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WO2014021637A1 - Composition comprenant du rébamipide comme ingrédient actif pour prévenir ou traiter l'hyperlipidémie et des maladies lui sont associées - Google Patents

Composition comprenant du rébamipide comme ingrédient actif pour prévenir ou traiter l'hyperlipidémie et des maladies lui sont associées Download PDF

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WO2014021637A1
WO2014021637A1 PCT/KR2013/006897 KR2013006897W WO2014021637A1 WO 2014021637 A1 WO2014021637 A1 WO 2014021637A1 KR 2013006897 W KR2013006897 W KR 2013006897W WO 2014021637 A1 WO2014021637 A1 WO 2014021637A1
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Prior art keywords
hyperlipidemia
cells
composition
related diseases
levamipid
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Korean (ko)
Inventor
조미라
민준기
전주연
변재경
임예빈
김은경
양은지
정정희
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Industry Academic Cooperation Foundation of Catholic University of Korea
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Industry Academic Cooperation Foundation of Catholic University of Korea
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Priority to JP2015525356A priority Critical patent/JP6023328B2/ja
Priority to CN201380040234.2A priority patent/CN104768551B/zh
Publication of WO2014021637A1 publication Critical patent/WO2014021637A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical use of rebamipide used to prevent or treat hyperlipidemia and related diseases. Specifically, the present invention relates to the prevention of hyperlipidemia and related diseases including rebamipide as an active ingredient. Or to a therapeutic composition.
  • Hyperlipemia refers to a condition in which a lot of fatty substances are present in the blood and accumulated on the walls of blood vessels, causing inflammation and consequently cardiovascular disease.
  • Hyperlipidemia consists of 50-150 mg / dl of triglycerides, which are the normal ranges of serum lipids on fasting levels of serum lipids such as cholesterol, triglycerides, phospholipids and free fatty acids. / dl, cholesterol 130 ⁇ 230 mg / dl and free fatty acids 5 ⁇ 10mg / dl. If left untreated, hyperlipidemia is likely to cause serious complications such as hypertension, coronary atherosclerosis (angina, myocardial infarction), and cerebral atherosclerosis (cerebral infarction).
  • HMG-CoA reductase inhibitors that are major enzymes in cholesterol biosynthesis processes (e.g., lovastatin, fluvastatin, Simvastatin, pravastatin] and the like are used in the clinic, there is a risk of side effects when taking long-term.
  • statin drugs which are inhibitors of HMG-CoA reductase, are known to cause liver damage and myopathy.
  • cholesterol lowering agents are mainly 3-hydroxy-3-methylglutayl-CoA (HMG-CoA) reductase inhibitors, bile-salt sequestrants, fibrates and niconic acid derivatives.
  • HMG-CoA 3-hydroxy-3-methylglutayl-CoA reductase inhibitors
  • bile-salt sequestrants mainly bile-salt sequestrants
  • fibrates mainly niconic acid derivatives.
  • lovastatin, simvastatin and pravastatin are the most well known cholesterol-lowering agents that inhibit HMG-CoA reductase in the early stages of cholesterol biosynthesis, but also cause serious side effects by inhibiting the synthesis of steroid hormones and dolichol (Havel, RL et al., Ann.Internal Med., 107: 609-615, 1987; Illingworth, DR and Bacon, S. Am. J. Cardiolopy 60: 33-42, 1987).
  • the present inventors therefore inhibit the production of TNF-a, IL-6 and IL-1b, hyperlipidemia-induced inflammatory cytokines secreted from macrophages by rebamipide, currently used as a treatment for gastric ulcers; Inhibit the production of Foam cells forming Artherosclerotic plaque progenitor cells; Improves blood lipids by lowering total cholesterol, LDL-cholesterol and triglyceride levels in the blood; Improve fatty liver; Inhibit the activity of B cells; For the first time, it has been shown to reduce the expression of Th17, which accelerates the production of artherosclerotic plaques, and to increase the expression of Treg cells that can control the inflammatory response, thereby making it useful as a therapeutic agent for hyperlipidemia and related diseases. The present invention has been completed by confirming that it can be used.
  • the present invention provides a composition for the prevention or treatment of hyperlipidemia and related diseases comprising a rebamipide compound or a pharmaceutically acceptable salt thereof as an active ingredient. .
