WO2022186042A1 - Cholesterol-lowering agent - Google Patents

Cholesterol-lowering agent Download PDF

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Publication number
WO2022186042A1
WO2022186042A1 PCT/JP2022/007617 JP2022007617W WO2022186042A1 WO 2022186042 A1 WO2022186042 A1 WO 2022186042A1 JP 2022007617 W JP2022007617 W JP 2022007617W WO 2022186042 A1 WO2022186042 A1 WO 2022186042A1
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Prior art keywords
cholesterol
red yeast
lowering agent
yeast rice
monascus
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PCT/JP2022/007617
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French (fr)
Japanese (ja)
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幸一 浅野
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小林製薬株式会社
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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

Definitions

  • the present invention relates to an agent for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  • CM chylomicron
  • VLDL very low density lipoprotein
  • IDL intermediate density lipoprotein
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • Lipoproteins are a combination of lipids and apoproteins in the manner in which lipids are present in plasma. Lipoproteins are triacylglycerols (triglycerides, triglycerides) and spherical particles rich in cholesterol, which are essential for cell life support. There are proteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). The higher the specific gravity of lipoproteins, the smaller the particles, the higher the ratio of apolipoproteins, and the lower the ratio of lipids.
  • IDL proteins
  • LDL low density lipoproteins
  • HDL high density lipoproteins
  • Cholesterol is an essential component for maintaining biological functions, but if blood cholesterol increases due to excessive intake, etc., it may lead to dyslipidemia (hyperlipidemia) and induce arteriosclerosis.
  • statin compounds such as lovastatin are known to reduce blood cholesterol and are used as cholesterol-lowering agents.
  • Patent Document 1 reports that after heating bitter gourd, it is mixed with water, pulverized, and then extracted with hot water, and the resulting extract can be used as an LDL cholesterol-lowering agent.
  • Patent Document 2 reports that a tea beverage containing a component containing ⁇ -glucosylrutin and a tea component has an LDL cholesterol-lowering effect.
  • dyslipidemia is classified into type I with increased CM, type IIa with increased LDL (hyperLDLemia), type IIb with increased LDL and VLDL (complex dyslipidemia), hyper- ⁇ Type III (dysbetalipoproteinemia), indicating the presence of low-density lipoprotein; Type IV (endogenous hypertriglyceridemia), indicating increased VLDL; and Type V (mixed dyslipidemia), indicating increased VLDL and CM. disease) are classified into six types.
  • type I dyslipidemia requires reduction of CM cholesterol
  • type IV dyslipidemia requires reduction of VLDL cholesterol
  • type V dyslipidemia requires reduction of VLDL cholesterol and CM cholesterol.
  • statin compounds have been developed to exhibit the action of reducing blood LDL cholesterol, and cannot be used for reducing VLDL cholesterol or CM cholesterol.
  • lovastatin has the effect of suppressing cholesterol synthesis in the liver and reducing LDL cholesterol in the blood, but does not have the effect of reducing VLDL cholesterol and CM cholesterol.
  • remnants are intermediate metabolites produced during the metabolic process of chylomicrons and VLDL in the blood. Under normal conditions, remnants have a high metabolic rate and are rapidly taken up by receptors in the liver. Although it is almost absent in the blood, if for some reason metabolism slows down and accumulates in the blood, hyperremnantemia (symptom of remnant-like lipoprotein (RLP) cholesterol exceeding 2.5 mg/dl) occurs. is known to be a risk factor for arteriosclerosis. Therefore, conventional cholesterol-lowering agents that lower LDL cholesterol cannot be expected to be effective for the prevention or treatment of hyperremnantemia, and administration or intake of components that lower blood RLP cholesterol is necessary. Almost no studies have been conducted on components that reduce the
  • an object of the present invention is to provide a cholesterol-lowering agent that reduces blood levels of cholesterol contained in lipoproteins with a specific gravity of less than 1.019 g/mL.
  • red yeast rice or its processed product contains liposomes having a specific gravity of less than 1.019 g/mL such as RLP cholesterol, CM cholesterol, and VLDL cholesterol in the blood. It was found that it has the effect of reducing cholesterol contained in protein.
  • the present invention has been completed through further studies based on these findings.
  • Section 1 Containing red yeast rice or its processed product, A cholesterol-lowering agent for use in reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  • Section 2. Item 2. The cholesterol-lowering agent according to Item 1, wherein the cholesterol to be reduced is at least one selected from the group consisting of remnant-like lipoprotein cholesterol, chylomicron cholesterol and very low density lipoprotein cholesterol.
  • Item 3. Item 3.
  • the cholesterol-lowering agent according to Item 1 or 2 wherein the red yeast rice or a processed product thereof is a red yeast rice produced using Monascus pyrosus or a processed product thereof.
  • Section 4. Item 4.
  • Item 6. A method for reducing cholesterol, comprising the step of ingesting red yeast rice or a processed product thereof to a person who is required to reduce blood levels of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  • Red yeast rice or a processed product thereof for producing a cholesterol-lowering agent used for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  • Item 8 Red yeast rice or a processed product thereof, which is used for reducing blood levels of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  • Item 9 Non-therapeutic use of red yeast rice or its products for reducing blood levels of cholesterol contained in lipoproteins with a specific gravity of less than 1.019 g/mL.
  • the cholesterol-lowering agent of the present invention can reduce the concentration of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL, such as RLP cholesterol, CM cholesterol, and VLDL cholesterol in the blood. It is useful for the prevention or treatment of WHO classification type I, IV and V dyslipidemia.
  • Rabbits were given a high-fat, high-cholesterol diet (control group) or a high-fat, high-cholesterol diet containing processed red yeast rice (monascus group) for 12 weeks, and the plasma VLDL remnant cholesterol concentration was measured over time. is. Rabbits were given a high-fat, high-cholesterol diet (control group) or a high-fat, high-cholesterol diet containing processed red yeast rice (monascus group) for 12 weeks, and plasma CM-cholesterol concentrations were measured over time. be.
  • Rabbits were given a high-fat, high-cholesterol diet (control group) or a high-fat, high-cholesterol diet containing processed red yeast rice (monascus group) for 12 weeks, and the plasma VLDL cholesterol concentration was measured over time. be.
  • the cholesterol-lowering agent of the present invention is used for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL, and is characterized by containing red yeast rice or a processed product thereof.
  • the cholesterol-lowering agent of the present invention is described in detail below.
  • a lipoprotein having a specific gravity of less than 1.019 g/mL refers to a lipoprotein having a density of less than 1.019 g/mL as measured by ultracentrifugation. Lipoproteins with a specific gravity of less than 1.019 g/mL include remnant-like lipoproteins, chylomicrons, and very low density lipoproteins.
  • RLP cholesterol is an abbreviation for remnant-like lipoprotein cholesterol, and means cholesterol contained in remnant-like lipoproteins. Further, remnant-like lipoprotein means a lipoprotein having a specific gravity of 1.006 g/mL or more and 1.019 g/mL or less.
  • VLDL remnant cholesterol means cholesterol contained in VLDL remnants, which are a type of remnant-like lipoproteins.
  • chylomicron remnant cholesterol means cholesterol contained in chylomicron remnants, which are a type of remnant-like lipoproteins.
  • CM cholesterol is an abbreviation for chylomicron cholesterol and means cholesterol contained in chylomicron. Also, chylomicrons refer to lipoproteins with a specific gravity of less than 0.94 g/mL.
  • VLDL cholesterol is an abbreviation for very low density lipoprotein cholesterol and means cholesterol contained in very low density lipoprotein.
  • ultra-low-density lipoprotein means lipoprotein having a specific gravity of 0.94 g/mL or more and less than 1.006 g/mL.
  • cholesterol-lowering agent means an agent used to reduce blood cholesterol levels.
  • reducing the blood cholesterol level includes suppressing an increase in the blood cholesterol level and reducing an elevated blood cholesterol level.
