WO2019107531A1 - Composition for suppressing increase in or reducing blood lipids - Google Patents

Composition for suppressing increase in or reducing blood lipids Download PDF

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Publication number
WO2019107531A1
WO2019107531A1 PCT/JP2018/044130 JP2018044130W WO2019107531A1 WO 2019107531 A1 WO2019107531 A1 WO 2019107531A1 JP 2018044130 W JP2018044130 W JP 2018044130W WO 2019107531 A1 WO2019107531 A1 WO 2019107531A1
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composition
adonixanthin
adonirubin
present
suppressing
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PCT/JP2018/044130
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French (fr)
Japanese (ja)
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季之 高橋
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Ｊｘｔｇエネルギー株式会社
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Priority to JP2019557343A priority Critical patent/JPWO2019107531A1/en
Publication of WO2019107531A1 publication Critical patent/WO2019107531A1/en

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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 a composition for suppressing or reducing blood lipid elevation, and more particularly, to a composition for suppressing or reducing blood lipid elevation comprising one or more carotenoids selected from adonirubin and adonixanthin. .
  • Adonirubin and adonixanthin are a type of carotenoid and are widely distributed in animals, plants and microorganisms. It is known that adonirubin or adonixanthin has an anxiolytic effect (Patent Document 1).
  • Patent Document 2 states that astaxanthin may be useful for hyperlipidemia.
  • Patent Document 3 describes that carotenoids such as lycopene can be useful for delivering cargo molecules such as whey protein to the blood stream. It is described that depending on the nature of the cargo molecule, the disease may be ameliorated or reduced, and it may be useful for lowering cholesterol when whey protein is used as the cargo molecule.
  • the present invention aims to provide a new technical means for effectively suppressing or reducing blood lipid elevation.
  • the present inventors have now found that when adonirubin or adonixanthin is administered to a living being, the rise in blood lipids can be effectively suppressed or reduced.
  • the present invention includes the following inventions.
  • a composition for suppressing or reducing blood lipid elevation comprising one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts.
  • the composition according to any one of (1) to (7), wherein the composition is a food or drink or a food additive.
  • the composition of the present invention by taking the composition of the present invention, it is possible to effectively suppress the increase in blood lipids in the subject or to reduce the blood lipids.
  • the composition of the present invention is advantageous in suppressing or reducing the increase in at least one blood lipid selected from the group consisting of triglyceride, total cholesterol, and LDL cholesterol.
  • the composition of the present invention can be advantageously used in the improvement of dyslipidemia, the suppression or reduction of visceral fat accumulation, the improvement of obesity, or the suppression of weight gain.
  • composition for suppressing or reducing blood lipid elevation is characterized by comprising one or more carotenoids selected from adonirubin and adonixanthin.
  • Carotenoids in the present invention are one or more selected from adonirubin, adonixanthin, and pharmaceutically acceptable salts thereof, and, for example, a combination of adonirubin, adonixanthin and two carotenoids It can be mentioned.
  • a carotenoid a free form or fatty acid ester form may be sufficient, and a free form can be used from an absorbable viewpoint.
  • Carotenoids may be stereoisomers such as optical isomers and cis-trans isomers. Furthermore, these carotenoids are preferably used as an active ingredient.
  • the chemical formula of adonirubin is 3-hydroxy- ⁇ , ⁇ -carotene-4,4′-dione (C 40 H 52 O 3 , molecular weight 580.853), and the structural formula is represented by the following formula.
  • the cis-trans isomer of adonirubin may be cis, trans or a combination thereof, and the cis may include 13-cis.
  • adonixanthin is 3,3'-dihydroxy- ⁇ , ⁇ - carotene-4-one (C 40 H 54 0 3, molecular weight 582.869) and the structural formula is represented by the following formula.
  • optical isomers of adonixanthin 3S, 3'R-adonixanthin, 3S, 3'S-adonixanthin, 3R, 3'S-adonixanthin and 3R, 3'R-adonixanthin and Mention may be made of at least one selected from the group consisting of these pharmaceutically acceptable salts, preferably 3S, 3'R-adonixanthin.
  • the cis-trans isomer of adonixanthin may be cis, trans or a combination thereof.
  • a cis-trans isomer of adonixanthin preferred is a combination of cis- and trans-isomers.
  • the carotenoid may be in the form of a pharmaceutically acceptable salt, and these salts are also included in the carotenoid in the present invention.
  • a carotenoid may form a salt with an acid or a base.
  • the pharmaceutically acceptable salt is not particularly limited as long as it forms a pharmaceutically acceptable salt with adonirubin and / or adonixanthin.
  • hydrohalide eg, hydrogen fluoride, hydrochloride, hydrobromide, hydroiodide, etc.
  • inorganic acid salt eg, sulfate, nitrate, perchloric acid
  • phosphates carbonates, bicarbonates, etc.
  • organic carboxylates eg acetate, oxalate, maleate, tartrate, fumarate, citrate etc.
  • organic sulfonates eg For example, methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, camphor sulfonate, etc.
  • amino acid salt eg, aspartate, glutamate etc.
  • quaternary amine examples thereof include, but are not limited to, salts, alkali metal salts (for example, sodium salt, potassium salt and the like), alkaline earth
  • the carotenoid of the present invention may be a commercial product, or a chemically synthesized product produced by a conventional chemical synthesis method, a fermentation method by a microorganism, or an extract and purification method from animals or plants etc.
  • (Naturally derived) also referred to as microbial, animal or plant derived
  • the microorganism, animal or plant-derived substance is a product obtained from a microorganism, animal or plant, preferably, it may be a Paracoccus microorganism-derived substance, more preferably Paracoccus carotinifaciens-derived substance. .
  • the following methods may be mentioned as methods for extracting and purifying adonirubin and adonixanthin from microorganisms.
  • the dried cells of Paracoccus carotinifaciens are subjected to room temperature extraction using acetone, the extract is concentrated by an evaporator, and the concentrate is separated into two layers, and the concentrate is hexane-chloroform (1 1) Add the mixed solution, mix well, and then separate to obtain an organic solvent layer. The organic solvent layer is concentrated to dryness with an evaporator. The concentrated dried product is dissolved in chloroform, and each carotenoid is separated on a silica gel column.
  • the fraction eluted with 300 mL of acetone: hexane (3: 7) is further purified by HPLC (Shim-pack PRC-SIL (Shimadzu Corp.), acetone: hexane (3: 7)) to further purify the adduct of adonirubin. You can get it.
  • the adonixanthin educt can be obtained by further purifying the fraction eluted with acetone by HPLC (Shim-pack PRC-SIL, acetone: hexane (4: 6)).
  • a carotenoid mixture containing astaxanthin in addition to adonirubin and adonixanthin as the carotenoid of the present invention may be used.
  • a carotenoid mixture extracted from the dried cells of Paracoccus carotinifaciens according to the methods described in JP-A-2007-261972 and JP-A-2009-50237 contains astaxanthin, adonirubin and adonixanthin. .
  • the content of the carotenoid in the composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and for example, 0.01 to 50% by mass can be mentioned with respect to the whole composition. It is 30% by mass, more preferably 0.07 to 15% by mass, and still more preferably 0.1 to 10% by mass.
  • the measurement of the content of adonirubin and / or adonixanthin in the composition of the present invention is carried out by HPLC according to the description of Toxicol Rep. 2014 Aug 25; 1: 582-588.
  • composition of the present invention can be provided as a composition optionally containing an orally acceptable or pharmaceutically acceptable additive together with the above-mentioned carotenoid.
  • additives solvents, solubilizers, solubilizers, lubricants, emulsifiers, tonicity agents, stabilizers, preservatives, preservatives, surfactants, regulators, chelating agents, pH adjusters, buffers Agents, excipients, thickeners, colorants, fragrances, perfumes and the like.
  • composition of the present invention can be prepared by known methods such as mixing, dissolving, dispersing, suspending, etc. the above-mentioned carotenoid and optionally orally acceptable or pharmaceutically acceptable additive. Moreover, in the preparation of the composition of the present invention, the mixture, the lysate, the dispersion, the suspension, etc. prepared by the above-mentioned method are subjected to homogenization treatment or sterilization treatment, as long as the effects of the present invention are not impaired. It is also good.
  • composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be solid, semi-solid (including paste, gel) or liquid (including oil, slurry). Although it may be, it is preferable that it is solid or liquid.
  • the dosage form of the composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and injections, tablets (eg, plain tablets, sugar-coated tablets, film-coated tablets, enteric tablets, sustained-release tablets, oral cavity Internally disintegrating tablets, sublingual tablets, chewable tablets, etc., capsules (eg hard capsules, soft capsules), elixirs, pills, powders, powders, granules, solutions, troches, syrups, dry syrups, Emulsion, suspension, solution, inhalant, aerosol, powder inhalant, suppository, ointment, cream, gel, patch, bop, lotion, drip, eye ointment, eye drop, nose Agents and the like.
  • tablets eg, plain tablets, sugar-coated tablets, film-coated tablets, enteric tablets, sustained-release tablets, oral cavity Internally disintegrating tablets, sublingual tablets, chewable tablets, etc., capsules (eg hard capsules, soft capsules), elixir
  • the dosage form of the composition of the present invention can be taken orally as the concentration of blood lipids is suppressed or reduced when the composition of the present invention is taken orally. It is preferably a dosage form for administration, and includes tablets, capsules, pills, powders, powders, granules, syrups, dry syrups, emulsions, solutions, suspensions, solutions, troches, etc. .