  • the rebamipide can inhibit the production of TNF-a, IL-6 and IL-1b, hyperlipidemia-induced inflammatory cytokines secreted from macrophages.
  • the rebamipide may not only suppress the production of foam cells forming artherosclerotic plaque progenitor cells, but also inhibit the production of atherosclerotic plaques.
  • Atherosclerosis plaque formation can be inhibited through reduced expression of Th17 to accelerate and increased expression of Treg cells that can control the inflammatory response.
  • the rebamipide can improve blood lipid by lowering the total cholesterol, LDL-cholesterol and triglyceride levels in the blood.
  • the rebamipide may be included in the composition at a concentration of 0.1 ⁇ M to 10000 ⁇ M.
  • the hyperlipidemia may be hyperlipidemia derived from autoimmune disease.
  • the disease associated with hyperlipidemia may be selected from the group consisting of arteriosclerosis, heart failure, hypertensive heart disease, arrhythmia, congenital heart disease, myocardial infarction, angina pectoris, stroke and peripheral vascular disease.
  • the rebamipide compound according to the present invention inhibits the production of TNF-a, IL-6 and IL-1b, which are hyperlipidemic inflammatory cytokines secreted by macrophages; Inhibit the production of Foam cells forming Artherosclerotic plaque progenitor cells; Improves blood lipids by lowering total cholesterol, LDL-cholesterol and triglyceride levels in the blood; Improve fatty liver; Inhibit the activity of B cells; In addition to reducing the expression of Th17, which accelerates the production of atherosclerotic plaques, it can increase the expression of Treg cells that can control the inflammatory response.
  • the rebamipide compound may be usefully used as a pharmaceutical composition capable of preventing or treating hyperlipidemia and related arteriosclerosis, heart failure, hypertensive heart disease, etc. through various mechanisms as described above.
  • there is no toxicity and side effects to the drug can be used safely even when taking long-term, has a stable effect on the body.
  • Figure 1 shows the amount of inflammatory cytokines secreted from macrophages following levamifeed treatment measured by ELISA analysis (Nil: LPS and levamifeed untreated group).
  • Figure 2 shows the results of MTT assay to determine the cytotoxicity of levamipid against macrophage RAW 264.7 (Nil: LPS and levamipid untreated group).
  • Figure 3 is a photograph showing the degree of foam cell formation according to the treatment of levamifeed by concentration (100, 250, 500, 1000 ⁇ M) in the formation of oxLDL-induced foam cells using THP1 cells, which are human macrophage lines, through oil red O staining. .
  • Figure 4 is a photograph showing the degree of foam cell formation according to the combination of levamipid alone, simvastatin alone or levamipid and simvastatin in the formation of oxLDL-induced foam cells using THP1 cells, which are human macrophage lines, through oil red O staining. .
  • FIG. 5 is a graph showing the change in total serum cholesterol, LDL-cholesterol and triglyceride levels in mouse serum after oral administration of levamipid to a hyperlipidemic animal model mouse.
  • FIG. 6 is a graph showing the measurement of AST and ALT activity levels in mouse serum after oral administration of levamipid to a hyperlipidemic animal model mouse.
  • Figure 7 is a photograph showing the degree of aorta branch in the aorta of the mouse after oral administration of levamipid to the hyperlipidemic animal model mouse through Oil red O staining.
  • FIG. 8 is a graph showing the measurement of total IgG and IgG1 levels in mouse serum after oral administration of levamipid to a hyperlipidemic animal model mouse.
  • FIG. 9 is a FACS analysis of the expression level of Th17 cells and Treg cells in spleen cells of mice after oral administration of levamipid to a hyperlipidemic animal model mouse.
  • FIG. 10 shows the expression level of Th17 cells and Treg cells in spleen fragments of mice after oral administration of levamipid to hyperlipidemic animal model mice through confocal microscopy.
  • FIG. 11 shows the mRNA expression level of MMP-9 in spleen cells of mice after oral administration of levamipid to hyperlipidemic animal model mice through RT-PCR.
  • the present invention relates to a composition for preventing or treating hyperlipidemia and related diseases comprising a rebamipide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Rebamipide is an acute exacerbation of gastric ulcer, acute gastritis or chronic gastritis.
  • Propionic acid is 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinone-4-yl].