  • the cholesterol-lowering agent of the present invention is used for the purpose of reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL. Refers to agents used to reduce blood levels of cholesterol contained in lipoproteins below 1.019 g/mL.
  • Red yeast rice or its processed product contains red yeast rice or a processed product thereof as an active ingredient.
  • Red yeast rice is a rice malt made by fermenting red yeast in cereals.
  • the monascus monascus used in the production of the monascus used in the present invention may be a filamentous fungus belonging to the Monascaceae family.
  • filamentous fungi belonging to the family Aspergillus include filamentous fungi belonging to the genus Monascus and BasIpetospora, preferably the genus Monascus.
  • filamentous fungi belonging to the genus Monascus include, for example, M. pilosus, M. purpureus, M. pubigerus, M. anka, and Monascus ceroleuscens. (M. serorubescens), M. rubellus, M. kaoliang, M. rubiginosus, M. major, M. ruber , Monascus paxii, M. fuliginosus, M. vitreus, M. barkeri, Monascus sp., variants thereof or A mutant strain is mentioned. Monascus used in the present invention may be produced using one type of Monascus, or may be produced by combining two or more types of Monascus. Monascus pyrosus is preferred among these Monascus pyrosus from the viewpoint of more effectively reducing blood levels of RLP-cholesterol, CM-cholesterol and/or VLDL-cholesterol.
  • the type of cereal used as a raw material for red yeast rice used in the present invention is not particularly limited as long as it is edible and can be fermented by red yeast rice.
  • species barley such as wheat, barley, rye, and oats; soybeans (white soybeans, black soybeans, green soybeans, etc.); defatted soybeans;
  • the monascus used in the present invention may be produced using one type of grain, or may be produced by combining two or more types of grains. Among these grains, rice is preferred, and polished rice is more preferred.
  • Monascus can be produced by a conventional method using monascus and cereals. Specifically, monascus can be produced by inoculating monascus in steamed (cooked or steamed) cereals and statically culturing under aerobic conditions of about 20 to 40°C. In addition, grains used as raw materials may be subjected to chopping or pulverization before or after steaming, if necessary.
  • the fermented red yeast rice may be used as it is, or the fermented red yeast rice may be subjected to one or more treatments such as heating, drying, crushing, crushing, grinding, and extraction. Processed products of red yeast rice may also be used.
  • processed products of monascus include dried monascus, powder of dried monascus, fine granules of dried monascus, and dried monascus extract powder; paste of monascus; including concentrated extracts) and the like.
  • processed products of monascus preferably dried products, more preferably dried monascus powder, dried monascus granules, and even more preferably dried monascus powder are mentioned.
  • the monascus and enzymes contained in the processed product of monascus may be viable or in an active state, or may be inactivated by heat treatment or the like.
  • red yeast rice can be used.
  • powdered dried rice red yeast rice is sold under the trade names "V. Red yeast rice 3P-D” and "V. Red yeast rice 3P-D20" (both manufactured by Kobayashi Value Support Co., Ltd.). These commercially available products can be used.
  • the cholesterol-lowering agent of the present invention is provided in a desired dosage form by combining the red yeast rice or its processed product as an active ingredient with other edible ingredients.
  • the dosage form of the cholesterol-lowering agent of the present invention is not particularly limited, and may be solid, semi-solid, or liquid.
  • the cholesterol-lowering agent of the present invention is preferably in the form of oral ingestion or oral administration. good.
  • the forms of use of the cholesterol-lowering agent of the present invention include food and drink, drugs for internal use (including quasi-drugs for internal use), feeds, pet foods, and the like.
  • foods and drinks and medicines for internal use are preferred, and foods and drinks are more preferred.
  • red yeast rice or a processed product thereof is used.
  • a food or drink that is, when provided as a food or drink for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL
  • red yeast rice or a processed product thereof is used.
  • examples of such food and drink include general food and drink, food with health claims (including specified health food, food with nutrient function claims, supplements, etc.), food for sick people, and the like.
  • the form of these foods and drinks is not particularly limited, but specifically supplements such as capsules (soft capsules, hard capsules), tablets, granules, powders, jellies; tea beverages, nutritional drinks, fruit juice beverages, Beverages such as carbonated beverages and lactic acid beverages; luxury goods such as gummies, candies, and jellies.
  • supplements such as capsules (soft capsules, hard capsules), tablets, granules, powders, jellies; tea beverages, nutritional drinks, fruit juice beverages, Beverages such as carbonated beverages and lactic acid beverages; luxury goods such as gummies, candies, and jellies.
  • supplements are preferred, and capsules, tablets, granules and powders are more preferred.
  • red yeast rice or a processed product thereof may be prepared into a desired form as it is or in combination with other additives. Just do it.
  • Specific examples of such internal medicines include tablets, pills, powders, fine granules, granules, capsules (including hard capsules and soft capsules), troches, chewables, drinks, extracts ( soft extracts, dry extracts, etc.), jellies, syrups, spirits, elixirs, liposome preparations and the like.
  • red yeast rice or its processed product may be prepared into a desired form as it is or in combination with other materials, additives, and the like.
  • specific examples of the feed include livestock such as cattle, pigs and sheep; and poultry such as chickens, quails and ostriches.
  • pet foods specifically include pet foods fed to dogs, cats, rabbits, hamsters, and the like.
  • the content of red yeast rice or its processed product is determined by taking into consideration the physique, age, symptoms of the subject, the form of the cholesterol-lowering agent, etc. - It may be set as appropriate based on the dosage, but may be, for example, 1 to 100% by weight.
  • the cholesterol-lowering agent of the present invention is used for reducing blood levels of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  • Cholesterol to be reduced by the cholesterol-lowering agent of the present invention may be contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  • cholesterol contained in proteins more preferably cholesterol contained in lipoproteins with a specific gravity of 0.1 to 1.019 g/mL, more preferably cholesterol contained in lipoproteins with a specific gravity of 0.5 to 1.019 g/mL, Cholesterol contained in lipoproteins having a specific gravity of 0.9 to 1.019 g/mL is particularly preferred.
  • the cholesterol-lowering agent of the present invention can be used for reducing at least one of RLP cholesterol, CM cholesterol and VLDL cholesterol.
  • the cholesterol-lowering agent of the present invention can preferably be used for reducing at least two types of RLP cholesterol, CM cholesterol and VLDL cholesterol, and more preferably for reducing all of RLP cholesterol, CM cholesterol and VLDL cholesterol.
  • the cholesterol-lowering agent of the present invention when used for reducing RLP cholesterol, it may be used for reducing both chylomicron remnant cholesterol and VLDL remnant cholesterol, preferably for reducing VLDL remnant cholesterol.
  • an increase in blood RLP cholesterol is a factor in hyperremnantemia (a condition in which blood RLP cholesterol exceeds 2.5 mg/dl), and the cholesterol-lowering agent of the present invention reduces blood RLP cholesterol. Since it shows action, it can be used for the purpose of prevention or treatment of hyperremnantemia.
  • CM cholesterol is one of the causes of WHO classification type I dyslipidemia. It can be used for the purpose of prevention or treatment of disease.
  • An increase in blood VLDL cholesterol is one of the causes of WHO classification IV dyslipidemia (endogenous hypertriglyceridemia), and the cholesterol-lowering agent of the present invention exhibits a blood VLDL cholesterol-lowering effect. , can be used for the prevention or treatment of WHO classification IV dyslipidemia.
  • the intake/dosage of red yeast rice or its processed product per day may be set according to the subject's physique, age, symptoms, purpose of use of the cholesterol-lowering agent, etc.
  • the dry weight of monascus may be set to about 100 to 60,000 mg, preferably about 200 to 30,000 mg.
  • "converted to the dry weight of red yeast rice” is the dry weight when unprocessed red yeast rice is used. is the dry weight of red yeast rice contained in the processed product, and in the case of using red yeast rice extract or red yeast rice extract powder, the drying of red yeast rice used as a raw material for extracting red yeast rice extract or red yeast rice extract powder Weight.