  • the method of administration or intake of the composition of the present invention is not particularly limited, but injections such as infusion, intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, oral, transmucosal, transdermal, intranasal, oral cavity Administration or intake by inwards etc. may be mentioned.
  • oral intake or administration is preferred because the composition of the present invention suppresses or reduces the increase in blood lipid concentration when taken orally.
  • composition of the present invention includes food and drink such as food and drink, food and drink additives, feed, medicine, quasi drug and cosmetics, and food and drink are preferable from the viewpoint of convenience of intake.
  • the food and drink of the present invention are prepared by preparing the composition of the present invention directly as a food and drink, various proteins, saccharides, fats, trace elements, vitamins, other active ingredients (eg, lactic acid bacteria, Bacillus bacteria (Bacillus), etc. Or a mixture of bacteria, yeasts and other fungi, dietary fiber, DHA or EPA), etc., and the composition of the present invention in liquid, semi-liquid or solid state such as aqueous solution, etc.
  • the composition of the present invention may be added to general food and drink.
  • instant foods such as instant noodles, retort foods, canned foods, microwave foods, instant soups and miso soups, freeze-dried foods, etc .
  • soft drinks, fruit juices, vegetable drinks, soy milk Beverages such as beverages, coffee beverages, tea beverages, powdered beverages, concentrated beverages, alcoholic beverages, etc .
  • Nutritional drinks Food products such as pasta, noodles, cake mix, bread crumbs; Strawberries, gummi, jelly, caramel, chewing gum, chocolate , Cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, dessert sweets, etc .; Nutritional bar; Sauce, processed tomato seasoning, flavored seasoning, cooking mix, sauces, dressings, soy sauce, curry, Seasoning ingredients such as stews; Processed fats and oils, butter, margarine, mayonnaise, etc .; Milk beverages, yogs Foods such as milk, lactic acid bacteria beverages, ice creams and creams; agricultural products such as canned agricultural products, jams and
  • the food and drink of the present invention include health food, supplement, functional food (for example, food for specified health use, nutritional function food or functional display food), nutritional supplement, special purpose food (for example, food for sick people) Also included are infant formula, maternal, lactating mother's milk or food for infants with dyspnea or dyspnea) or infant liquid formula (also referred to as infant liquid milk).
  • the composition of the present invention has a blood lipid reduction or elevation suppressive action, an improvement effect of dyslipidemia, an accumulation suppression or reduction action of visceral fat, an obesity improvement action, or a weight gain suppression action.
  • the present invention provides a food or drink for reducing or suppressing elevation of blood lipid, a food or drink for improvement of dyslipidemia or obesity, or suppression of body weight gain.
  • the food and drink of the present invention are food and drink for humans who are concerned about blood lipids, food and drinks for humans who are concerned about blood cholesterol or triglycerides (neutral fats), and who care about obesity or weight.
  • a food and drink for humans and a food and drink for humans who are concerned about visceral fat are concerned about visceral fat.
  • food and drink products such as functional foods, "If blood fat is high,” “If weight is anxious,” “If obesity is anxious,” “Ease fat consumption” , And may be provided with an indication such as “for those who are concerned about visceral fat”.
  • the intake or dose of the composition of the present invention is not particularly limited, and formulation of the composition, type of carotenoid, purity, type of subject, age or weight of subject, symptoms, intake or administration time, form of composition Depending on the method of intake or administration, other carotenoids or drug combinations, etc.
  • the composition of the present invention is preferably constituted in the form of a daily intake unit so as to be an effective amount for reducing or suppressing the rise of blood lipids.
  • compositions of the present invention when orally ingesting the composition of the present invention, 0.01 to 10000 mg of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts per day per adult weighing 60 kg
  • the carotenoids can be formulated into compositions such that intakes or doses preferably range from 0.1 to 1000 mg, more preferably 1 to 100 mg.
  • Other carotenoids or drugs used in combination with the carotenoids of the present invention can also be appropriately determined based on the clinically used intake or dose, respectively.
  • the daily intake or dose of the composition of the present invention is appropriately selected according to the formulation of the composition, etc., similarly to the intake or dose of the above-mentioned composition.
  • the daily intake or dose of the composition of the present invention may be taken or administered to the subject, for example, once or several times, but is preferably taken or administered to the subject at one time .
  • the number of daily intakes or administrations of the composition of the present invention is 1 to 5 times a day, preferably 1 to 3 times a day, more preferably once a day is there.
  • the subject to which the composition of the present invention is applied is preferably a mammal, more preferably a human.
  • the subject may be a healthy person or a patient.
  • the composition of the present invention it is possible to exert an excellent blood lipid lowering action or a blood lipid elevation inhibiting action.
  • reducing blood lipid which is at least one selected from the group consisting of triglyceride, total cholesterol, LDL cholesterol, or suppressing elevation of the blood lipid.
  • the composition of the present invention is provided as a composition for suppressing or reducing blood lipid elevation.
  • at least one selected from the group consisting of triglyceride, total cholesterol and LDL cholesterol is preferable.
  • the composition of the present invention is provided as a composition for improving dyslipidemia, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain.
  • the dyslipidemia is preferably at least one selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and hyper-LDL cholesterolemia.
  • "improvement” not only includes the meaning of "treatment” that is improvement of an established pathological condition, but also “prevents” prevention of occurrence of diseases by preparing in advance for possible deterioration. Also includes the meaning.
  • Adonixanthin or adonirubin may act on adipocytes to further increase adiponectin secretion.
  • Adiponectin is a secreted protein secreted from fat cells, and it is known that an increase in adiponectin correlates with a decrease in visceral fat mass.
  • Adonixanthin or adonirubin may have an effect of bringing TNF- ⁇ secretion from fat cells close to normal. It is known that normalizing TNF- ⁇ inhibits the uptake of glucose into cells.
  • a subject comprising administering or ingesting a composition comprising an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and pharmaceutically acceptable salts thereof
  • a method of reducing blood lipids in a subject or suppressing elevation of blood lipids comprising the method of
  • a method of reducing blood lipids in a subject or suppressing elevation of blood lipids which comprises ingesting.
  • the "effective amount" is set similarly to the content etc.
  • the blood lipid is preferably at least one selected from the group consisting of triglyceride, total cholesterol, and LDL cholesterol.
  • administering or ingesting a composition comprising an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts
  • a method of improving dyslipidemia in a subject, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain comprising:
  • a method for improving dyslipidemia in a subject, reducing or reducing visceral fat accumulation, improving obesity, or suppressing weight gain which comprises ingesting.
  • the above-mentioned dyslipidemia is preferably at least one selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and hyper-LDL cholesterolemia.
  • a method for reducing blood lipids in a subject or suppressing elevation of blood lipids as described above, a method for improving dyslipidemia in a subject, and a method for inhibiting accumulation or reduction of visceral fat in a subject is a non-therapeutic method excluding medical practice for humans when the subject is healthy.
  • the medical practice for a human means an act of taking (administering) a pharmaceutical product to a human in need of prescription by a doctor or the like.
  • the method for suppressing body weight gain can be practiced according to the contents described herein for the composition of the present invention.
  • adonirubin selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts for suppressing or reducing blood lipid elevation.
  • adonirubin, adonixanthin and their pharmaceutically acceptable for improving dyslipidemia, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain is provided.
  • one or more carotenoids selected from adonirubin, adonixanthin and pharmaceutically acceptable salts thereof in the manufacture of a composition for suppressing or reducing blood lipid elevation is provided.
  • adonirubin, adonixanthin and their pharmaceuticals in the manufacture of a composition for ameliorating dyslipidemia, inhibiting or reducing visceral fat accumulation, ameliorating obesity or inhibiting weight gain Use of one or more carotenoids selected from highly acceptable salts is provided.
  • adonirubin, adonixanthin and their pharmaceutically acceptable for improving dyslipidemia, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain are provided.
  • Preparation Example 1 Preparation of adonixanthin and adonirubin According to the method described in JP-A-2012-158569, an adonirubin free body and an adonixanthin free body were prepared. Briefly described below. Dry cells of Paracoccus carotinifaciens were subjected to room temperature extraction using acetone. The obtained extract is concentrated by an evaporator, and when the concentrate is separated into two layers, a mixed solution of hexane-chloroform (1: 1) is added to the concentrate and mixed well, and then an organic solvent layer is obtained by liquid separation operation. The obtained organic solvent layer was concentrated to dryness with an evaporator.
  • the concentrated dried product was dissolved in chloroform, and each carotenoid was separated by a silica gel column. Specifically, the fraction eluted with 300 mL of acetone: hexane (3: 7) is further purified by HPLC (Shim-pack PRC-SIL (Shimadzu Corporation), acetone: hexane (3: 7)), and adonirubin A free form (hereinafter, also simply referred to as adonirubin) was obtained.
  • adonixanthin free form (hereinafter, also simply referred to as adonixanthin).
  • Preparation Example 2 Preparation of adonixanthin-containing composition (administration solution) and adonirubin-containing composition (administration solution) A corn oil is added to the adonixanthin or adonirubin obtained in Preparation Example 1 and suspended, and each 1.2 mg The adonixanthin-containing administration solution and the adonirubin-containing administration solution were prepared so as to have a concentration of / mL. Corn oil was used as a control.
  • Preparation example 3 Preparation of high fat feed
  • powder feed MF, Oriental Yeast Co., Ltd.
  • the feed mixed with was used.
