared by molding a mixture of ezetimibe, an active ingredient of the present invention, an excipient, a binder, a disintegrant, and the like by a conventionally known method and, if necessary, Or the surface may be coated with a material such as starch, talc.

The granular health functional food can be prepared by granulating a mixture of ezetimibe, an active ingredient of the present invention, an excipient, a binder, a disintegrant, and the like into granules by a conventionally known method and, if necessary, adding a flavoring agent, ≪ / RTI >

The health functional food may be a beverage, a meat, a chocolate, a food, a confectionery, a pizza, a ramen, a noodle, a gum, a candy, an ice cream, an alcoholic beverage, a vitamin complex and a health supplement food.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited to these embodiments.

Example 1 Evaluation of Treg Expression of Ezetimibe in Th17 Cell Differentiation Condition

T cells were isolated from spleen of normal mouse (C57BL / 6, 7 weeks old), and Th17 cell differentiation condition was applied to the separated T cells to induce differentiation of Th17 cells. The differentiation conditions were anti-CD3 (0.5 ug / ml), anti CD28 (2 ug / ml), anti IL-4 (2 ug / ml) And TGFbeta (2 ng / ml), respectively, to differentiate Th17 cells. Th17 cell differentiation condition, eugemtibe treated with 1 uM, 5 uM, 10 uM and stimulated for 3 days, then Foxp3 Treg cells were analyzed to determine whether ezetimibe induces Treg cell activation under Th17 cell differentiation condition. 1. As shown in FIG. 1, it was confirmed that the expression of Foxp3-expressing regulatory T cells was increased.

Example 2: Efficacy evaluation of ankylosing spondylitis by ezetimibe

Manufacture of ankylosing spondylitis animal model

ZAP70 mutant mouse SKG was orally administered curdlan at a dose of 150 mg / kg, and 300 mg / kg ip was administered to cause ankylosing spondylitis. From 1 week after the onset of the disease, 10 mg / kg of ezetimibe was orally administered daily.

Arthritis Control Evaluation

After administration of ezetimibe as described above, evaluation of onset of arthritis and visual evaluation of spinal abnormality were conducted twice a week. As a result, it was confirmed that arthritis was significantly inhibited by the administration of ezetimibe as shown in Fig.

Evaluation of uveitis control effect

The development of uveitis and the infiltration of inflammatory cells in the eye tissues were analyzed by H & E staining (tissue paraffin block) at 6 weeks of ankylosing spondylitis. As a result, as shown in FIG. 3, it was confirmed that the administration of ezetimibe inhibited the development of uveitis (reduction of eyelid swelling and redness), suppression of inflammatory cell infiltration and inflammation of choroid, cornea, and iris & ciliary sites there was.

Evaluating the effect of inhibiting small intestine destruction

In the sixth week of ankylosing spondylitis, the small intestine of each mouse group was paraffin-blocked and the degree of tissue destruction was analyzed by H & E staining (tissue paraffin block). As a result, as shown in FIG. 4, intestinal tissue destruction and infiltration of inflammatory cells were observed in the control group of spondyloarthropathies, but intestinal tissue destruction and inflammatory cells and abnormal tissue formation in the ezetimibe- It was confirmed that it was significantly suppressed. Thus, it can be seen that ezetimibe can also inhibit inflammatory bowel disease.

Inhibitory effect of inflammatory cytokine in small intestine

In the sixth week of ankylosing spondylitis, the small intestine of each mouse group was paraffin-blocked and stained for inflammatory cytokines IL-1beta and Il-17 by IHE staining (tissue paraffin block). As a result, as shown in FIG. 5 and FIG. 6, it was confirmed that the activity of IL-1beta and IL-17, which are inflammatory cytokines in intestinal tissues, was markedly suppressed.

Evaluation of spinal stenosis reduction effect

The mice were sacrificed at the 12th week of ankylosing spondylitis, and spinal stenosis was fixed with formalin fixation. As can be seen from FIG. 7, it was confirmed that the degree of stenosis and the angle of warpage were remarkably improved by the administration of ezetimibe as compared with the disease group.