  • the drug protects gastric mucosa by promoting PGE2 biosynthesis to increase mucus, promotes cell proliferation, and inhibits bacterial adhesion and invasion to gastric mucosa cells, especially in patients infected with Helicobacter pylori. Suppresses stomach inflammation.
  • rebamipide compounds may be used for the prevention or treatment of hyperlipidemia and related diseases, and in particular, the production of hyperlipidemia-induced inflammatory cytokines TNF-a, IL-6 and IL-1b.
  • Inhibit Inhibit the production of Foam cells forming Artherosclerotic plaque progenitor cells; Improves blood lipids by lowering total cholesterol, LDL-cholesterol and triglyceride levels in the blood; Improve fatty liver; Inhibit the activity of B cells;
  • Th17 which accelerates the formation of atherosclerotic plaques, and increasing the expression of Treg cells that can control the inflammatory response can lead to the prevention or treatment of hyperlipidemia and related diseases. It was.
  • hyperlipidemia causes a lot of complications due to the presence of more fatty substances in the blood than necessary, and these complications are very dangerous diseases such as arteriosclerosis, angina pectoris, and myocardial infarction. There is a situation.
  • Atherosclerosis is characterized by the accumulation of lipids in the endothelium and inflammatory reactions leading to the formation of atherosclerotic plaques. Plaques narrow the arteries and the narrowed arteries can easily rupture if clogged by blood clots, leading to cardiovascular disease.
  • macrophages derived from monocytes.
  • macrophages use scavenger receptors to introduce oxidized LDL (oxLDL).
  • Macrophages are called foam cells.
  • foam cells In general, pathogen-induced macrophages migrate to other places, but since foam cells do not leave their place after the introduction of oxidized LDL, they lose their normal biological function, penetrate into vascular endothelial cells and become atherosclerotic. thickens smooth muscle through plaque) formation.
  • foam cells are known to trigger a local inflammatory response when trapped in the artery's endothelium.
  • Example 1 of the present invention in order to examine the effect of rebamipide on macrophages, when treated with LPS after treatment of levamipids in mouse peritoneal macrophages, TNF-a which is a hyperlipidemic factor , It was confirmed that effectively inhibit the production of IL-6 and IL-1b (see Fig. 1).
  • Example 3 the effect of levamifeed on the production of foam cells forming artherosclerotic plaque progenitor cells was examined, and as a result, levamifeed treatment concentration
  • foam cell production which is an vascular pathogen cell, was suppressed (see FIG. 3), and in particular, it was confirmed that foam cell production was superior to the conventional hyperlipidemic drug simvastatin (Simvastatin). See FIG. 4).
  • Example 4 of the present invention the blood lipid improvement effect of the administration of levamipid to the hyperlipidemic animal model was examined, and as a result, total or cholesterol in serum when levamipid was orally administered to the hyperlipidemic animal model mouse , LDL-cholesterol and triglyceride concentration was confirmed that the effective reduction (see Figure 5).
  • Example 5 of the present invention the effect of fatty liver improvement according to the administration of levamipid to the hyperlipidemic animal model was examined, and as a result, serum AST and ALT activity was increased when levamipid was orally administered to the hyperlipidemic animal model mouse. It was shown to be significantly reduced, it was confirmed that levamifeed can suppress liver damage in hyperlipidemic animal model (see FIG. 6).
  • Example 6 of the present invention the effect of inhibiting arteriosclerosis formation according to the administration of levamipid to the hyperlipidemic animal model was examined, and as a result, the aorta in the experimental group orally administered levamipid to the hyperlipidemic animal model mouse It was confirmed that the aorta branch showed significantly less oil red O positive, and levamifeed actually inhibited the formation of atherosclerotic plaques (see FIG. 7).
  • Example 7 of the present invention the B-cell antibody immune response was investigated in the hyperlipidemic animal model according to the administration of levamipid, and as a result, when oral administration of levamipid to the hyperlipidemic animal model mouse was performed, It was shown that the number is reduced, it was confirmed that the activity of B cells by levamifeed (see Figure 8).
  • Example 8 of the present invention we examined the Th17 cell inhibition and Treg cell induction co-regulation response according to the administration of levamipid to the hyperlipidemic animal model, and as a result, oral administration of levamipid to the hyperlipidemic animal model mouse
  • the expression of Th17 which accelerates the production of artherosclerotic plaque
  • Treg cells which are immunoregulatory cells
  • T cells are one of cell groups that play a central role in the immune system as a biological defense system against various pathogens.