  • the high-fat feed can be obtained by weighing the required amounts of powdered feed, cholesterol and cholic acid, adding the required amount of lard little by little and further mixing while sufficiently stirring with a Kenmix mixer (Aiko Co., Ltd.) It was done.
  • Test Example 1 Animal test using adonixanthin-containing composition (administration solution) for high-fat diet-loaded KK-A y mice (weight measurement) As experimental animals, 6-week-old male SPF mice (KK-A y / TaJcl strain) were used. Based on the body weight measured at the end of acclimatization, 20 animals (weight range: 27.3-32.2 g) are selected, and the mean weight of each experimental group will be equal by complete random sampling using a computer Ten animals were assigned to two groups. The administration solution obtained in Preparation Example 2 was administered to each experimental group. The test substance in each experimental group, the concentration thereof, and the dose per day (once) are shown in Table 1.
  • the administration was performed once a day for 28 days (when the administration start date of the test substance was calculated from the first day) using a disposable syringe and an oral sound. During the administration period, the mice were allowed to freely consume the high-fat diet and tap water obtained in Preparation Example 3, and were reared at 20 to 26 ° C. with a 12-hour light-dark cycle. Body weight was measured twice weekly during the dosing period.
  • the measurement results of body weight are shown in FIG.
  • the measured values were expressed as mean values.
  • the adonixanthin administration group showed a tendency to suppress weight gain as compared to the control group.
  • Test Example 2 Animal test for high-fat diet-loaded KK-A y mice using adonixanthin-containing composition (administration solution) and adonirubin-containing composition (administration solution) (measurement of blood lipid and visceral fat) As experimental animals, 6-week-old male SPF mice (KK-A y / TaJcl strain) were used. 30 animals (weight range: 27.3-32.2 g) were selected based on the weight measured on the end of acclimatization, so that the mean weight of each experimental group would be equal by complete random sampling using a computer Ten animals were assigned to three groups. The administration solution obtained in Preparation Example 2 was administered to each experimental group. The test substance in each experimental group, the concentration thereof, and the dose per day (once) are shown in Table 2.
  • mice were allowed to freely consume the high-fat diet and tap water obtained in Preparation Example 3, and were reared at 20 to 26 ° C. with a 12-hour light-dark cycle.
  • the measurement results are shown in FIGS.
  • the measured values were expressed as mean ⁇ standard error.
  • an assay between two groups was performed in the adonixanthin administration group or the adonirubin administration group relative to the control group.
  • the test between the two groups used the Student t test when the variance showed uniformity, and the Aspin-Welch t test when the variance did not show uniformity.
  • the significance level was displayed at 5% or 1%.
  • Data analysis For Office 2003 and Office 2004 (Microsoft Corporation), SAS ver. 8.02 (SAS Institute Japan Co., Ltd.) and EXSAS ver. 7.14 (Scientist Corporation) were used.
  • FIG. 2 shows the results of measurement of triglyceride concentration in plasma.
  • the triglyceride concentration in the plasma was significantly reduced as compared to the control group.
  • the triglyceride concentration in plasma was reduced as compared with the control group.
  • FIG. 3 shows the measurement results of total cholesterol concentration in plasma.
  • the total cholesterol concentration in the plasma was significantly reduced as compared to the control group.
  • the total cholesterol concentration in plasma was reduced as compared with the control group.
  • FIG. 4 shows the measurement results of LDL cholesterol concentration in plasma.
  • the LDL cholesterol concentration in the plasma was significantly reduced as compared to the control group. Also in the adonixanthin administration group, the LDL cholesterol concentration in the plasma was reduced as compared to the control group. Furthermore, in the adonixanthin administration group and the adonirubin administration group, it was confirmed that the visceral fat content was reduced as compared to the control group (average visceral fat mass of the control group: 3.274 g, in the adonixanthin administration group) Average value of visceral fat mass: 2.805 g, average value of visceral fat mass of adonirubin administration group: 2.987 g). Therefore, adonixanthin and / or adonirubin were considered to have an inhibitory effect on visceral fat accumulation.

Abstract

The present invention provides a novel composition for suppressing an increase in or reducing blood lipids. More specifically, the present invention provides a composition for suppressing an increase in or reducing blood lipids, the composition containing one or more types of carotenoids selected from adonirubin, adonixanthin, and pharmaceutically acceptable salts thereof.

Description

血中脂質の上昇抑制または低減用組成物Composition for suppressing or reducing blood lipid elevation 関連出願の参照Reference to related applications
　本特許出願は、２０１７年１２月１日に出願された日本国特許出願２０１７－２３１９８２号に基づく優先権の主張を伴うものであり、かかる先の特許出願における全開示内容は、引用することにより本明細書の一部とされる。 This patent application is accompanied by a claim of priority based on Japanese Patent Application No. 2017-231982 filed on Dec. 1, 2017, and the entire disclosure content of such prior patent application is incorporated by reference. It is part of this specification.
　本発明は、血中脂質の上昇抑制または低減用組成物に関し、より詳しくは、アドニルビンおよびアドニキサンチンから選択される一種以上のカロテノイドを含んでなる血中脂質の上昇抑制または低減用組成物に関する。 The present invention relates to a composition for suppressing or reducing blood lipid elevation, and more particularly, to a composition for suppressing or reducing blood lipid elevation comprising one or more carotenoids selected from adonirubin and adonixanthin. .
　アドニルビンおよびアドニキサンチンはカロテノイドの一種であり、動物、植物、微生物に広く分布している。アドニルビンまたはアドニキサンチンには抗不安の効果があることが知られている(特許文献１）。 Adonirubin and adonixanthin are a type of carotenoid and are widely distributed in animals, plants and microorganisms. It is known that adonirubin or adonixanthin has an anxiolytic effect (Patent Document 1).
　一方、カロテノイドの一種であるアスタキサンチンには種々の効果があることが報告されている。例えば、特許文献２には、アスタキサンチンが高脂血症に有用であり得ると記載されている。 On the other hand, astaxanthin, which is a type of carotenoid, has been reported to have various effects. For example, Patent Document 2 states that astaxanthin may be useful for hyperlipidemia.
　また、特許文献３には、リコペン等のカロテノイドが、乳清タンパク質等のカーゴ分子を血流へ送達するのに有用となり得ることが記載されている。カーゴ分子の性質に依存して疾患が回復または軽減され、カーゴ分子として乳清タンパク質を用いた場合には、コレステロールの低下に有用となり得ることが記載されている。 In addition, Patent Document 3 describes that carotenoids such as lycopene can be useful for delivering cargo molecules such as whey protein to the blood stream. It is described that depending on the nature of the cargo molecule, the disease may be ameliorated or reduced, and it may be useful for lowering cholesterol when whey protein is used as the cargo molecule.
　しかしながら、アドニルビンおよび／またはアドニキサンチンと、血中脂質の上昇抑制または低減との関係については何ら報告されていない。 However, there has been no report on the relationship between adonirubin and / or adonixanthin and the suppression or reduction of blood lipid elevation.
特開２０１２－０２５７１２号公報JP, 2012-025712, A 特表２０１７－５１６７５０号公報JP-A-2017-516750 特表２０１４－５０５０６８号公報JP 2014-505068 gazette
　本発明は、効果的に血中脂質の上昇を抑制または低減させる新たな技術的手段を提供することを目的としている。 The present invention aims to provide a new technical means for effectively suppressing or reducing blood lipid elevation.
　本発明者らは、今般、アドニルビンまたはアドニキサンチンを生体に投与したところ、効果的に血中脂質の上昇が抑制または低減させうることを見出した。 The present inventors have now found that when adonirubin or adonixanthin is administered to a living being, the rise in blood lipids can be effectively suppressed or reduced.
　本発明には、以下の発明が包含される。
（１）　アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドを含んでなる、血中脂質の上昇抑制または低減用組成物。
（２）　前記カロテノイドが、パラコッカス・カロティニファシエンス(Paracoccus carotinifaciens)由来である、（１）に記載の組成物。
（３）　前記血中脂質が、トリグリセリド、総コレステロール、およびＬＤＬコレステロールからなる群から選択される少なくとも一種である、（１）または（２）に記載の組成物。
（４）　脂質異常症の改善のための、（１）～（３）のいずれか一つに記載の組成物。
（５）　前記脂質異常症が、高脂血症、高コレステロール血症、高トリグリセリド血症、および高ＬＤＬコレステロール血症からなる群から選択される少なくとも一種である、（４）に記載の組成物。
（６）　内臓脂肪の蓄積抑制または低減のための、（１）～（５）のいずれか一つに記載の組成物。
（７）　肥満の改善または体重増加の抑制のための、（１）～（６）のいずれか一つに記載の組成物。
（８）　前記組成物が飲食品または食品添加物である、（１）～（７）のいずれか一つに記載の組成物。
（９）　前記組成物が機能性食品である、（１）～（８）のいずれか一つに記載の組成物。
（１０）　前記組成物が医薬品である、（１）～（９）のいずれか一つに記載の組成物。
（１１）　血中脂質の上昇抑制または低減用組成物の製造における、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの使用。
（１２）　アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの有効量を、それを必要とする対象に投与することまたは摂取させることを含んでなる、対象の血中脂質の低減または血中脂質の上昇の抑制方法。
（１３）　血中脂質の上昇抑制または低減のための、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイド。 The present invention includes the following inventions.
(1) A composition for suppressing or reducing blood lipid elevation comprising one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts.