  • the cholesterol-lowering agent of the present invention may be ingested or administered once a day, or divided into multiple times per day, and divided into once or 2 to 3 times per day. preferably ingested or administered.
  • Test example 1 Test materials and test methods 1-1. Processed product of red yeast rice As a processed product of red yeast rice, dried rice red yeast powder (trade name “3P-D20”, manufactured by Kobayashi Value Support Co., Ltd.) was used. The dried red yeast rice powder is a dried red yeast powder obtained by fermenting white rice with Monascus pyrosus, and the heat treatment deactivates the red yeast mold and enzymes.
  • dried rice red yeast powder (trade name “3P-D20”, manufactured by Kobayashi Value Support Co., Ltd.) was used.
  • the dried red yeast rice powder is a dried red yeast powder obtained by fermenting white rice with Monascus pyrosus, and the heat treatment deactivates the red yeast mold and enzymes.

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Abstract

[Problem] The purpose of the present invention is to provide a cholesterol-lowering agent for lowering the concentration, in blood, of the cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL. [Solution] In the present invention, Monascus purpureus or the processed product thereof has the effect of lowering the concentration, in blood, of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL, such as remnant-like lipoprotein cholesterol, chylomicron cholesterol, and ultra-low-density lipoprotein cholesterol, and is useful as an agent for lowering each of these cholesterols.

Description

コレステロールの低減剤cholesterol lowering agent
　本発明は、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの低減剤に関する。 The present invention relates to an agent for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
　生体内に存在するコレステロールは、食事に由来するものと、体内で生成されるものとがある。コレステロールは、血中で、主に、カイロミクロン（ＣＭ）コレステロール、超低比重リポ蛋白（ＶＬＤＬ）コレステロール、中間比重リポ蛋白（ＩＤＬ）コレステロール、低比重リポ蛋白（ＬＤＬ）コレステロール、及び高比重リポ蛋白（ＨＤＬ）コレステロールとして存在している。 There are two types of cholesterol in the body: those derived from diet and those produced in the body. Cholesterol is mainly found in the blood as chylomicron (CM) cholesterol, very low density lipoprotein (VLDL) cholesterol, intermediate density lipoprotein (IDL) cholesterol, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) exists as cholesterol.
　リポ蛋白は、脂質が血漿中に存在する様態で、脂質とアポタンパク質が結合したものである。リポ蛋白は、トリアシルグリセロール（トリグリセリド、中性脂肪）および、細胞の生命維持に不可欠なコレステロールを多く含む球状粒子であり、カイロミクロン（ＣＭ）、超低密度リポ蛋白（ＶＬＤＬ）、中間密度リポ蛋白（ＩＤＬ）、低密度リポ蛋白（ＬＤＬ）高密度リポ蛋白（ＨＤＬ）がある。リポ蛋白は、比重が大きいほど粒子が小さくなり、アポリポ蛋白の割合が高く、逆に脂質の割合が低くなる。 Lipoproteins are a combination of lipids and apoproteins in the manner in which lipids are present in plasma. Lipoproteins are triacylglycerols (triglycerides, triglycerides) and spherical particles rich in cholesterol, which are essential for cell life support. There are proteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). The higher the specific gravity of lipoproteins, the smaller the particles, the higher the ratio of apolipoproteins, and the lower the ratio of lipids.
　コレステロールは、生体機能の維持に不可欠な成分であるが、過剰摂取等によって血中コレステロールが高くなると、脂質異常症（高脂血症）になり、動脈硬化を誘発することがある。 Cholesterol is an essential component for maintaining biological functions, but if blood cholesterol increases due to excessive intake, etc., it may lead to dyslipidemia (hyperlipidemia) and induce arteriosclerosis.
　そこで、従来、コレステロールの吸収を抑制したり、コレステロールの血中濃度を低減させたりする成分について種々開発されている。例えば、従来、ロバスタチン等のスタチン化合物が、血中コレステロールを低減させることが知られており、コレステロール低減剤として使用されている。また、特許文献１では、ゴーヤを加熱した後、水と混合して粉砕し、その後熱水抽出することにより得られた抽出物を、ＬＤＬコレステロール低減剤として使用できることが報告されている。更に、特許文献２には、α－グルコシルルチンを含む成分と茶成分とを含有する茶飲料は、ＬＤＬコレステロール低減作用があることが報告されている。 Therefore, conventionally, various ingredients have been developed that suppress the absorption of cholesterol and reduce the blood concentration of cholesterol. For example, conventionally, statin compounds such as lovastatin are known to reduce blood cholesterol and are used as cholesterol-lowering agents. Moreover, Patent Document 1 reports that after heating bitter gourd, it is mixed with water, pulverized, and then extracted with hot water, and the resulting extract can be used as an LDL cholesterol-lowering agent. Furthermore, Patent Document 2 reports that a tea beverage containing a component containing α-glucosylrutin and a tea component has an LDL cholesterol-lowering effect.
特開２０１９－１４２７８８号公報JP 2019-142788 A 特開２０１９－１３５９９２号公報JP 2019-135992 A
　脂質異常症は、ＷＨＯ分類に従って、ＣＭの増加を示すＩ型、ＬＤＬの増加を示すＩＩａ型（高ＬＤＬ血症）、ＬＤＬとＶＬＤＬの増加を示すＩＩb型（複合型脂質異常症）、β超低比重リポ蛋白の存在を示すＩＩＩ型（異常βリポ蛋白血症）、ＶＬＤＬの増加を示すＩＶ型（内因性高トリグリセライド血症）、及びＶＬＤＬとＣＭの増加を示すＶ型（混合型脂質異常症）の６つのタイプに分類されている。脂質異常症の予防又は治療には、ＷＨＯ分類に従ってタイプ分けを行い、それに基づいて適切な方針を決定することが必要とされている。例えば、Ｉ型の脂質異常症ではＣＭコレステロール、ＩＶ型の脂質異常症ではＶＬＤＬコレステロール、Ｖ型脂質異常症ではＶＬＤＬコレステロールとＣＭコレステロールを、それぞれ低減させることが必要になる。 According to the WHO classification, dyslipidemia is classified into type I with increased CM, type IIa with increased LDL (hyperLDLemia), type IIb with increased LDL and VLDL (complex dyslipidemia), hyper-β Type III (dysbetalipoproteinemia), indicating the presence of low-density lipoprotein; Type IV (endogenous hypertriglyceridemia), indicating increased VLDL; and Type V (mixed dyslipidemia), indicating increased VLDL and CM. disease) are classified into six types. For the prevention or treatment of dyslipidemia, it is necessary to classify it according to the WHO classification and determine an appropriate policy based on the classification. For example, type I dyslipidemia requires reduction of CM cholesterol, type IV dyslipidemia requires reduction of VLDL cholesterol, and type V dyslipidemia requires reduction of VLDL cholesterol and CM cholesterol.
　しかしながら、従来報告されているスタチン化合物によるコレステロール低減剤は血中ＬＤＬコレステロールの低減作用を示すものとして開発されており、ＶＬＤＬコレステロールやＣＭコレステロールの低減用途に使用できるものではない。実際、ロバスタチンは、肝臓におけるコレステロール合成を抑え、血中のＬＤＬコレステロールを低減させる作用があるが、ＶＬＤＬコレステロールやＣＭコレステロールを低減させる作用がないことが報告されている。 However, conventionally reported cholesterol-lowering agents based on statin compounds have been developed to exhibit the action of reducing blood LDL cholesterol, and cannot be used for reducing VLDL cholesterol or CM cholesterol. In fact, it has been reported that lovastatin has the effect of suppressing cholesterol synthesis in the liver and reducing LDL cholesterol in the blood, but does not have the effect of reducing VLDL cholesterol and CM cholesterol.