  • T cells are produced in the thymus of the human body and undergo a series of differentiation processes to differentiate into T cells with unique characteristics.
  • T cells which have completed differentiation, are largely divided into type 1 helper cells (Th1) and type 2 according to their function. It is divided into helper cells (Th2).
  • Th1 cells the main function of Th1 cells is involved in cell mediated immunity
  • Th2 cells are involved in humoral immunity
  • these two cell populations are balanced with each other so that they are not activated with each other.
  • Th1 cells On the other hand, according to recent research on the differentiation of Th1 cells, the existence of a new group that regulates the activity of Th1 cells (regulatory T cells, hereinafter abbreviated as 'Treg') is known. Researches on the treatment of immune diseases have emerged. Treg cells are characterized by controlling the inflammatory response by inhibiting the function of abnormally activated immune cells. Many experiments have been reported to treat the disease.
  • Th17 cells are known to be formed through a process similar to the differentiation of Treg cells during the differentiation of undifferentiated T cells. That is, differentiation of Treg cells and Th17 cells is performed in the presence of TGF- ⁇ in common but does not require IL-6 in Treg cells, whereas IL-6 is present in combination with TGF- ⁇ in Th17 cells. Differentiate in situations In addition, differentiated Th17 cells are characterized by the secretion of IL-17.
  • Th17 cells Unlike Treg cells, Th17 cells have been found to be involved in the forefront of inflammatory reactions seen in immune diseases, maximizing the signal of inflammatory responses and accelerating disease progression.
  • Th17 cell suppression and Treg cell induction are co-regulated, excessive immune response or inflammatory response can be effectively suppressed.
  • Treg cell expression can be enhanced simultaneously with inhibition of Th17 cell expression. It was determined that the immune or inflammatory response can be effectively suppressed.
  • Example 9 of the present invention the mRNA expression level of MMP-9 according to the administration of levamifeed to the hyperlipidemic animal model was investigated.
  • MMP-9 which degrades non-fibrillar collagen, is expressed in atherosclerotic plaques and is known to play a major role in pathophysiological mechanisms in atherosclerotic plaque rupture.
  • the expression level of MMP-9 in the spleen cells of the mouse was significantly reduced in the ratio of simvastatin orally administered group, which is a positive control group (Fig. 11). Reference).
  • the present inventors determined that levamifeed effectively reduces the expression of MMP-9, thereby more effectively preventing the occurrence of cerebral infarction or myocardial infarction caused by atherosclerotic plaque rupture.
  • levamipid is effective in the prevention and treatment of hyperlipidemia and related diseases through various mechanisms.
  • composition of the present invention containing rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully used for the prevention or treatment of hyperlipidemia and related diseases.
  • the levamipid according to the present invention may be a compound represented by the following Chemical Formula 1.
  • the rebamipide compound according to the present invention may be used in the form of a salt, preferably a pharmaceutically acceptable salt.
  • the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid.
  • the organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
  • the rebamipide compound according to the present invention may be commercially available, or may be one that is separated from nature or manufactured by chemical synthesis known in the art.
  • the rebamipide (rebamipide) of hyperlipidemia and related diseases through a mechanism that inhibits the production of hyperlipidemia-induced inflammatory cytokines TNF-a, IL-6 and IL-1b in macrophages It may have a prophylactic or therapeutic effect.
  • the rebamipide may be included in the composition of the present invention at a concentration of 0.1 to 10000 ⁇ M.
  • composition for preventing or treating hyperlipidemia and related diseases provided by the present invention is preferably a pharmaceutical composition.
  • hyperlipidemia related disease refers to a disease caused or promoted by hyperlipidemia, for example, arteriosclerosis, heart failure, hypertensive heart disease, arrhythmia, congenital heart disease, myocardial infarction, angina pectoris, stroke and peripheral vascular disease It may be selected from the group consisting of, but is not particularly limited in kind.
  • treatment refers to a disease or condition to which the term applies, or to reverse, alleviate, inhibit, or prevent the progression of one or more symptoms of the disease or condition.
  • treatment refers to the act of treating when "treating” is defined as above.