(2) The composition according to (1), wherein the carotenoid is derived from Paracoccus carotinifaciens.
(3) The composition according to (1) or (2), wherein the blood lipid is at least one selected from the group consisting of triglyceride, total cholesterol, and LDL cholesterol.
(4) The composition according to any one of (1) to (3), for the improvement of dyslipidemia.
(5) The composition according to (4), wherein the dyslipidemia is at least one selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and hyper-LDL cholesterolemia. .
(6) The composition according to any one of (1) to (5), for suppressing or reducing the accumulation of visceral fat.
(7) The composition according to any one of (1) to (6), for improving obesity or suppressing weight gain.
(8) The composition according to any one of (1) to (7), wherein the composition is a food or drink or a food additive.
(9) The composition according to any one of (1) to (8), wherein the composition is a functional food.
(10) The composition according to any one of (1) to (9), wherein the composition is a pharmaceutical.
(11) Use of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts in the manufacture of a composition for suppressing or reducing blood lipid elevation.
(12) comprising administering or taking an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts to a subject in need thereof, A method of reducing blood lipids in a subject or suppressing elevation of blood lipids.
(13) One or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts, for suppressing or reducing blood lipid elevation.
　本発明によれば、本発明の組成物を摂取することにより、効果的に対象の血中脂質の上昇を抑制するか、または血中脂質を低減することができる。また、本発明の組成物は、トリグリセリド、総コレステロール、ＬＤＬコレステロールからなる群から選択される少なくとも一種の血中脂質の上昇を抑制するかまたは低減する上で有利である。さらに、本発明の組成物は、脂質異常症の改善、内臓脂肪の蓄積抑制もしくは低減、肥満の改善、または体重増加の抑制において有利に利用することができる。 According to the present invention, by taking the composition of the present invention, it is possible to effectively suppress the increase in blood lipids in the subject or to reduce the blood lipids. In addition, the composition of the present invention is advantageous in suppressing or reducing the increase in at least one blood lipid selected from the group consisting of triglyceride, total cholesterol, and LDL cholesterol. Furthermore, the composition of the present invention can be advantageously used in the improvement of dyslipidemia, the suppression or reduction of visceral fat accumulation, the improvement of obesity, or the suppression of weight gain.
アドニキサンチン投与群（黒三角：▲）および対照群（白丸：○）における、マウスの体重変化を示すグラフである。It is a graph which shows the weight change of a mouse in the adonixanthin administration group (black triangle:)) and a control group (white circle: ○). アドニキサンチン投与群および対照群における、マウスの血漿中のトリグリセリド濃度の測定結果を示すグラフである。It is a graph which shows the measurement result of the triglyceride concentration in the plasma of a mouse in the adonixanthin administration group and a control group. アドニルビン投与群および対照群における、マウスの血漿中の総コレステロール濃度の測定結果を示すグラフである。It is a graph which shows the measurement result of the total cholesterol concentration in the plasma of a mouse in an adonirubin administration group and a control group. アドニルビン投与群および対照群における、マウスの血液中のＬＤＬコレステロール濃度の測定結果を示すグラフである。It is a graph which shows the measurement result of the LDL cholesterol concentration in the blood of a mouse in an adonirubin administration group and a control group.
発明の具体的説明Detailed Description of the Invention
　本発明の血中脂質の上昇抑制または低減用組成物は、アドニルビンおよびアドニキサンチンから選択される一種以上のカロテノイドを含んでなることを特徴としている。 The composition for suppressing or reducing blood lipid elevation according to the present invention is characterized by comprising one or more carotenoids selected from adonirubin and adonixanthin.
カロテノイド
　本発明におけるカロテノイドとしては、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のものであり、例えば、アドニルビン、アドニキサンチンおよびこれら２種のカロテノイドの組み合わせが挙げられる。また、カロテノイドとしては、遊離体、脂肪酸エステル体であってもよく、吸収性の観点から、遊離体を使用することができる。カロテノイドは、光学異性体、シス-トランス異性体等の立体異性体であってもよい。さらに、これらカロテノイドは有効成分として用いることが好ましい。 Carotenoids Carotenoids in the present invention are one or more selected from adonirubin, adonixanthin, and pharmaceutically acceptable salts thereof, and, for example, a combination of adonirubin, adonixanthin and two carotenoids It can be mentioned. Moreover, as a carotenoid, a free form or fatty acid ester form may be sufficient, and a free form can be used from an absorbable viewpoint. Carotenoids may be stereoisomers such as optical isomers and cis-trans isomers. Furthermore, these carotenoids are preferably used as an active ingredient.
　アドニルビンの化学式は3-hydroxy-β,β-carotene-4,4’-dione （C40H5203、分子量580.853）であり、構造式は下記式で表される。
Figure JPOXMLDOC01-appb-C000001
 　アドニルビンのシス-トランス異性体としては、シス体、トランス体またはそれらの組み合わせであってもよく、シス体としては１３－シス体を挙げることができる。 The chemical formula of adonirubin is 3-hydroxy-β, β-carotene-4,4′-dione (C 40 H 52 O 3 , molecular weight 580.853), and the structural formula is represented by the following formula.
Figure JPOXMLDOC01-appb-C000001
 The cis-trans isomer of adonirubin may be cis, trans or a combination thereof, and the cis may include 13-cis.
　アドニキサンチンの化学式は3,3’-dihydroxy-β,β-carotene-4-one （C40H5403、分子量582.869）であり、構造式は下記式で表される。
Figure JPOXMLDOC01-appb-C000002
 　アドニキサンチンの光学異性体としては、３Ｓ，３’Ｒ－アドニキサンチン、３Ｓ，３’Ｓ－アドニキサンチン、３Ｒ，３’Ｓ－アドニキサンチンおよび３Ｒ，３’Ｒ－アドニキサンチンならびにこれらの薬学的に許容可能な塩からなる群から選ばれる少なくとも１つを挙げることができ、好ましくは、３Ｓ，３’Ｒ－アドニキサンチンである。また、アドニキサンチンのシス-トランス異性体としては、シス体、トランス体またはそれらの組み合わせであってもよい。アドニキサンチンのシス-トランス異性体として、好ましくは、シス体およびトランス体の組み合わせである。 The chemical formula of adonixanthin is 3,3'-dihydroxy-β, β- carotene-4-one (C 40 H 54 0 3, molecular weight 582.869) and the structural formula is represented by the following formula.
Figure JPOXMLDOC01-appb-C000002
 As optical isomers of adonixanthin, 3S, 3'R-adonixanthin, 3S, 3'S-adonixanthin, 3R, 3'S-adonixanthin and 3R, 3'R-adonixanthin and Mention may be made of at least one selected from the group consisting of these pharmaceutically acceptable salts, preferably 3S, 3'R-adonixanthin. The cis-trans isomer of adonixanthin may be cis, trans or a combination thereof. As a cis-trans isomer of adonixanthin, preferred is a combination of cis- and trans-isomers.
　本発明において、カロテノイドは、薬学的に許容可能な塩の形態であってもよく、これらの塩も本発明におけるカロテノイドに含まれる。本発明において、カロテノイドは、酸または塩基と塩を形成する場合もある。本発明において、薬学的に許容可能な塩は、アドニルビンおよび／またはアドニキサンチンと薬学的に許容可能な塩を形成するものであれば特に限定されない。具体的には、例えば、ハロゲン化水素酸塩（例えばフッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等）、無機酸塩（例えば硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩等）、有機カルボン酸塩（例えば酢酸塩、シュウ酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、クエン酸塩等）、有機スルホン酸塩（例えばメタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、カンファースルホン酸塩等）、アミノ酸塩（例えばアスパラギン酸塩、グルタミン酸塩等）、四級アミン塩、アルカリ金属塩（例えばナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例えばマグネシウム塩、カルシウム塩等）等が挙げられるが、これに限定されない。 In the present invention, the carotenoid may be in the form of a pharmaceutically acceptable salt, and these salts are also included in the carotenoid in the present invention. In the present invention, a carotenoid may form a salt with an acid or a base. In the present invention, the pharmaceutically acceptable salt is not particularly limited as long as it forms a pharmaceutically acceptable salt with adonirubin and / or adonixanthin. Specifically, for example, hydrohalide (eg, hydrogen fluoride, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salt (eg, sulfate, nitrate, perchloric acid) Salts, phosphates, carbonates, bicarbonates, etc., organic carboxylates (eg acetate, oxalate, maleate, tartrate, fumarate, citrate etc.), organic sulfonates (eg For example, methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, camphor sulfonate, etc., amino acid salt (eg, aspartate, glutamate etc.), quaternary amine Examples thereof include, but are not limited to, salts, alkali metal salts (for example, sodium salt, potassium salt and the like), alkaline earth metal salts (for example, magnesium salt, calcium salt and the like) and the like.
　本発明のカロテノイドは、市販品であってもよく、あるいは従来の化学合成法により製造された化学合成品、微生物による発酵法、または動物もしくは植物等からの抽出および精製方法等により製造されたもの（天然由来）（微生物、動物または植物由来物ともいう）を使用することができる。ここで、微生物、動物または植物由来物とは、微生物、動物または植物から得られる産生物であり、好ましくは、パラコッカス属微生物由来物、より好ましくはパラコッカス・カロティニファシエンス由来物であってよい。 The carotenoid of the present invention may be a commercial product, or a chemically synthesized product produced by a conventional chemical synthesis method, a fermentation method by a microorganism, or an extract and purification method from animals or plants etc. (Naturally derived) (also referred to as microbial, animal or plant derived) can be used. Here, the microorganism, animal or plant-derived substance is a product obtained from a microorganism, animal or plant, preferably, it may be a Paracoccus microorganism-derived substance, more preferably Paracoccus carotinifaciens-derived substance. .