　また、レムナントは、カイロミクロンやＶＬＤＬが血中での代謝過程で生じる中間代謝産物であり、レムナントは正常な状態では代謝速度が速く、速やかに肝臓のレセプターに取り込まれるため、健常者の空腹時には血中には殆ど存在していないが、何らかの原因で代謝が遅くなり、血中に蓄積して高レムナント血症（レムナント様リポ蛋白（ＲＬＰ）コレステロールが２．５ｍｇ／ｄｌを超える症状）になると、動脈硬化の危険因子になることが知られている。そのため、高レムナント血症の予防又は治療には、従来のＬＤＬコレステロールを低減させるコレステロール低減剤では効果が期待できず、血中ＲＬＰコレステロールを低減させる成分の投与又は摂取が必要になるが、ＲＬＰコレステロールを低減させる成分については殆ど検討されていない。 In addition, remnants are intermediate metabolites produced during the metabolic process of chylomicrons and VLDL in the blood. Under normal conditions, remnants have a high metabolic rate and are rapidly taken up by receptors in the liver. Although it is almost absent in the blood, if for some reason metabolism slows down and accumulates in the blood, hyperremnantemia (symptom of remnant-like lipoprotein (RLP) cholesterol exceeding 2.5 mg/dl) occurs. is known to be a risk factor for arteriosclerosis. Therefore, conventional cholesterol-lowering agents that lower LDL cholesterol cannot be expected to be effective for the prevention or treatment of hyperremnantemia, and administration or intake of components that lower blood RLP cholesterol is necessary. Almost no studies have been conducted on components that reduce the
　このように、レムナント様リポ蛋白コレステロール、カイロミクロンコレステロール、超低比重リポ蛋白コレステロール等の比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールを低減させ得る飲食品や医薬品の開発が求められているが、従来、当該コレステロールを低減させ得る成分については殆ど検討されていない。 Thus, there is a demand for the development of foods, beverages, and pharmaceuticals capable of reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL, such as remnant-like lipoprotein cholesterol, chylomicron cholesterol, and ultra-low-density lipoprotein cholesterol. However, conventionally, almost no studies have been conducted on components capable of lowering the cholesterol.
　そこで、本発明の目的は、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの血中濃度を低減させるコレステロール低減剤を提供することである。 Accordingly, an object of the present invention is to provide a cholesterol-lowering agent that reduces blood levels of cholesterol contained in lipoproteins with a specific gravity of less than 1.019 g/mL.
　本発明者は、前記課題を解決すべく鋭意検討を行ったところ、紅麹又はその加工物には、血中のＲＬＰコレステロール、ＣＭコレステロール、及びＶＬＤＬコレステロール等の比重１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールを低減させる作用があることを見出した。本発明は、かかる知見に基づいて更なる検討を重ねることにより完成したものである。 As a result of intensive studies to solve the above problems, the present inventors found that red yeast rice or its processed product contains liposomes having a specific gravity of less than 1.019 g/mL such as RLP cholesterol, CM cholesterol, and VLDL cholesterol in the blood. It was found that it has the effect of reducing cholesterol contained in protein. The present invention has been completed through further studies based on these findings.
　即ち、本発明は、下記に掲げる態様の発明を提供する。
項１．　紅麹又はその加工物を含有し、
　比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの低減に使用される、コレステロール低減剤。
項２．　低減対象となるコレステロールが、レムナント様リポ蛋白コレステロール、カイロミクロンコレステロール及び超低比重リポ蛋白コレステロールよりなる群から選択される少なくとも１種である、項１に記載のコレステロール低減剤。
項３．　前記紅麹又はその加工物が、モナスカス・ピローサスを用いて製造された紅麹又はその加工物である、項１又は２に記載のコレステロール低減剤。
項４．　高レムナント血症、或はＷＨＯ分類のＩ型、ＩＶ型、又はＶ型の脂質異常症の予防又は治療に使用される、項１～３のいずれかに記載のコレステロール低減剤。
項５．　飲食品、内服用医薬品、飼料、又はペットフードとして使用される、項１～４のいずれかに記載のコレステロール低減剤。
項６．　比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの血中濃度の低減が求められる者に、紅麹又はその加工物を摂取させる工程を含む、前記コレステロールの低減方法。
項７．　紅麹又はその加工物の、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの低減に使用されるコレステロール低減剤の製造のための使用。
項８．　比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの血中濃度の低減のために使用される、紅麹又はその加工物。
項９．　比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの血中濃度の低減のための、紅麹又はその加工物の非治療的使用。 That is, the present invention provides inventions in the following aspects.
Section 1. Containing red yeast rice or its processed product,
A cholesterol-lowering agent for use in reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
Section 2. Item 2. The cholesterol-lowering agent according to Item 1, wherein the cholesterol to be reduced is at least one selected from the group consisting of remnant-like lipoprotein cholesterol, chylomicron cholesterol and very low density lipoprotein cholesterol.
Item 3. Item 3. The cholesterol-lowering agent according to Item 1 or 2, wherein the red yeast rice or a processed product thereof is a red yeast rice produced using Monascus pyrosus or a processed product thereof.
Section 4. Item 4. The cholesterol-lowering agent according to any one of items 1 to 3, which is used for the prevention or treatment of hyperremnantemia or WHO classification type I, IV, or V dyslipidemia.
Item 5. Item 5. The cholesterol-lowering agent according to any one of Items 1 to 4, which is used as a food or drink, an internal medicine, a feed, or a pet food.
Item 6. A method for reducing cholesterol, comprising the step of ingesting red yeast rice or a processed product thereof to a person who is required to reduce blood levels of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
Item 7. Use of red yeast rice or a processed product thereof for producing a cholesterol-lowering agent used for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
Item 8. Red yeast rice or a processed product thereof, which is used for reducing blood levels of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
Item 9. Non-therapeutic use of red yeast rice or its products for reducing blood levels of cholesterol contained in lipoproteins with a specific gravity of less than 1.019 g/mL.
　本発明のコレステロール低減剤によれば、血中のＲＬＰコレステロール、ＣＭコレステロール、ＶＬＤＬコレステロール等の比重１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの濃度を低減できるので、高レムナント血症や、ＷＨＯ分類のＩ型、ＩＶ型及びＶ型の脂質異常症の予防又は治療に有用である。 The cholesterol-lowering agent of the present invention can reduce the concentration of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL, such as RLP cholesterol, CM cholesterol, and VLDL cholesterol in the blood. It is useful for the prevention or treatment of WHO classification type I, IV and V dyslipidemia.
ウサギに、高脂肪高コレステロール飼料（コントロール群）又は紅麹の加工物を含む高脂肪高コレステロール飼料（紅麹群）を１２週間摂取させ、血漿中のＶＬＤＬレムナントコレステロール濃度を経時的に測定した結果である。Rabbits were given a high-fat, high-cholesterol diet (control group) or a high-fat, high-cholesterol diet containing processed red yeast rice (monascus group) for 12 weeks, and the plasma VLDL remnant cholesterol concentration was measured over time. is. ウサギに、高脂肪高コレステロール飼料（コントロール群）又は紅麹の加工物を含む高脂肪高コレステロール飼料（紅麹群）を１２週間摂取させ、血漿中のＣＭコレステロール濃度を経時的に測定した結果である。Rabbits were given a high-fat, high-cholesterol diet (control group) or a high-fat, high-cholesterol diet containing processed red yeast rice (monascus group) for 12 weeks, and plasma CM-cholesterol concentrations were measured over time. be. ウサギに、高脂肪高コレステロール飼料（コントロール群）又は紅麹の加工物を含む高脂肪高コレステロール飼料（紅麹群）を１２週間摂取させ、血漿中のＶＬＤＬコレステロール濃度を経時的に測定した結果である。Rabbits were given a high-fat, high-cholesterol diet (control group) or a high-fat, high-cholesterol diet containing processed red yeast rice (monascus group) for 12 weeks, and the plasma VLDL cholesterol concentration was measured over time. be.