  • “treatment” or “therapy” of hyperlipidemia and related diseases may include one or more of the following:
  • the pharmaceutical composition of the present invention may be prepared using a pharmaceutically suitable and physiologically acceptable adjuvant, in addition to rebamipide, which is an active ingredient, and the adjuvant may include excipients, disintegrants, sweeteners, binders, Coatings, swelling agents, lubricants, lubricants, or flavoring agents can be used.
  • the pharmaceutical composition may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to rebamipide as an active ingredient for administration.
  • Formulation forms of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops or injectable solutions.
  • the active ingredient may be combined with an oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture.
  • Suitable binders include but are not limited to natural and synthetic gums such as starch, gelatin, glucose or beta-lactose, corn sweeteners, acacia, trackercance or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Acceptable pharmaceutical carriers in compositions formulated in liquid solutions are sterile and physiologically compatible, including saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA can be formulated according to each disease or component, as appropriate in the art.
  • rebamipide of the present invention may be included in the composition at a concentration of 0.1 to 10000 ⁇ M, and also rebamipide of the present invention is 0.1 to 95 with respect to the total weight of the composition It may be included in weight percent.
  • diseases in which the pharmaceutical composition of the present invention may exhibit a therapeutic effect include a group consisting of hyperlipidemia, arteriosclerosis, heart failure, hypertensive heart disease, arrhythmia, congenital heart disease, myocardial infarction, angina pectoris, stroke and peripheral vestibular disease
  • the disease may be selected from, but is not limited thereto.
  • the pharmaceutical composition of the present invention may comprise rebamipide in a pharmaceutically effective amount together with a pharmaceutically acceptable carrier.
  • the "pharmaceutically effective amount” refers to an amount of an active ingredient that exhibits an alleviating, suppressing, improving and / or curative effect on a disease to be treated.
  • the dose of rebamipide of the present invention varies depending on the weight, age, sex, health condition, diet, time of administration, administration method and severity of disease of the patient.
  • therapeutically effective dosages can be initially determined using in vitro assays through cell culture. It will be possible to determine the amount effective for treatment without undue experimentation in the art, and this information can be used to more accurately determine the useful dose in humans.
  • the pharmaceutically effective amount of the rebamipide compound or salt thereof according to the present invention is 0.5-100 mg / day / kg body weight, preferably 0.5-5 mg / day / kg body weight Can be.
  • the present invention also provides the use of a composition comprising the rebamipide as an active ingredient for the manufacture of a medicament for the prevention or treatment of hyperlipidemia and related diseases.
  • the composition of the present invention comprising rebamipide as an active ingredient may be used for the manufacture of a medicament for preventing or treating hyperlipidemia and related diseases.
  • the invention also provides a method of preventing or treating hyperlipidemia and related diseases comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition of the invention.
  • mammal refers to a mammal that is the subject of treatment, observation or experimentation, preferably human.
  • the term “therapeutically effective amount” means an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, as thought by a researcher, veterinarian, doctor or other clinician, which Amounts that induce alleviation of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dosages and frequency of administrations for the active ingredients of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be readily determined by one skilled in the art and includes the type of disease, the severity of the disease, the amount of active ingredients and other ingredients contained in the composition, the type of formulation, and the age, weight, general health of the patient. It may be adjusted according to various factors including the condition, sex and diet, time of administration, route of administration and the rate of secretion of the composition, the duration of treatment, and the drugs used simultaneously.
  • the present invention also provides a health functional food for the prevention or improvement of hyperlipidemia and related diseases comprising rebamipide as an active ingredient.
  • the health functional food of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like for the purpose of preventing or improving hyperlipidemia and related diseases.
  • health functional food refers to a food prepared and processed using raw materials or ingredients having functional properties useful for the human body according to the Health Functional Food Act No. 6767, and nutrients for the structure and function of the human body. It is meant to be consumed for the purpose of regulating or obtaining a useful effect for health use such as physiological action.
  • the health functional food of the present invention may include a conventional food additive, and the suitability as a food additive, unless otherwise specified, in accordance with the General Regulations of the Food Additives and General Test Methods approved by the Food and Drug Administration, etc. Judging by the standards and standards.