　例えば、微生物からのアドニルビンおよびアドニキサンチンの抽出および精製方法として下記の方法が挙げられる。パラコッカス・カロティニファシエンス（Paracoccus carotinifaciens）の乾燥菌体を、アセトンを使用する室温抽出に供し、抽出液をエバポレーターで濃縮し、濃縮液が二層に分離したところで濃縮物にヘキサン－クロロホルム（１：１）混合液を加えて良く混和した後、分液操作により有機溶媒層を得る。前記有機溶媒層をエバポレーターで濃縮乾固する。濃縮乾固物をクロロホルムに溶解し、シリカゲルカラムにて各カロテノイドを分離する。例えばアセトン：ヘキサン（３：７）３００ｍＬで溶出する画分をさらにＨＰＬＣ（Ｓｈｉｍ－ｐａｃｋ　ＰＲＣ－ＳＩＬ（株式会社島津製作所）、アセトン：ヘキサン（３：７））で精製することでアドニルビン遊離体を得ることができる。また、アセトンで溶出する画分をさらにＨＰＬＣ（Ｓｈｉｍ－ｐａｃｋ　ＰＲＣ－ＳＩＬ、アセトン：ヘキサン（４：６））で精製することで、アドニキサンチン遊離体を得ることができる。 For example, the following methods may be mentioned as methods for extracting and purifying adonirubin and adonixanthin from microorganisms. The dried cells of Paracoccus carotinifaciens are subjected to room temperature extraction using acetone, the extract is concentrated by an evaporator, and the concentrate is separated into two layers, and the concentrate is hexane-chloroform (1 1) Add the mixed solution, mix well, and then separate to obtain an organic solvent layer. The organic solvent layer is concentrated to dryness with an evaporator. The concentrated dried product is dissolved in chloroform, and each carotenoid is separated on a silica gel column. For example, the fraction eluted with 300 mL of acetone: hexane (3: 7) is further purified by HPLC (Shim-pack PRC-SIL (Shimadzu Corp.), acetone: hexane (3: 7)) to further purify the adduct of adonirubin. You can get it. In addition, the adonixanthin educt can be obtained by further purifying the fraction eluted with acetone by HPLC (Shim-pack PRC-SIL, acetone: hexane (4: 6)).
　さらに、本発明の組成物においては、本発明のカロテノイドとしてのアドニルビンおよびアドニキサンチンに加えてアスタキサンチンを含むカロテノイド混合物を使用してもよい。例えば、特開２００７－２６１９７２号公報、特開２００９－５０２３７号公報に記載の方法に準じてパラコッカス・カロティニファシエンスの乾燥菌体から抽出したカロテノイド混合物は、アスタキサンチン、アドニルビンおよびアドニキサンチンを含む。 Furthermore, in the composition of the present invention, a carotenoid mixture containing astaxanthin in addition to adonirubin and adonixanthin as the carotenoid of the present invention may be used. For example, a carotenoid mixture extracted from the dried cells of Paracoccus carotinifaciens according to the methods described in JP-A-2007-261972 and JP-A-2009-50237 contains astaxanthin, adonirubin and adonixanthin. .
　本発明の組成物におけるカロテノイドの含有量は、本発明の効果を妨げない限り特に限定されないが、組成物全体に対し、例えば、０．０１～５０質量％が挙げられ、好ましくは０．０５～３０質量％、より好ましくは０．０７～１５質量％、さらに好ましくは０．１～１０質量％である。本発明の組成物におけるアドニルビンおよび／またはアドニキサンチンの含有量の測定は、ＨＰＬＣ法により、Toxicol Rep. 2014 Aug 25;1:582-588.の記載に準じて実施される。 The content of the carotenoid in the composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and for example, 0.01 to 50% by mass can be mentioned with respect to the whole composition. It is 30% by mass, more preferably 0.07 to 15% by mass, and still more preferably 0.1 to 10% by mass. The measurement of the content of adonirubin and / or adonixanthin in the composition of the present invention is carried out by HPLC according to the description of Toxicol Rep. 2014 Aug 25; 1: 582-588.
　本発明の組成物は、上記カロテノイドと共に、所望により経口上許容可能または薬学的に許容可能な添加剤を配合した組成物として提供することができる。上記添加剤として、溶剤、溶解補助剤、溶解剤、滑沢剤、乳化剤、等張化剤、安定化剤、保存剤、防腐剤、界面活性剤、調整剤、キレート剤、ｐＨ調整剤、緩衝剤、賦形剤、増粘剤、着色剤、芳香剤または香料等が挙げられる。 The composition of the present invention can be provided as a composition optionally containing an orally acceptable or pharmaceutically acceptable additive together with the above-mentioned carotenoid. As the above additives, solvents, solubilizers, solubilizers, lubricants, emulsifiers, tonicity agents, stabilizers, preservatives, preservatives, surfactants, regulators, chelating agents, pH adjusters, buffers Agents, excipients, thickeners, colorants, fragrances, perfumes and the like.
　本発明の組成物は、上記カロテノイドおよび所望により経口上許容可能または薬学的に許容可能な添加剤を混合、溶解、分散、懸濁するなどの公知の手法により、調製することができる。また、本発明の組成物の調製においては、本発明の効果を妨げない限り、上記手法により調製された混合物、溶解物、分散物、懸濁物などに、均質化処理や殺菌処理を施してもよい。 The composition of the present invention can be prepared by known methods such as mixing, dissolving, dispersing, suspending, etc. the above-mentioned carotenoid and optionally orally acceptable or pharmaceutically acceptable additive. Moreover, in the preparation of the composition of the present invention, the mixture, the lysate, the dispersion, the suspension, etc. prepared by the above-mentioned method are subjected to homogenization treatment or sterilization treatment, as long as the effects of the present invention are not impaired. It is also good.
　また、本発明の組成物の形態は、本発明の効果を妨げない限り、特に制限されず、固形状、半固形状（ペースト、ゲルを含む）または液状（油状、スラリー状を含む）であってもよいが、固形状または液状であることが好ましい。 In addition, the form of the composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be solid, semi-solid (including paste, gel) or liquid (including oil, slurry). Although it may be, it is preferable that it is solid or liquid.
　また、本発明の組成物の剤形は、本発明の効果を妨げない限り特に限定されないが、注射剤、錠剤（例えば、裸錠、糖衣錠、フィルムコーティング錠、腸溶錠、徐放錠、口腔内崩壊錠、舌下錠、チュアブル錠等）、カプセル剤（例えば、硬カプセル、軟カプセル）、エリキシル剤、丸剤、粉剤、散剤、顆粒剤、水剤、トローチ剤、シロップ剤、ドライシロップ剤、乳剤、懸濁剤、液剤、吸入剤、エアロゾル剤、粉末吸入剤、坐剤、軟膏、クリーム剤、ゲル剤、貼付剤、バップ剤、ローション剤、点滴剤、眼軟膏剤、点眼剤、点鼻剤等が挙げられる。本発明の組成物の剤形は、実施例に示す通り、本発明の組成物が経口摂取された場合に血中脂質の濃度の上昇が抑制されるかまたは低減していることから、経口摂取または投与用の剤形であることが好ましく、錠剤、カプセル剤、丸剤、粉剤、散剤、顆粒剤、シロップ剤、ドライシロップ剤、乳剤、液剤、懸濁剤、水剤、トローチ剤等が挙げられる。 Furthermore, the dosage form of the composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and injections, tablets (eg, plain tablets, sugar-coated tablets, film-coated tablets, enteric tablets, sustained-release tablets, oral cavity Internally disintegrating tablets, sublingual tablets, chewable tablets, etc., capsules (eg hard capsules, soft capsules), elixirs, pills, powders, powders, granules, solutions, troches, syrups, dry syrups, Emulsion, suspension, solution, inhalant, aerosol, powder inhalant, suppository, ointment, cream, gel, patch, bop, lotion, drip, eye ointment, eye drop, nose Agents and the like. The dosage form of the composition of the present invention, as shown in the examples, can be taken orally as the concentration of blood lipids is suppressed or reduced when the composition of the present invention is taken orally. It is preferably a dosage form for administration, and includes tablets, capsules, pills, powders, powders, granules, syrups, dry syrups, emulsions, solutions, suspensions, solutions, troches, etc. .
　本発明の組成物の投与または摂取方法としては、特に限定されないが、点滴、静脈内注射、筋肉内注射、皮下注射、皮内注射等の注射、経口、経粘膜、経皮、鼻腔内、口腔内等による投与または摂取が挙げられる。実施例に示す通り、本発明の組成物が経口摂取された場合に血中脂質の濃度の上昇が抑制されるかまたは低減していることから、経口摂取または投与が好ましい。 The method of administration or intake of the composition of the present invention is not particularly limited, but injections such as infusion, intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, oral, transmucosal, transdermal, intranasal, oral cavity Administration or intake by inwards etc. may be mentioned. As shown in the examples, oral intake or administration is preferred because the composition of the present invention suppresses or reduces the increase in blood lipid concentration when taken orally.