　本発明のコレステロール低減剤は、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの低減に使用されるものであって、紅麹又はその加工物を含有することを特徴とする。以下、本発明のコレステロール低減剤について詳述する。 The cholesterol-lowering agent of the present invention is used for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL, and is characterized by containing red yeast rice or a processed product thereof. The cholesterol-lowering agent of the present invention is described in detail below.
［定義］
　本明細書において「比重が１．０１９ｇ／ｍＬ未満のリポ蛋白」とは、超遠心分離法によって測定される密度が１．０１９ｇ／ｍＬ未満のリポ蛋白を指す。比重が１．０１９ｇ／ｍＬ未満のリポ蛋白には、レムナント様リポ蛋白、カイロミクロン、及び超低比重リポ蛋白が含まれる。 [definition]
As used herein, "a lipoprotein having a specific gravity of less than 1.019 g/mL" refers to a lipoprotein having a density of less than 1.019 g/mL as measured by ultracentrifugation. Lipoproteins with a specific gravity of less than 1.019 g/mL include remnant-like lipoproteins, chylomicrons, and very low density lipoproteins.
　本明細書において「ＲＬＰコレステロール」とは、レムナント様リポ蛋白コレステロールの略記であり、レムナント様リポ蛋白に含まれるコレステロールを意味する。また、レムナント様リポ蛋白は、比重が１．００６ｇ／ｍＬ以上１．０１９ｇ／ｍＬ以下のリポ蛋白を意味する。 As used herein, "RLP cholesterol" is an abbreviation for remnant-like lipoprotein cholesterol, and means cholesterol contained in remnant-like lipoproteins. Further, remnant-like lipoprotein means a lipoprotein having a specific gravity of 1.006 g/mL or more and 1.019 g/mL or less.
　本明細書において、「ＶＬＤＬレムナントコレステロール」はレムナント様リポ蛋白の一種であるＶＬＤＬレムナントに含まれるコレステロールを意味する。 As used herein, "VLDL remnant cholesterol" means cholesterol contained in VLDL remnants, which are a type of remnant-like lipoproteins.
　本明細書において、「カイロミクロンレムナントコレステロール」はレムナント様リポ蛋白の一種であるカイロミクロンレムナントに含まれるコレステロールを意味する。 As used herein, "chylomicron remnant cholesterol" means cholesterol contained in chylomicron remnants, which are a type of remnant-like lipoproteins.
　本明細書において「ＣＭコレステロール」とは、カイロミクロンコレステロールの略記であり、カイロミクロンに含まれるコレステロールを意味する。また、カイロミクロンは、比重が０．９４ｇ／ｍＬ未満のリポ蛋白を意味する。 As used herein, "CM cholesterol" is an abbreviation for chylomicron cholesterol and means cholesterol contained in chylomicron. Also, chylomicrons refer to lipoproteins with a specific gravity of less than 0.94 g/mL.
　本明細書において「ＶＬＤＬコレステロール」とは、超低比重リポ蛋白コレステロールの略記であり、超低比重リポ蛋白に含まれるコレステロールを意味する。また、超低比重リポ蛋白は、比重が０．９４ｇ／ｍＬ以上１．００６ｇ／ｍＬ未満のリポ蛋白を意味する。 As used herein, "VLDL cholesterol" is an abbreviation for very low density lipoprotein cholesterol and means cholesterol contained in very low density lipoprotein. Also, ultra-low-density lipoprotein means lipoprotein having a specific gravity of 0.94 g/mL or more and less than 1.006 g/mL.
　本明細書において「コレステロール低減剤」とは、血中のコレステロール濃度を低減させるために使用される剤を意味する。ここで、「血中のコレステロール濃度を低減させる」とは、血中のコレステロール濃度の上昇を抑制すること、及び上昇した血中のコレステロール濃度を低下させることが包含される。本発明のコレステロール低減剤は、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールを低減させる目的で使用されるので、「本発明のコレステロール低減剤」と表記する場合には、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの血中濃度を低減させるために使用される剤を指す。 As used herein, the term "cholesterol-lowering agent" means an agent used to reduce blood cholesterol levels. Here, "reducing the blood cholesterol level" includes suppressing an increase in the blood cholesterol level and reducing an elevated blood cholesterol level. The cholesterol-lowering agent of the present invention is used for the purpose of reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL. Refers to agents used to reduce blood levels of cholesterol contained in lipoproteins below 1.019 g/mL.
［紅麹又はその加工物］
　本発明のコレステロール低減剤は、有効成分として、紅麹又はその加工物を含有する。紅麹とは、穀類に紅麹菌を発酵させた麹である。 [Red yeast rice or its processed product]
The cholesterol-lowering agent of the present invention contains red yeast rice or a processed product thereof as an active ingredient. Red yeast rice is a rice malt made by fermenting red yeast in cereals.
　本発明で使用される紅麹の製造に使用される紅麹菌は、ベニコウジカビ科（Monascaceae）に属する糸状菌であればよい。ベニコウジカビ科に属する糸状菌としては、例えば、モナスカス属（Monascus）、及びバシペトスポラ属（BasIpetospora） に属する糸状菌が挙げられ、好ましくはモナスカス属（Monascus）が挙げられる。 The monascus monascus used in the production of the monascus used in the present invention may be a filamentous fungus belonging to the Monascaceae family. Examples of filamentous fungi belonging to the family Aspergillus include filamentous fungi belonging to the genus Monascus and BasIpetospora, preferably the genus Monascus.
　モナスカス属に属する糸状菌としては、例えば、モナスカス・ピローサス（M. pilosus）、モナスカス・パープレウス(M. purpureus）、モナスカス・プビゲレス（M. pubigerus）、モナスカス・アンカ（M. anka）、モナスカス・セロルベセンス（M. serorubescens）、モナスカス・ルベルス（M. rubellus）、モナスカス・カオリアング（M. kaoliang）、モナスカス・ルビギノサス（M. rubiginosus）、モナスカス・メイジャー（M. major）、モナスカス・ルバー（M. ruber）、モナスカス・パキシイ（M. paxii）、モナスカス・フリギノサス（M. fuliginosus）、モナスカス・ビトレウス（M. vitreus）、モナスカス・バルケリ（M. barkeri）、モナスカス・エスピー（Monascus sp.）、これらの変種又は変異株が挙げられる。本発明で使用される紅麹は、１種の紅麹菌を使用して製造されたものであってもよく、２種以上の紅麹菌を組み合わせて製造されたものであってもよい。これらの紅麹菌の中でも、ＲＬＰコレステロール、ＣＭコレステロール、及び／又はＶＬＤＬコレステロールの血中濃度をより一層効果的に低減させるという観点から、好ましくはモナスカス・ピローサスが挙げられる。 Examples of filamentous fungi belonging to the genus Monascus include, for example, M. pilosus, M. purpureus, M. pubigerus, M. anka, and Monascus ceroleuscens. (M. serorubescens), M. rubellus, M. kaoliang, M. rubiginosus, M. major, M. ruber , Monascus paxii, M. fuliginosus, M. vitreus, M. barkeri, Monascus sp., variants thereof or A mutant strain is mentioned. Monascus used in the present invention may be produced using one type of Monascus, or may be produced by combining two or more types of Monascus. Monascus pyrosus is preferred among these Monascus pyrosus from the viewpoint of more effectively reducing blood levels of RLP-cholesterol, CM-cholesterol and/or VLDL-cholesterol.
　本発明で使用される紅麹の原料として使用される穀類の種類については、可食性があり、紅麹菌による発酵が可能であることを限度として特に制限されないが、例えば、白米や玄米等の米類；小麦、大麦、ライ麦、燕麦等の麦類、大豆（白大豆、黒大豆、青大豆等）、これらの脱脂大豆、これらの胚軸等の豆類等が挙げられる。本発明で使用される紅麹は、１種の穀類を使用して製造されたものであってもよく、２種以上の穀類を組み合わせて製造されたものであってもよい。これらの穀類の中でも、好ましくは米類、より好ましくは白米が挙げられる。 The type of cereal used as a raw material for red yeast rice used in the present invention is not particularly limited as long as it is edible and can be fermented by red yeast rice. species: barley such as wheat, barley, rye, and oats; soybeans (white soybeans, black soybeans, green soybeans, etc.); defatted soybeans; The monascus used in the present invention may be produced using one type of grain, or may be produced by combining two or more types of grains. Among these grains, rice is preferred, and polished rice is more preferred.