Evaluation of inhibition of spinal cord destruction

On the 12th week of ankylosing spondylitis, the spinal tissues of each arm were paraffin-blocked and the degree of tissue destruction was analyzed by H & E staining (tissue paraffin block). As can be seen from Fig. 8, vertebral fracture and infiltration of inflammatory cells were observed in the control group of ankylosing spondylitis, whereas in the ezetimibe group, vertebral and disk destruction, inflammatory cells and abnormal tissue formation were significantly inhibited there was. Therefore, it was confirmed that ezetimibe can inhibit spinal injury.

Example 3: Inflammatory bowel disease control effect

Normal C57BL / 6 mice were injected with 3% DSS water to induce inflammatory bowel disease, and the disease control effect was evaluated by oral administration of 600 mg / kg of ezetimibe. As a result, as can be seen from Fig. 9, it was confirmed that ezetimibe can control inflammatory bowel disease.

Example 4: Inflammatory cytokine inhibitory effect by ezetimibe in PBMC

After peripheral blood mononuclear cells were isolated from normal human and inflammatory patients, ejemative was pretreated (5 uM and 20 uM) and stimulated with 1 μg / ml of aCD3 for 2 hours, followed by culture for 3 days. Then, inflammatory cytokines 10 and 11 show the results of ELISA for confirming the expression of IL-17 and IFN-r. As shown in FIG. 10, in PBMC of normal human subjects, inflammatory cytokine Expression was inhibited. Fig. 11 shows the results in PBMC of patients with inflammation, and it was confirmed that the expression of inflammatory cytokine was inhibited dependently on the concentration of ezetimibe.

Example 5: Estimation of the effect of ankylosing spondylitis on the efficacy of combined administration of ezetimibe and metformin

ZAP70 mutant mouse SKG was orally administered curdlan at a dose of 150 mg / kg, and 300 mg / kg ip was administered to cause ankylosing spondylitis. Ezetimibe was orally administered at a dose of 10 mg / kg daily for 1 week after disease induction and metformin was orally administered at a daily dose of 50 mg / kg. After the administration of the drug, evaluation of onset of arthritis and evaluation of spinal abnormality were conducted twice a week. As can be seen from Fig. 12, it was confirmed that the disease was suppressed by the administration of ezetimibe alone and the combined administration of ezetimibe and metformin.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (8)

A pharmaceutical composition for preventing or treating an immunological disease or inflammatory disease, which comprises Ezetimibe as an active ingredient. The method according to claim 1,
Wherein the ezetimibe induces Treg cell activity under Th17 cell differentiation conditions. The method according to claim 1,
Wherein the ezetimibe is included at a throughput of 0.1 to 1000 mg / kg / day. The method according to claim 1,
Wherein said immune or inflammatory disease is selected from the group consisting of ankylosing spondylitis, uveitis, psoriasis, multiple sclerosis, conjunctivitis, atherosclerosis, Crohn's disease, rheumatoid arthritis, osteoarthritis, Behcet's disease, autoimmune hemopneumonia, autoimmune myocarditis, The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prophylaxis of cirrhosis, dermatomyositis, gastrophaetism, autoimmune meningitis, Sjogren's syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, ankylosing spondylitis, Epididymitis, epididymitis, glomerulonephritis, Graves' disease, Gilanvales syndrome, Hashimoto disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, sarcoidosis, scleroderma, spondyloarthropathy, anemia, scleroderma, mitochondrial related syndrome Inflammatory bowel disease < RTI ID = 0.0 > . The method according to claim 1,
Wherein the composition further comprises metformin. The method according to claim 1,
Wherein the metformin is included at a throughput ranging from 0.5 to 5000 mg / kg / day. A health-functional food composition for preventing or ameliorating an immunological disease or inflammatory disease comprising ezetimibe as an active ingredient. 8. The method of claim 7,
Wherein the composition further comprises metformin.

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