　本発明の組成物としては、食品もしくは飲料等の飲食品、飲食品添加物、飼料、医薬品、医薬部外品、または化粧料が挙げられ、摂取の簡便性の観点から飲食品が好ましい。 The composition of the present invention includes food and drink such as food and drink, food and drink additives, feed, medicine, quasi drug and cosmetics, and food and drink are preferable from the viewpoint of convenience of intake.
　本発明の飲食品は、本発明の組成物をそのまま飲食品として調製したもの、各種タンパク質、糖類、脂肪、微量元素、ビタミン類、他の有効成分（例えば、乳酸菌、バチルス属菌（Bacillus）等の細菌、酵母等の真菌、食物繊維、ＤＨＡまたはＥＰＡ）等を更に配合したもの、本発明の組成物を水溶液状等の液状、半液体状または固体状にしたものでよく、また、本発明の組成物を一般の飲食品へ添加したものであってもよい。 The food and drink of the present invention are prepared by preparing the composition of the present invention directly as a food and drink, various proteins, saccharides, fats, trace elements, vitamins, other active ingredients (eg, lactic acid bacteria, Bacillus bacteria (Bacillus), etc. Or a mixture of bacteria, yeasts and other fungi, dietary fiber, DHA or EPA), etc., and the composition of the present invention in liquid, semi-liquid or solid state such as aqueous solution, etc. The composition of the present invention may be added to general food and drink.
　上記飲食品としては、具体的には、例えば、即席麺、レトルト食品、缶詰、電子レンジ食品、即席スープ・みそ汁類、フリーズドライ食品等の即席食品類；清涼飲料、果汁飲料、野菜飲料、豆乳飲料、コーヒー飲料、茶飲料、粉末飲料、濃縮飲料、アルコール飲料等の飲料類；栄養ドリンク；パン、パスタ、麺、ケーキミックス、パン粉等の小麦粉製品；飴、グミ、ゼリー、キャラメル、チューイングガム、チョコレート、クッキー、ビスケット、ケーキ、パイ、スナック、クラッカー、和菓子、デザート菓子等の菓子類；栄養バー；ソース、トマト加工調味料、風味調味料、調理ミックス、たれ類、ドレッシング類、つゆ類、カレー・シチューの素類等の調味料；加工油脂、バター、マーガリン、マヨネーズ等の油脂類；乳飲料、ヨーグルト類、乳酸菌飲料、アイスクリーム類、クリーム類等の乳製品；農産缶詰、ジャム・マーマレード類、シリアル等の農産加工品；ハム、ベーコン、ソーセージ、焼き豚等の畜肉加工食品：冷凍食品等を例示することができるが、これらに限定されない。 As the food and drink, specifically, for example, instant foods such as instant noodles, retort foods, canned foods, microwave foods, instant soups and miso soups, freeze-dried foods, etc .; soft drinks, fruit juices, vegetable drinks, soy milk Beverages such as beverages, coffee beverages, tea beverages, powdered beverages, concentrated beverages, alcoholic beverages, etc .; Nutritional drinks; Bread products such as pasta, noodles, cake mix, bread crumbs; Strawberries, gummi, jelly, caramel, chewing gum, chocolate , Cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, dessert sweets, etc .; Nutritional bar; Sauce, processed tomato seasoning, flavored seasoning, cooking mix, sauces, dressings, soy sauce, curry, Seasoning ingredients such as stews; Processed fats and oils, butter, margarine, mayonnaise, etc .; Milk beverages, yogs Foods such as milk, lactic acid bacteria beverages, ice creams and creams; agricultural products such as canned agricultural products, jams and marmalades and cereals; processed meat products such as ham, bacon, sausages and grilled pork: frozen foods etc. Although it can do, it is not limited to these.
　本発明の飲食品には、健康食品、サプリメント、機能性食品（例えば、特定保健用食品、栄養機能食品または機能性表示食品を含む）、栄養補助食品、特別用途食品（例えば、病者用食品、乳児用調製粉乳、妊産婦、授乳婦用粉乳またはえん下困難者・咀嚼困難者用食品を含む）または乳児用液体調製乳（乳児用液体ミルクともいう）も包含される。後述のように、本発明の組成物は血中脂質の低減もしくは上昇抑制作用、脂質異常症の改善作用、内臓脂肪の蓄積抑制もしくは低減作用、肥満の改善作用、または体重増加抑制作用を有することから、血中脂質の低減もしくは上昇抑制のための飲食品、脂質異常症もしくは肥満の改善、または体重の増加抑制のための飲食品が提供される。すなわち、本発明の飲食品は、血中脂質が気になるヒトのための飲食品、血中コレステロールまたはトリグリセリド（中性脂肪）が気になるヒトのための飲食品、肥満または体重が気になるヒトのための飲食品、内臓脂肪が気になるヒトのための飲食品として提供できる。さらに、機能性食品等の飲食品において、「血中脂肪が高めの方に」、「体重が気になる方に」、「肥満が気になる方に」、「脂肪を消費しやすくする」、「内臓脂肪が気になる方に」等の表示を付して提供してもよい。 The food and drink of the present invention include health food, supplement, functional food (for example, food for specified health use, nutritional function food or functional display food), nutritional supplement, special purpose food (for example, food for sick people) Also included are infant formula, maternal, lactating mother's milk or food for infants with dyspnea or dyspnea) or infant liquid formula (also referred to as infant liquid milk). As described later, the composition of the present invention has a blood lipid reduction or elevation suppressive action, an improvement effect of dyslipidemia, an accumulation suppression or reduction action of visceral fat, an obesity improvement action, or a weight gain suppression action. Thus, the present invention provides a food or drink for reducing or suppressing elevation of blood lipid, a food or drink for improvement of dyslipidemia or obesity, or suppression of body weight gain. That is, the food and drink of the present invention are food and drink for humans who are concerned about blood lipids, food and drinks for humans who are concerned about blood cholesterol or triglycerides (neutral fats), and who care about obesity or weight. Provided as a food and drink for humans and a food and drink for humans who are concerned about visceral fat. Furthermore, in food and drink products such as functional foods, "If blood fat is high," "If weight is anxious," "If obesity is anxious," "Ease fat consumption" , And may be provided with an indication such as “for those who are concerned about visceral fat”.
　本発明の組成物の摂取量または投与量は、特に限定されず、組成物の処方、カロテノイドの種類、純度、対象の種類、対象の年齢または体重、症状、摂取または投与時間、組成物の形態、摂取または投与方法、他のカロテノイドまたは薬剤の組み合わせ等に依存して決定できる。また、本発明の組成物は、血中脂質の低減または上昇抑制のための有効量となるように、１日の摂取量単位の形態から構成されることが好ましい。例えば、本発明の組成物を経口摂取する場合、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドが体重６０ｋｇの成人１人１日当たり０．０１～１００００ｍｇ、好ましくは０．１～１０００ｍｇ、より好ましくは１～１００ｍｇの範囲の摂取量または投与量となるように該カロテノイドを組成物に配合することができる。本発明のカロテノイドと組み合わせて用いる他のカロテノイドまたは薬剤も、それぞれ臨床上用いられる摂取量または投与量を基準として適宜決定できる。 The intake or dose of the composition of the present invention is not particularly limited, and formulation of the composition, type of carotenoid, purity, type of subject, age or weight of subject, symptoms, intake or administration time, form of composition Depending on the method of intake or administration, other carotenoids or drug combinations, etc. In addition, the composition of the present invention is preferably constituted in the form of a daily intake unit so as to be an effective amount for reducing or suppressing the rise of blood lipids. For example, when orally ingesting the composition of the present invention, 0.01 to 10000 mg of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts per day per adult weighing 60 kg The carotenoids can be formulated into compositions such that intakes or doses preferably range from 0.1 to 1000 mg, more preferably 1 to 100 mg. Other carotenoids or drugs used in combination with the carotenoids of the present invention can also be appropriately determined based on the clinically used intake or dose, respectively.
　また、本発明の組成物の１日の摂取量または投与量は、上述の組成物の摂取量または投与量と同様、組成物の処方等に応じて適宜選択されるものである。本発明の組成物の１日の摂取量または投与量は、例えば１回または複数回で対象に摂取させるかまたは投与してもよいが、１回で対象に摂取させるかまたは投与することが好ましい。したがって、本発明の組成物の１日の摂取または投与回数は、１日に１～５回であり、好ましくは、１日に１～３回であり、より好ましくは、１日に１回である。 Further, the daily intake or dose of the composition of the present invention is appropriately selected according to the formulation of the composition, etc., similarly to the intake or dose of the above-mentioned composition. The daily intake or dose of the composition of the present invention may be taken or administered to the subject, for example, once or several times, but is preferably taken or administered to the subject at one time . Accordingly, the number of daily intakes or administrations of the composition of the present invention is 1 to 5 times a day, preferably 1 to 3 times a day, more preferably once a day is there.
　一つの態様によれば、本発明の組成物を適用する対象としては、好ましくは哺乳動物であり、より好ましくはヒトである。当該対象は健常者であっても患者であってもよい。 According to one embodiment, the subject to which the composition of the present invention is applied is preferably a mammal, more preferably a human. The subject may be a healthy person or a patient.