　紅麹は、紅麹菌及び穀類を用いて、慣用の方法によって製造することができる。具体的には、蒸煮（炊き上げ、蒸し上げ）された穀類に紅麹菌を接種し、２０～４０℃程度の好気的条件で静置培養することによって紅麹を製造することができる。また、原料として使用される穀類は、必要に応じて、蒸煮前又は蒸煮後に細切又は粉砕処理に供していてもよい。 Monascus can be produced by a conventional method using monascus and cereals. Specifically, monascus can be produced by inoculating monascus in steamed (cooked or steamed) cereals and statically culturing under aerobic conditions of about 20 to 40°C. In addition, grains used as raw materials may be subjected to chopping or pulverization before or after steaming, if necessary.
　本発明では、発酵後の紅麹をそのまま使用してもよく、また、発酵後の紅麹を、加熱、乾燥、破砕、粉砕、磨砕、抽出等の内１種以上の処理に供された紅麹の加工物を使用してもよい。 In the present invention, the fermented red yeast rice may be used as it is, or the fermented red yeast rice may be subjected to one or more treatments such as heating, drying, crushing, crushing, grinding, and extraction. Processed products of red yeast rice may also be used.
　紅麹の加工物としては、具体的には、乾燥紅麹、乾燥紅麹の粉末物、乾燥紅麹の細粒物、紅麹エキス末等の乾燥物；紅麹のペースト；紅麹エキス（濃縮エキスを含む）等が挙げられる。これらの紅麹の加工物の中でも、好ましくは乾燥物、より好ましくは乾燥紅麹の粉末物、乾燥紅麹の細粒物、更に好ましくは乾燥紅麹の粉末物が挙げられる。また、紅麹の加工物に含まれる紅麹菌及び酵素は、生菌又は活性を維持した状態であってもよく、また、加熱処理等により失活されていてもよい。 Examples of processed products of monascus include dried monascus, powder of dried monascus, fine granules of dried monascus, and dried monascus extract powder; paste of monascus; including concentrated extracts) and the like. Among these processed products of monascus, preferably dried products, more preferably dried monascus powder, dried monascus granules, and even more preferably dried monascus powder are mentioned. In addition, the monascus and enzymes contained in the processed product of monascus may be viable or in an active state, or may be inactivated by heat treatment or the like.
　紅麹の加工物は、商業的に入手したものを使用することができる。例えば、乾燥米紅麹の粉末物は、商品名「Ｖ．紅麹３Ｐ－Ｄ」、「Ｖ．紅麹３Ｐ－Ｄ２０」（いずれも小林バリューサポート株式会社製）として販売されており、本発明ではこれらの市販品を使用することができる。 Commercially obtained red yeast rice can be used. For example, powdered dried rice red yeast rice is sold under the trade names "V. Red yeast rice 3P-D" and "V. Red yeast rice 3P-D20" (both manufactured by Kobayashi Value Support Co., Ltd.). These commercially available products can be used.
［剤型・使用形態等］
　本発明のコレステロール低減剤は、有効成分である紅麹又はその加工物をそのまま、或は他の可食性成分と組み合わせて、所望の剤型にして提供される。本発明のコレステロール低減剤の剤型については、特に限定されず、固体状、半固体状、又は液体状のいずれであってもよい。 [Dosage form, form of use, etc.]
The cholesterol-lowering agent of the present invention is provided in a desired dosage form by combining the red yeast rice or its processed product as an active ingredient with other edible ingredients. The dosage form of the cholesterol-lowering agent of the present invention is not particularly limited, and may be solid, semi-solid, or liquid.
　本発明のコレステロール低減剤は、経口摂取又は経口投与される形態であることが好ましいが、経腸投与、注射投与、静脈投与、経肺投与、経粘膜投与等で使用される形態であってもよい。 The cholesterol-lowering agent of the present invention is preferably in the form of oral ingestion or oral administration. good.
　本発明のコレステロール低減剤の使用形態として、具体的には、飲食品、内服用医薬品（内服用の医薬部外品を含む）、飼料、ペットフード等が挙げられる。これらの中でも、好ましくは飲食品及び内服用医薬品、より好ましくは飲食品が挙げられる。 Specific examples of the forms of use of the cholesterol-lowering agent of the present invention include food and drink, drugs for internal use (including quasi-drugs for internal use), feeds, pet foods, and the like. Among these, foods and drinks and medicines for internal use are preferred, and foods and drinks are more preferred.
　本発明のコレステロール低減剤を飲食品に使用する場合（即ち、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの低減用の飲食品として提供する場合）、紅麹又はその加工物を、そのまま又は他の飲食品素材や添加成分と組み合わせて所望の形態に調製すればよい。このような飲食品としては、一般の飲食品の他、保健機能食品（特定保健用食品、栄養機能食品、サプリメント等を含む）、病者用食品等の食品等が挙げられる。これらの飲食品の形態として、特に限定されないが、具体的には、カプセル剤（ソフトカプセル剤、ハードカプセル剤）、錠剤、顆粒剤、粉剤、ゼリー剤等のサプリメント；茶飲料、栄養ドリンク、果汁飲料、炭酸飲料、乳酸飲料等の飲料；グミ、キャンディー、ゼリー等の嗜好品等が挙げられる。これらの飲食品の中でも、好ましくはサプリメント、より好ましくはカプセル剤、錠剤、顆粒剤、粉剤が挙げられる。 When the cholesterol-lowering agent of the present invention is used in a food or drink (that is, when provided as a food or drink for reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL), red yeast rice or a processed product thereof is used. , may be prepared into a desired form as it is or in combination with other food and drink materials and additives. Examples of such food and drink include general food and drink, food with health claims (including specified health food, food with nutrient function claims, supplements, etc.), food for sick people, and the like. The form of these foods and drinks is not particularly limited, but specifically supplements such as capsules (soft capsules, hard capsules), tablets, granules, powders, jellies; tea beverages, nutritional drinks, fruit juice beverages, Beverages such as carbonated beverages and lactic acid beverages; luxury goods such as gummies, candies, and jellies. Among these foods and drinks, supplements are preferred, and capsules, tablets, granules and powders are more preferred.
　本発明のコレステロール低減剤を内服用医薬品（内服用の医薬部外品を含む）に使用する場合、紅麹又はその加工物を、そのまま又は他の添加剤等と組み合わせて所望の形態に調製すればよい。このような内服用医薬品としては、具体的には、錠剤、丸剤、散剤、細粒剤、顆粒剤、カプセル剤（ハードカプセル及びソフトカプセルを含む）、トローチ剤、チュアブル剤、ドリンク剤、エキス剤（軟エキス剤、乾燥エキス剤等を含む）、ゼリー剤、シロップ剤、酒精剤、エリキシル剤、リポソーム製剤等が挙げられる。 When the cholesterol-lowering agent of the present invention is used in pharmaceuticals for internal use (including quasi-drugs for internal use), red yeast rice or a processed product thereof may be prepared into a desired form as it is or in combination with other additives. Just do it. Specific examples of such internal medicines include tablets, pills, powders, fine granules, granules, capsules (including hard capsules and soft capsules), troches, chewables, drinks, extracts ( soft extracts, dry extracts, etc.), jellies, syrups, spirits, elixirs, liposome preparations and the like.