  • Food Additive Reduction examples include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid and cinnamic acid; Natural additives such as dark blue pigment, licorice extract, crystalline cellulose, high color pigment and guar gum; And mixed preparations such as sodium L-glutamate, algae additives, preservatives and tar dyes.
  • the health functional food in the form of tablets is a conventional method of granulating a mixture of rebamipide, an active ingredient of the present invention with an excipient, a binder, a disintegrant and other additives, and then a lubricant and the like. Compression molding, or the mixture may be directly compression molded.
  • the health functional food in the form of tablets may contain a mating agent or the like as necessary.
  • Hard capsules among the health functional foods in the form of capsules may be prepared by filling a mixture of additives such as rebamipide, an active ingredient of the present invention, in a conventional hard capsule with an excipient, and the like.
  • (Rebamipide) may be prepared by mixing a mixture of additives such as excipients with a capsule base such as gelatin.
  • the soft capsule agent may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.
  • the health functional food in the form of a cyclic form can be prepared by molding a mixture of an excipient, a binder, a disintegrant, and the like of rebamipide, which is an active ingredient of the present invention.
  • Other coatings may be applied, or the surface may be coated with materials such as starch, talc.
  • the health functional food in the form of granules may be prepared by granulation of a mixture of rebamipide, an active ingredient of the present invention, an excipient, a binder, a disintegrant, and the like by a conventionally known method. And a copper may be contained.
  • the health functional food may be beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements.
  • the present inventors pretreated levamifeed in mouse macrophages and stimulated with LPS (lipopolysaccharide) to secrete inflammatory cytokines TNF-a (tumor necrosis factor). -alpha), IL-6 (interleukin-6) and IL-1 ⁇ (interleukin-1 ⁇ ) production was evaluated by ELISA analysis.
  • LPS lipopolysaccharide
  • Macrophage lines of mice, RAW 264.7 cells were obtained from the Korea Cell Line Bank (KCLB), and used DMEM (Dulbeccos Modified Eagle Medium) medium containing 10% FBS and 1% penicillin-streptomycin for cell culture. Cells were incubated at 37 ° C., 5% CO 2 .
  • KCLB Korea Cell Line Bank
  • DMEM Dulbeccos Modified Eagle Medium
  • cytokines produced TNF- ⁇ , IL-6 and IL-1 ⁇
  • the supernatants of the cultured cells were collected and purified by ELISA for TNF- ⁇ , IL-6 and IL-1 ⁇ .
  • the degree of production was investigated separately.
  • Monoclonal anti-TNF- ⁇ , anti-IL-6, and anti-IL-1 ⁇ were reacted overnight at 4 ° C. at 1 ⁇ g / mL in a 96-well plate, followed by nonspecific binding with blocking solution (1% BSA / PBST). Blocked.
  • TNF- ⁇ recombinant, IL-6 recombinant, IL-1 ⁇ recombinant were used as a standard by diluting 1/2 successively, the cell culture supernatant was added and reacted at room temperature for 2 hours. Thereafter, biotinylated anti-TNF- ⁇ , biotinylated anti-IL-6, and biotinylated anti-IL-1 ⁇ were reacted at room temperature for 2 hours, washed four times, and then diluted by adding the ExtraAvidin-Alkaline Phosphatase conjugate, followed by 2 at room temperature. The reaction was carried out for a time. Thereafter, PNPP / DEA solution was added and developed, and then absorbance was measured at 405 nm.
  • levamifeed may be useful for preventing or treating hyperlipidemia and related diseases through a mechanism that inhibits the inflammatory response of macrophages, which play an important role in hyperlipidemia and atherosclerosis.
  • MTT assay was performed to determine the cytotoxicity of levamifeed against mouse macrophage RAW 264.7.
  • This method measures the conversion of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide) to formazan.
  • the 96 well plate contains 1 ⁇ 10 4 cells / well.
  • RAW 264.7 cells were dispensed and levamifeed was treated for 18 hours by concentration (20, 100, 500, 1000, 5000 ⁇ M).
  • 100 ⁇ l of MTT solution was added to each well for 4 hours at 37 ° C., 5% CO 2 incubator, and then the change in absorbance at 570 nm was measured using a microplate reader (VERSAmax, Molecular Devices, USA).
  • the 'angiogenic cell' refers to a foam cell that forms atherosclerosis (Artherosclerotic plaque) progenitor cells that induce atherosclerosis, and is a cell that causes atherosclerosis in the present invention.