　本発明の組成物によれば、優れた血中脂質低減作用または血中脂質上昇の抑制作用を奏することが可能である。有利には、本発明の組成物によれば、トリグリセリド、総コレステロール、ＬＤＬコレステロールからなる群から選択される少なくとも一種である血中脂質を低減すること、または当該血中脂質の上昇を抑制することができる。したがって、本発明の組成物は血中脂質の上昇抑制または低減用組成物として提供される。さらに、上記血中脂質としては、トリグリセリド、総コレステロール、ＬＤＬコレステロールからなる群から選択される少なくとも一種が好ましい。 According to the composition of the present invention, it is possible to exert an excellent blood lipid lowering action or a blood lipid elevation inhibiting action. Advantageously, according to the composition of the present invention, reducing blood lipid which is at least one selected from the group consisting of triglyceride, total cholesterol, LDL cholesterol, or suppressing elevation of the blood lipid. Can. Therefore, the composition of the present invention is provided as a composition for suppressing or reducing blood lipid elevation. Furthermore, as the above-mentioned blood lipid, at least one selected from the group consisting of triglyceride, total cholesterol and LDL cholesterol is preferable.
　また、本発明の組成物によれば、脂質異常症を改善させること、内臓脂肪の蓄積を抑制もしくは内臓脂肪を低減すること、肥満を改善させること、または体重増加を抑制させることができる。したがって、本発明の一つの態様によれば、本発明の組成物は、脂質異常症の改善、内臓脂肪の蓄積抑制もしくは低減、肥満の改善または体重増加の抑制のための組成物として提供される。ここで、脂質異常症としては、好ましくは、高脂血症、高コレステロール血症、および高トリグリセリド血症、高ＬＤＬコレステロール血症からなる群から選択される少なくとも一種である。本明細書における「改善」とは、確立された病態の改善という「治療」の意味を含むだけでなく、想定される悪化に対して事前に備え、疾患の発生を未然に防ぐ「予防」の意味も含む。 Moreover, according to the composition of the present invention, it is possible to improve dyslipidemia, to suppress accumulation of visceral fat or to reduce visceral fat, to improve obesity, or to suppress weight gain. Therefore, according to one aspect of the present invention, the composition of the present invention is provided as a composition for improving dyslipidemia, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain. . Here, the dyslipidemia is preferably at least one selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and hyper-LDL cholesterolemia. In the present specification, "improvement" not only includes the meaning of "treatment" that is improvement of an established pathological condition, but also "prevents" prevention of occurrence of diseases by preparing in advance for possible deterioration. Also includes the meaning.
　アドニキサンチンまたはアドニルビンの作用機序は現時点では不明であるが、以下のように推測される。
（１）アドニキサンチンまたはアドニルビンが、脂肪細胞に作用して、アディポネクチンの分泌をより増加させる可能性がある。アディポネクチンとは、脂肪細胞から分泌される分泌される蛋白質であり、アディポネクチンの増加は内臓脂肪量の低減と相関関係があることが知られている。
（２）アドニキサンチンまたはアドニルビンが、脂肪細胞からのＴＮＦ－αの分泌を正常な状態に近づける作用がある可能性がある。ＴＮＦ－αを正常な状態とすることで細胞内へのグルコースの取り込みが阻害されることが知られている。 Although the mechanism of action of adonixanthin or adonirubin is unknown at present, it is presumed as follows.
(1) Adonixanthin or adonirubin may act on adipocytes to further increase adiponectin secretion. Adiponectin is a secreted protein secreted from fat cells, and it is known that an increase in adiponectin correlates with a decrease in visceral fat mass.
(2) Adonixanthin or adonirubin may have an effect of bringing TNF-α secretion from fat cells close to normal. It is known that normalizing TNF-α inhibits the uptake of glucose into cells.
　本発明の別の態様によれば、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドを有効量含んでなる組成物を対象に投与することまたは摂取させることを含んでなる、対象の血中脂質の低減または血中脂質の上昇の抑制方法が提供される。本発明のさらに別の態様によれば、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの有効量を、それを必要とする対象に投与することまたは摂取させることを含んでなる、対象の血中脂質の低減または血中脂質の上昇の抑制方法が提供される。ここで、「有効量」とは、１日の摂取量単位における、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの含有量等と同様に設定することができる。上記血中脂質としては、トリグリセリド、総コレステロール、およびＬＤＬコレステロールからなる群から選択される少なくとも一種であるものが好ましい。本発明のさらに別の態様によれば、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドを有効量含んでなる組成物を対象に投与することまたは摂取させることを含んでなる、対象の脂質異常症の改善、内臓脂肪の蓄積抑制もしくは低減、肥満の改善または体重増加の抑制方法が提供される。本発明のさらに別の態様によれば、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの有効量を、それを必要とする対象に投与することまたは摂取させることを含んでなる、対象の脂質異常症の改善、内臓脂肪の蓄積抑制もしくは低減、肥満の改善または体重増加の抑制方法が提供される。上記脂質異常症としては、高脂血症、高コレステロール血症、高トリグリセリド血症および高ＬＤＬコレステロール血症からなる群から選択される少なくとも一種であるものが好ましい。本発明のさらに別の態様によれば、上述の、対象の血中脂質の低減もしくは血中脂質の上昇の抑制方法、対象の脂質異常症の改善方法、対象の内臓脂肪の蓄積抑制もしくは低減方法、対象の肥満の改善方法、または対象の体重増加の抑制方法は、対象が健常者である場合、ヒトに対する医療行為を除く非治療的方法とされる。ここで、ヒトに対する医療行為とは、医師等の処方を必要として、ヒトに対して医薬品を摂取させる（投与する）行為等を意味する。本発明の、対象の血中脂質の低減もしくは血中脂質の上昇の抑制方法、対象の脂質異常症の改善方法、対象の内臓脂肪の蓄積抑制もしくは低減方法、対象の肥満の改善方法、または対象の体重増加の抑制方法は、本発明の組成物について、本明細書に記載された内容に従って実施することができる。 According to another aspect of the present invention, a subject comprising administering or ingesting a composition comprising an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and pharmaceutically acceptable salts thereof There is provided a method of reducing blood lipids in a subject or suppressing elevation of blood lipids comprising the method of According to yet another aspect of the invention, administering to a subject in need thereof an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and pharmaceutically acceptable salts thereof or There is provided a method of reducing blood lipids in a subject or suppressing elevation of blood lipids, which comprises ingesting. Here, the "effective amount" is set similarly to the content etc. of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts in the daily intake unit. be able to. The blood lipid is preferably at least one selected from the group consisting of triglyceride, total cholesterol, and LDL cholesterol. According to yet another aspect of the present invention, administering or ingesting a composition comprising an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts There is provided a method of improving dyslipidemia in a subject, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain, comprising: According to yet another aspect of the invention, administering to a subject in need thereof an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and pharmaceutically acceptable salts thereof or Provided is a method for improving dyslipidemia in a subject, reducing or reducing visceral fat accumulation, improving obesity, or suppressing weight gain, which comprises ingesting. The above-mentioned dyslipidemia is preferably at least one selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and hyper-LDL cholesterolemia. According to still another aspect of the present invention, a method for reducing blood lipids in a subject or suppressing elevation of blood lipids as described above, a method for improving dyslipidemia in a subject, and a method for inhibiting accumulation or reduction of visceral fat in a subject A method for improving obesity in a subject, or a method for suppressing weight gain in a subject is a non-therapeutic method excluding medical practice for humans when the subject is healthy. Here, the medical practice for a human means an act of taking (administering) a pharmaceutical product to a human in need of prescription by a doctor or the like. A method of reducing blood lipids in a subject or suppressing elevation of blood lipids according to the present invention, a method of ameliorating dyslipidemia in a subject, a method of inhibiting accumulation or reduction of visceral fat in a subject, a method of ameliorating obesity in a subject, or a subject The method for suppressing body weight gain can be practiced according to the contents described herein for the composition of the present invention.
　また、本発明の別の態様によれば、血中脂質の上昇抑制または低減のための、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの使用が提供される。本発明の別の態様によれば、脂質異常症の改善、内臓脂肪の蓄積抑制もしくは低減、肥満の改善または体重増加の抑制のための、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの使用が提供される。 Also, according to another aspect of the present invention, there is provided the use of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts for suppressing or reducing blood lipid elevation. Provided. According to another aspect of the present invention, adonirubin, adonixanthin and their pharmaceutically acceptable for improving dyslipidemia, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain The use of one or more carotenoids selected from salts is provided.
　また、本発明の別の態様によれば、血中脂質の上昇抑制または低減用組成物の製造における、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの使用が提供される。本発明の別の態様によれば、脂質異常症の改善、内臓脂肪の蓄積抑制もしくは低減、肥満の改善または体重増加の抑制のための組成物の製造における、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの使用が提供される。 Also, according to another aspect of the present invention, there is provided one or more carotenoids selected from adonirubin, adonixanthin and pharmaceutically acceptable salts thereof in the manufacture of a composition for suppressing or reducing blood lipid elevation. The use of is provided. According to another aspect of the present invention, adonirubin, adonixanthin and their pharmaceuticals in the manufacture of a composition for ameliorating dyslipidemia, inhibiting or reducing visceral fat accumulation, ameliorating obesity or inhibiting weight gain Use of one or more carotenoids selected from highly acceptable salts is provided.
　また、本発明の別の態様によれば、血中脂質の上昇抑制または低減のための、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドが提供される。本発明の別の態様によれば、脂質異常症の改善、内臓脂肪の蓄積抑制もしくは低減、肥満の改善または体重増加の抑制のための、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドが提供される。 Also, according to another aspect of the present invention, there is provided one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts for suppressing or reducing blood lipid elevation. Ru. According to another aspect of the present invention, adonirubin, adonixanthin and their pharmaceutically acceptable for improving dyslipidemia, suppressing or reducing visceral fat accumulation, improving obesity or suppressing weight gain One or more carotenoids selected from salts are provided.