　本発明のコレステロール低減剤を飼料又はペットフードに使用する場合、紅麹又はその加工物を、そのまま又は他の素材や添加剤等と組み合わせて所望の形態に調製すればよい。飼料としては、具体的には、牛、豚、羊等の家畜；ニワトリ、ウズラ、ダチョウ等の家禽等に給餌される飼料が挙げられる。また、ペットフードとしては、具体的には、イヌ、ネコ、ウサギ、ハムスター等に給餌されるペットフードが挙げられる。 When the cholesterol-lowering agent of the present invention is used in feed or pet food, red yeast rice or its processed product may be prepared into a desired form as it is or in combination with other materials, additives, and the like. Specific examples of the feed include livestock such as cattle, pigs and sheep; and poultry such as chickens, quails and ostriches. Further, pet foods specifically include pet foods fed to dogs, cats, rabbits, hamsters, and the like.
　本発明のコレステロール低減剤において、紅麹又はその加工物の含有量は、対象者の体格、年齢、症状、コレステロール低減剤の形態等を勘案して、１日当たりの紅麹又はその加工物の摂取・投与量を踏まえて適宜設定すればよいが、例えば１～１００重量％が挙げられる。 In the cholesterol-lowering agent of the present invention, the content of red yeast rice or its processed product is determined by taking into consideration the physique, age, symptoms of the subject, the form of the cholesterol-lowering agent, etc. - It may be set as appropriate based on the dosage, but may be, for example, 1 to 100% by weight.
［用途・用量］
　本発明のコレステロール低減剤は、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの血中濃度の低減用途に使用される。 [Usage/dosage]
The cholesterol-lowering agent of the present invention is used for reducing blood levels of cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
　本発明のコレステロール低減剤の低減対象となるコレステロールは、比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるものであればよいが、好ましくは比重が０．０１～１．０１９ｇ／ｍＬのリポ蛋白に含まれるコレステロール、より好ましくは比重が０．１～１．０１９ｇ／ｍＬのリポ蛋白に含まれるコレステロール、更に好ましくは比重が０．５～１．０１９ｇ／ｍＬのリポ蛋白に含まれるコレステロール、特に好ましくは比重が０．９～１．０１９ｇ／ｍＬのリポ蛋白に含まれるコレステロールが挙げられる。 Cholesterol to be reduced by the cholesterol-lowering agent of the present invention may be contained in lipoproteins having a specific gravity of less than 1.019 g/mL. cholesterol contained in proteins, more preferably cholesterol contained in lipoproteins with a specific gravity of 0.1 to 1.019 g/mL, more preferably cholesterol contained in lipoproteins with a specific gravity of 0.5 to 1.019 g/mL, Cholesterol contained in lipoproteins having a specific gravity of 0.9 to 1.019 g/mL is particularly preferred.
　具体的には、本発明のコレステロール低減剤は、ＲＬＰコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロールの少なくとも１種の低減用途に使用できる。本発明のコレステロール低減剤として、好ましくは、ＲＬＰコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロールの少なくとも２種の低減用途に使用でき、更に好ましくはＲＬＰコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロール全ての低減用途に使用できる。 Specifically, the cholesterol-lowering agent of the present invention can be used for reducing at least one of RLP cholesterol, CM cholesterol and VLDL cholesterol. The cholesterol-lowering agent of the present invention can preferably be used for reducing at least two types of RLP cholesterol, CM cholesterol and VLDL cholesterol, and more preferably for reducing all of RLP cholesterol, CM cholesterol and VLDL cholesterol.
　本発明のコレステロール低減剤をＲＬＰコレステロールの低減用途に使用する場合、カイロミクロンレムナントコレステロール及びＶＬＤＬレムナントコレステロールのいずれの低減用途で使用してもよいが、好ましくはＶＬＤＬレムナントコレステロールの低減用途が挙げられる。 When the cholesterol-lowering agent of the present invention is used for reducing RLP cholesterol, it may be used for reducing both chylomicron remnant cholesterol and VLDL remnant cholesterol, preferably for reducing VLDL remnant cholesterol.
　また、血中ＲＬＰコレステロールの増加は、高レムナント血症（血中ＲＬＰコレステロールが２．５ｍｇ／ｄｌを超える症状）の要因となっており、本発明のコレステロール低減剤は、血中ＲＬＰコレステロールの低減作用を示すので、高レムナント血症の予防又は治療の目的で使用することができる。 In addition, an increase in blood RLP cholesterol is a factor in hyperremnantemia (a condition in which blood RLP cholesterol exceeds 2.5 mg/dl), and the cholesterol-lowering agent of the present invention reduces blood RLP cholesterol. Since it shows action, it can be used for the purpose of prevention or treatment of hyperremnantemia.
　血中ＣＭコレステロールの増加は、ＷＨＯ分類のＩ型脂質異常症の一因になっており、本発明のコレステロール低減剤は、血中ＣＭコレステロールの低減作用を示すので、ＷＨＯ分類のＩ型脂質異常症の予防又は治療の目的で使用することができる。 An increase in blood CM cholesterol is one of the causes of WHO classification type I dyslipidemia. It can be used for the purpose of prevention or treatment of disease.
　血中ＶＬＤＬコレステロールの増加は、ＷＨＯ分類のＩＶ型脂質異常症（内因性高トリグリセライド血症）の一因になっており、本発明のコレステロール低減剤は、血中ＶＬＤＬコレステロールの低減作用を示すので、ＷＨＯ分類のＩＶ型脂質異常症の予防又は治療の目的で使用することができる。 An increase in blood VLDL cholesterol is one of the causes of WHO classification IV dyslipidemia (endogenous hypertriglyceridemia), and the cholesterol-lowering agent of the present invention exhibits a blood VLDL cholesterol-lowering effect. , can be used for the prevention or treatment of WHO classification IV dyslipidemia.
　また、血中ＶＬＤＬコレステロール及びＣＭコレステロールの増加は、ＷＨＯ分類のＶ型脂質異常症（混合型脂質異常症）の一因になっており、本発明のコレステロール低減剤は、血中ＶＬＤＬコレステロール及びＣＭコレステロールの双方に対して低減作用を示すので、ＷＨＯ分類のＩＶ型脂質異常症の予防又は治療の目的で使用することができる。 An increase in blood VLDL cholesterol and CM cholesterol is one of the causes of WHO classification V type dyslipidemia (mixed dyslipidemia). Since it exhibits both cholesterol-lowering effects, it can be used for the prevention or treatment of WHO classification IV dyslipidemia.
　本発明のコレステロール低減剤において、１日当たりの紅麹又はその加工物の摂取・投与量としては、対象者の体格、年齢、症状、コレステロール低減剤の使用目的等に応じて設定すればよいが、例えば、紅麹の乾燥重量換算で１００～６０，０００ｍｇ程度、好ましくは２００～３０，０００ｍｇ程度となるように設定すればよい。ここで、「紅麹の乾燥重量換算」とは、未加工の紅麹を使用する場合であればその乾燥重量であり、紅麹エキス及び紅麹エキス末以外の加工物を使用する場合であれば当該加工物に含まれる紅麹の乾燥重量であり、紅麹エキス又は紅麹エキス末を使用する場合であれば、紅麹エキス又は紅麹エキス末の抽出原料として使用された紅麹の乾燥重量である。 In the cholesterol-lowering agent of the present invention, the intake/dosage of red yeast rice or its processed product per day may be set according to the subject's physique, age, symptoms, purpose of use of the cholesterol-lowering agent, etc. For example, the dry weight of monascus may be set to about 100 to 60,000 mg, preferably about 200 to 30,000 mg. Here, "converted to the dry weight of red yeast rice" is the dry weight when unprocessed red yeast rice is used. is the dry weight of red yeast rice contained in the processed product, and in the case of using red yeast rice extract or red yeast rice extract powder, the drying of red yeast rice used as a raw material for extracting red yeast rice extract or red yeast rice extract powder Weight.
　また、本発明のコレステロール低減剤は、１日当たりの摂取・投与量を１日当たり１回、又は１日当たり複数回に分けて摂取又は投与すればよいが、１日当たり１回又は２乃至３回に分けて摂取又は投与することが好ましい。 In addition, the cholesterol-lowering agent of the present invention may be ingested or administered once a day, or divided into multiple times per day, and divided into once or 2 to 3 times per day. preferably ingested or administered.