  • Pathogen cells were randomly named.
  • THP1 cells human macrophages
  • PMA phorbol 12'-myristate 13'-acetate
  • PAF platelet-activating factor
  • simvastatin which is currently used as a hypolipidemic drug (hyperlipidemic drug).
  • THP1 cells human macrophages
  • PMA phorbol 12'-myristate 13'-acetate
  • PAF platelet-activating factor
  • mice 8-week-old Apoe ko mice (mouse with apolipoprotein E gene removed) were given oral administration of 100 mg / kg of levamifeed, followed by Western diet, and sacrificed at 8 weeks after Western diet. Cholesterol, LDL-cholesterol and triglyceride levels were measured. The positive control group was orally administered 25 mg / kg of simvastatin, which is currently used as a lipid lowering agent, in place of levamipid.
  • AST Aspar wheelchairmino-transferase
  • ALT Alanine aminotransferase
  • serum AST and ALT levels were measured to verify whether levamifeed is effective in preventing fatty liver and improving fatty liver.
  • ALT values were measured.
  • the positive control group was orally administered 25 mg / kg of simvastatin, which is currently used as a lipid lowering agent, in place of levamipid.
  • AST and ALT activity was measured by quantitative kit reagent (Youngdong Pharmaceutical, Korea). 1.0 mL of AST and ALT substrate solution were warmed for 2 minutes in a 37 tank, and then 0.2 mL of plasma was added and reacted for 30 minutes in a 37 °C water bath.
  • mice 8-week-old Apoe ko mice (mouse with apolipoprotein E gene removed) were given oral administration of 100 mg / kg of levamifeed, followed by a Western diet, and sacrificed at 8 weeks after the Western diet. ) was fixed and oil red O staining was performed.
  • the positive control group was orally administered 25 mg / kg of simvastatin, which is currently used as a lipid lowering agent, in place of levamipid.
  • the aorta branch was mostly oil red O-positive in the negative control group (hyperlipidemic animal model mouse), whereas the aorta branch seen in the aorta in the experimental group orally administered levamipid to the hyperlipidemic animal model mouse. It was confirmed that the oil red O positive was significantly less, and in particular, compared to the positive control group (simvastatin oral administration group), the aorta branch was found to have less oil red O positive portion.
  • mice eight-week-old Apoe ko mice (mouse with apolipoprotein E gene removed) were fed orally with 100 mg / kg of levamifeed while feeding a Western diet and sacrificed at 8 weeks post-Western diet. And IgG1 levels were measured by ELISA analysis.
  • the positive control group was orally administered 25 mg / kg of simvastatin, which is currently used as a lipid lowering agent, instead of levamipid.
  • Serum total IgG and IgG1 concentrations were measured according to the manufacturer's instructions using an ELISA kit (bethyl).
  • mice 8-week-old Apoe ko mice (mouse with apolipoprotein E gene removed) were fed orally with 100 mg / kg of levamifeed while feeding the Western diet, and sacrificed at 4 weeks after the Western diet.
  • the expression of Th17 cells was analyzed by measuring IL-17 expression levels of cells, and the expression of Treg cells was analyzed by measuring Foxp3 expression levels of CD4 + CD25 + cells.
  • Expression analysis of Th17 cells and Tregs was performed via FACS and confocal microscopy via staining. Meanwhile, the positive control group orally administered 25 mg / kg of simvastatin, which is currently used as a lipid lowering agent, instead of levamipid.
  • Th17 cells are characterized by secreting IL-17
  • IL-17 is an indicator for measuring the activity or amplification of Th17 cells.
  • Foxp3 is mainly present in regulatory T cells (Tregs) derived from the thymus, and is a transcriptional factor present in cells with CD4 + CD25 + labeled antigens, whose function is Foxp3.
  • IL-recognized T cells which have low reactivity to the antigen upon recognition of T-expressing T cells, and potentially CD4 + CD25- T cells that do not express Foxp3 differentiated from the thymus, may cause autoimmunity. It has a role as a suppressor T cell that inhibits the production of -2 and cell division.