　以下に実施例を示して本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 The present invention will be more specifically described below by showing Examples, but the present invention is not limited to these.
試験例
１．試験材料・試験方法
１－１．紅麹の加工物
　紅麹の加工物として、乾燥米紅麹の粉末物（商品名「３Ｐ－Ｄ２０」、小林バリューサポート株式会社製）を使用した。当該乾燥米紅麹の粉末物は、モナスカス・ピローサスで白米を発酵させた紅麹の乾燥粉末物であり、加熱処理により紅麹菌及び酵素は失活した状態になっている。 Test example
1. Test materials and test methods
1-1. Processed product of red yeast rice As a processed product of red yeast rice, dried rice red yeast powder (trade name “3P-D20”, manufactured by Kobayashi Value Support Co., Ltd.) was used. The dried red yeast rice powder is a dried red yeast powder obtained by fermenting white rice with Monascus pyrosus, and the heat treatment deactivates the red yeast mold and enzymes.
１－２．血中ＲＬＰコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロールの低減作用の評価試験
　日本白色ウサギ（２ヶ月齢）を１週間普通食で予備飼育し、その後、コントロール群（ｎ＝８）と紅麹群（ｎ＝８）の２群に分けた。コントロール群では、１２週間にわたり、普通食に高脂肪高コレステロール負荷（０．２５重量％コレステロール負荷）したペレット（オリエンタル酵母工業株式会社）を１羽当たり毎日１００ｇ摂取させた。紅麹群では、普通食に高脂肪高コレステロール負荷（０．２５重量％コレステロール負荷）すると共に前記紅麹の加工物（５００ｍｐｋ：１日当たりの摂取量が紅麹の加工物５００ｍｇ／ｋｇ－ウサギ体重となる量）を添加したペレット（オリエンタル酵母工業株式会社）を１羽当たり毎日１００ｇ摂取させた。なお、各ウサギはケージに１匹ずつ個飼いし、水は自由摂取させた。 1-2. Evaluation test for the effect of reducing blood RLP cholesterol, CM cholesterol and VLDL cholesterol Japanese white rabbits (2 months old) were preliminarily bred on a normal diet for 1 week, then a control group (n = 8) and a red yeast rice group (n = 1). 8) were divided into two groups. In the control group, 100 g of pellets (Oriental Yeast Co., Ltd.) loaded with high fat and high cholesterol (loaded with 0.25% by weight of cholesterol) were fed daily to normal diet for 12 weeks. In the red yeast rice group, the normal diet was loaded with high fat and high cholesterol (0.25 wt% cholesterol loading), and the processed red yeast rice (500 mpk: the daily intake of the processed red yeast rice was 500 mg/kg-rabbit body weight). 100 g of pellets (Oriental Yeast Co., Ltd.) added with the above amount) were fed per bird every day. Each rabbit was housed individually in a cage and given water ad libitum.
　前記各ペレットの摂取開始時、摂取開始から４週間後、８週間後、及び１２週間後に、各群のウサギを１２時間絶食させた後に、ウサギの耳介辺縁静脈から採血し、遠心分離により血漿を得た。得られた血漿に対して、LipoSEARCH（登録商標）（株式会社スカイライト・バイオテック）を使用して、リポ蛋白脂質プロファイル解析を行い、血漿中のＲＬＰコレステロールの一種であるＶＬＤＬレムナントコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロール濃度を測定した。リポ蛋白脂質プロファイル解析の手法は、文献［Toshima G,et al J.Biol.Macromol.2013,13(2):21-32 LipoSEARCH; Analytical GP-HPLC method for lipoprotein profiling and its applications; http://www.jsb.gr.jp/jbm/2013/1302_1.pdf］に記載の方法に準じて行った。 At the start of ingestion of each pellet, 4 weeks, 8 weeks, and 12 weeks after the start of ingestion, the rabbits in each group were fasted for 12 hours, blood was collected from the marginal auricular vein of the rabbit, and centrifuged. Plasma was obtained. Lipoprotein lipid profile analysis was performed on the obtained plasma using LipoSEARCH (registered trademark) (Skylight Biotech Co., Ltd.), and VLDL remnant cholesterol and CM cholesterol, which are a type of RLP cholesterol in plasma, were analyzed. and VLDL cholesterol concentrations were measured. The method of lipoprotein lipid profile analysis is described in the literature [Toshima G, et al J.Biol.Macromol.2013,13(2):21-32 LipoSEARCH; Analytical GP-HPLC method for lipoprotein profiling and its applications; www.jsb.gr.jp/jbm/2013/1302_1.pdf ].
２．試験結果
　結果を図１～３に示す。高脂肪高コレステロール負荷したペレットを摂取させたコントロール群では、血漿中のＶＬＤＬレムナントコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロール濃度が増加していた。これに対して、高脂肪高コレステロール負荷すると共に紅麹の加工物を含有させたペレットを摂取させた紅麹群では、血漿中のＶＬＤＬレムナントコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロール濃度を十分に低減できていた。以上の結果から、紅麹及びその加工物には、血中のＶＬＤＬレムナントコレステロール、ＣＭコレステロール及びＶＬＤＬコレステロールの濃度を低減させる作用があることが明らかとなった。 2. The test results are shown in Figures 1-3. In the control group fed with the high-fat, high-cholesterol loaded pellets, plasma VLDL remnant cholesterol, CM cholesterol and VLDL cholesterol levels increased. On the other hand, in the red yeast rice group, which was loaded with high-fat, high-cholesterol foods and ingested pellets containing processed red yeast rice, VLDL remnant cholesterol, CM cholesterol, and VLDL cholesterol levels in plasma could be sufficiently reduced. rice field. From the above results, it was revealed that red yeast rice and its processed products have the effect of reducing the concentration of VLDL remnant cholesterol, CM cholesterol and VLDL cholesterol in the blood.

Claims (5)

  1. 　紅麹又はその加工物を含有し、
    　比重が１．０１９ｇ／ｍＬ未満のリポ蛋白に含まれるコレステロールの低減に使用される、コレステロール低減剤。     Containing red yeast rice or its processed product,
    A cholesterol-lowering agent for use in reducing cholesterol contained in lipoproteins having a specific gravity of less than 1.019 g/mL.
  2. 　低減対象となるコレステロールが、レムナント様リポ蛋白コレステロール、カイロミクロンコレステロール及び超低比重リポ蛋白コレステロールよりなる群から選択される少なくとも１種である、請求項１に記載のコレステロール低減剤。 The cholesterol-lowering agent according to claim 1, wherein the cholesterol to be reduced is at least one selected from the group consisting of remnant-like lipoprotein cholesterol, chylomicron cholesterol and ultra-low density lipoprotein cholesterol.
  3. 　前記紅麹又はその加工物が、モナスカス・ピローサスを用いて製造された紅麹又はその加工物である、請求項１又は２に記載のコレステロール低減剤。 The cholesterol-lowering agent according to claim 1 or 2, wherein the red yeast rice or a processed product thereof is a red yeast rice produced using Monascus pyrosus or a processed product thereof.
  4. 　高レムナント血症、或はＷＨＯ分類のＩ型、ＩＶ型、又はＶ型の脂質異常症の予防又は治療に使用される、請求項１～３に記載のコレステロール低減剤。 The cholesterol-lowering agent according to claims 1 to 3, which is used for the prevention or treatment of hyperremnantemia or WHO classification type I, IV, or V dyslipidemia.
  5. 　飲食品、内服用医薬品、飼料、又はペットフードとして使用される、請求項１～４のいずれかに記載のコレステロール低減剤。 The cholesterol-lowering agent according to any one of claims 1 to 4, which is used as a food or drink, an internal medicine, a feed, or a pet food.
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