  • Foxp3 is not only affected by IL-2, but also by the transcription factor NFAT on CD25- T cells through regulatory T cells expressing Foxp3 and through cell-cell contact. It has been found to function to suppress transcriptional regulation of the back. Therefore, in the case of T cells expressing Foxp3 having such a function, it is applied to the treatment of immune diseases through the action of inhibiting or regulating an immune response, and also of CD4 + T cells expressing Foxp3 present in humans. To apply self-antigen specific T cell clones to cell therapy by increasing their number through high concentration of IL-2 cytokine and combination treatment with anti-CD3 and anti-CD28 antibodies There have been attempts. Therefore, confirming the expression of Foxp3 is an indicator to measure the activity or amplification of Treg cells.
  • FACS staining was performed on splenocytes of mice after lethal mice. Th17 cells were first reacted with anti-CD4 antibody for 30 minutes at 4, followed by 30 minutes reaction with Cytofix / Cytoperm, followed by 30 minutes reaction with anti-IL-17 antibody, followed by reading with FACScalibur and flow. The analysis was performed using the jo program. Treg cells were treated with anti-CD4 and anti-CD25 antibodies for 30 minutes and then reacted with Treg-specific Cytofix / Cytoperm for 30 minutes.Then, washed and then reacted with anti-Foxp3 antibody for 30 minutes and read with FACScalibur. Analysis was performed using the Flow jo program.
  • the mouse was killed and the OCT compound was embedded using the spleen fragments of the mouse, and the liquid nitrogen rapid cooled tissue was attached to the slide with a 7 m thickness using a frozen slicer.
  • the sections were fixed with acetone and blocked for 30 minutes of nonspecific reaction with 10% normal goat serum.
  • Th17 cells used PE-labeled anti-CD4 and FITC-labeled anti-IL-17 antibodies.
  • Treg cells used PE-labeled anti-CD4, FITC-labeled anti-Foxp3 and APC-labeled anti-CD25 antibodies.
  • Stained tissue was analyzed by confocal microscopy (LSM 510 Meta. Zeiss, Go ttingen, Germany).
  • MMP-9 Matrix metalloproteinase-9
  • mice 8-week-old Apoe ko mice (mouse with apolipoprotein E gene removed) were fed orally with levamifeed 20 mg / kg and 100 mg / kg, respectively, and sacrificed at 8 weeks after Western diet. Splenocytes were obtained. The splenocytes thus obtained were treated with PMA 25ng / ml and Ionomycin 250ng / ml for 4 hours, and then the expression of MMP-9 in the RNA of the cells was examined by RT-PCR.
  • RT-PCR was performed using an ABI PCR machine with a LightCycler FastStart DNAmaster SYBR green I (Takara) fluorescent dye, and the reaction compound for this was 1 ⁇ l of 1 ⁇ g of synthesized cDNA in 1 ⁇ l, LightCycler FastStart DNAmaster SYBR green After mixing 10 ⁇ l of I (Takara) and 1 ⁇ l of Taqman probe (Applied biosystems), the final volume was used to make 20 ⁇ l of distilled water. The reaction conditions were reacted 50 times at 95 degreeC for 10 minutes, 95 degreeC 10 second, and 64 degreeC 30 second.
  • the cycle threshold (Ct) values were analyzed to express the mRNA expression level of MMP-9 as a relative quantitative expression of the mRNA expression level of ⁇ -actin, a house keeping gene.
  • Ct cycle threshold
  • the rebamipide compound according to the present invention can be usefully used as a pharmaceutical composition that can prevent or treat hyperlipidemia and related arteriosclerosis, heart failure, hypertensive heart disease, etc. through various mechanisms.

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KR20200042311A (ko) * 2018-10-15 2020-04-23 한국과학기술연구원 산초 추출물을 포함하는 중성지방에 의한 대식세포 사멸 억제용 조성물
KR102143968B1 (ko) 2018-10-15 2020-08-12 한국과학기술연구원 산초 추출물을 포함하는 중성지방에 의한 대식세포 사멸 억제용 조성물
WO2021048314A1 (fr) * 2019-09-11 2021-03-18 Square Power Ltd Rebamipide destiné à être utilisé dans la prévention et/ou le traitement de la rigidité artérielle
EP3797774A1 (fr) * 2019-09-11 2021-03-31 Square Power Ltd Rebamipide destiné à être utilisé dans la prévention et/ou le traitement de la rigidité artérielle

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