　上記の使用、化合物（カロテノイド）の態様は何れも、本発明の組成物または方法に関する記載に準じて実施することができる。 Any of the above uses and embodiments of the compound (carotenoid) can be carried out according to the description of the composition or method of the present invention.
　以下、調製例、試験例により、本発明をより具体的に説明するが、本発明の技術範囲は、これらの例示に限定されるものではない。なお、特に記載しない限り、本発明で用いられる全部のパーセンテージや比率は質量による。また、特に記載しない限り、本明細書に記載の単位や測定方法はJIS規格による。 The present invention will be more specifically described below by Preparation Examples and Test Examples, but the technical scope of the present invention is not limited to these examples. It should be noted that, unless stated otherwise, all percentages and proportions used in the present invention are by weight. Moreover, unless otherwise indicated, the unit and measuring method as described in this specification conform to the JIS standard.
調製例１：アドニキサンチンおよびアドニルビンの調製
　特開２０１２－１５８５６９号公報に記載の方法に準じて、アドニルビン遊離体およびアドニキサンチン遊離体の調製を行った。以下に簡単に記載する。
　パラコッカス・カロティニファシエンス(Paracoccus carotinifaciens)の乾燥菌体を、アセトンを使用する室温抽出に供した。得られた抽出液をエバポレーターで濃縮し、濃縮液が二層に分離したところで濃縮物にヘキサン-クロロホルム（１：１）混合液を加えて良く混和した後、分液操作により有機溶媒層を得た。
　得られた有機溶媒層をエバポレーターで濃縮乾固した。濃縮乾固物をクロロホルムに溶解し、シリカゲルカラムにて各カロテノイドを分離した。具体的には、アセトン：ヘキサン（３：７）３００ｍＬで溶出する画分をさらにＨＰＬＣ（Ｓｈｉｍ－ｐａｃｋ　ＰＲＣ－ＳＩＬ（株式会社島津製作所）、アセトン：ヘキサン（３：７））で精製し、アドニルビン遊離体（以下、単にアドニルビンともいう）を得た。アセトンで溶出する画分をさらにＨＰＬＣ（Ｓｈｉｍ－ｐａｃｋ　ＰＲＣ－ＳＩＬ、アセトン：ヘキサン（４：６））で精製し、アドニキサンチン遊離体（以下、単にアドニキサンチンともいう）を得た。 Preparation Example 1: Preparation of adonixanthin and adonirubin According to the method described in JP-A-2012-158569, an adonirubin free body and an adonixanthin free body were prepared. Briefly described below.
Dry cells of Paracoccus carotinifaciens were subjected to room temperature extraction using acetone. The obtained extract is concentrated by an evaporator, and when the concentrate is separated into two layers, a mixed solution of hexane-chloroform (1: 1) is added to the concentrate and mixed well, and then an organic solvent layer is obtained by liquid separation operation. The
The obtained organic solvent layer was concentrated to dryness with an evaporator. The concentrated dried product was dissolved in chloroform, and each carotenoid was separated by a silica gel column. Specifically, the fraction eluted with 300 mL of acetone: hexane (3: 7) is further purified by HPLC (Shim-pack PRC-SIL (Shimadzu Corporation), acetone: hexane (3: 7)), and adonirubin A free form (hereinafter, also simply referred to as adonirubin) was obtained. The fraction eluted with acetone was further purified by HPLC (Shim-pack PRC-SIL, acetone: hexane (4: 6)) to obtain adonixanthin free form (hereinafter, also simply referred to as adonixanthin).
調製例２：アドニキサンチン含有組成物（投与液）およびアドニルビン含有組成物（投与液）の調製
　調製例１で得られたアドニキサンチンまたはアドニルビンにコーン油を加えて懸濁し、それぞれ１．２ｍｇ／ｍＬの濃度となるように調製し、アドニキサンチン含有投与液およびアドニルビン含有投与液を得た。対照としてはコーン油を用いた。 Preparation Example 2: Preparation of adonixanthin-containing composition (administration solution) and adonirubin-containing composition (administration solution) A corn oil is added to the adonixanthin or adonirubin obtained in Preparation Example 1 and suspended, and each 1.2 mg The adonixanthin-containing administration solution and the adonirubin-containing administration solution were prepared so as to have a concentration of / mL. Corn oil was used as a control.
調製例３：高脂肪飼料の調製
　試験例では、高脂肪飼料として、粉末飼料（ＭＦ、オリエンタル酵母工業株式会社）：ラード：コレステロール：コール酸＝７８．７：２０：１：０．３の割合で混合した飼料を用いた。前記高脂肪飼料は、必要量の粉末飼料、コレステロールおよびコール酸を秤量し、ケンミックスミキサー（株式会社愛工製作所）で充分撹拌しながら、必要量のラードを少量ずつ加えて更に混合することにより得られた。 Preparation example 3: Preparation of high fat feed In the test example, as a high fat feed, powder feed (MF, Oriental Yeast Co., Ltd.): lard: cholesterol: choric acid = 78.7: 20: 1: 0.3 ratio The feed mixed with was used. The high-fat feed can be obtained by weighing the required amounts of powdered feed, cholesterol and cholic acid, adding the required amount of lard little by little and further mixing while sufficiently stirring with a Kenmix mixer (Aiko Co., Ltd.) It was done.
試験例１：アドニキサンチン含有組成物（投与液）を用い、高脂肪食負荷ＫＫ－Ａ ｙ マウスを対象とした動物試験（体重測定）
　実験動物には、６週齢の雄のＳＰＦマウス（ＫＫ－Ａｙ／ＴａＪｃｌ系統）を用いた。
順化終了日に測定した体重に基づいて、２０匹（体重範囲：２７．３～３２．２ｇ）を選択し、コンピュータを用いた完全無作為抽出法により各実験群の平均体重が等しくなるよう１０匹ずつ２群に割り当てた。
　各実験群について、調製例２で得られた投与液を投与した。各実験群における被験物質、その濃度、および１日（１回）当たりの投与液量を表１に示す。投与は、ディスポーザブルシリンジおよび経口ゾンデを用い、１日１回、２８日間（被験物質の投与開始日を1日目と起算）行った。投与期間中、マウスには調製例３で得た高脂肪飼料および上水道水を自由に摂取させ、１２時間明暗周期、２０～２６℃で飼育した。投与期間中は週２回体重を測定した。
Figure JPOXMLDOC01-appb-T000003
 Test Example 1: Animal test using adonixanthin-containing composition (administration solution) for high-fat diet-loaded KK-A y mice (weight measurement)
As experimental animals, 6-week-old male SPF mice (KK-A y / TaJcl strain) were used.
Based on the body weight measured at the end of acclimatization, 20 animals (weight range: 27.3-32.2 g) are selected, and the mean weight of each experimental group will be equal by complete random sampling using a computer Ten animals were assigned to two groups.
The administration solution obtained in Preparation Example 2 was administered to each experimental group. The test substance in each experimental group, the concentration thereof, and the dose per day (once) are shown in Table 1. The administration was performed once a day for 28 days (when the administration start date of the test substance was calculated from the first day) using a disposable syringe and an oral sound. During the administration period, the mice were allowed to freely consume the high-fat diet and tap water obtained in Preparation Example 3, and were reared at 20 to 26 ° C. with a 12-hour light-dark cycle. Body weight was measured twice weekly during the dosing period.
Figure JPOXMLDOC01-appb-T000003
　体重の測定結果を図１に示す。測定値は平均値で表した。図１に示される通り、アドニキサンチン投与群は、対照群と比較して体重増加を抑制する傾向を示した。 The measurement results of body weight are shown in FIG. The measured values were expressed as mean values. As shown in FIG. 1, the adonixanthin administration group showed a tendency to suppress weight gain as compared to the control group.
試験例２：アドニキサンチン含有組成物（投与液）およびアドニルビン含有組成物（投与液）を用い、高脂肪食負荷ＫＫ－Ａ ｙ マウスを対象とした動物試験（血中脂質および内臓脂肪測定）
　実験動物には、６週齢の雄のＳＰＦマウス（ＫＫ－Ａｙ／ＴａＪｃｌ系統）を用いた。
順化終了日に測定した体重に基づいて、３０匹（体重範囲：２７．３～３２．２ｇ）を選択し、コンピュータを用いた完全無作為抽出法により各実験群の平均体重が等しくなるよう１０匹ずつ３群に割り当てた。
　各実験群について、調製例２で得られた投与液を投与した。各実験群における被験物質、その濃度、および１日（１回）当たりの投与液量を表２に示す。投与は、ディスポーザブルシリンジおよび経口ゾンデを用い、１日１回、２８日間（被験物質の投与開始日を1日目と起算）行った。投与期間中、マウスには調製例３で得た高脂肪飼料および上水道水を自由に摂取させ、１２時間明暗周期、２０～２６℃で飼育した。
Figure JPOXMLDOC01-appb-T000004
 Test Example 2: Animal test for high-fat diet-loaded KK-A y mice using adonixanthin-containing composition (administration solution) and adonirubin-containing composition (administration solution) (measurement of blood lipid and visceral fat)
As experimental animals, 6-week-old male SPF mice (KK-A y / TaJcl strain) were used.
30 animals (weight range: 27.3-32.2 g) were selected based on the weight measured on the end of acclimatization, so that the mean weight of each experimental group would be equal by complete random sampling using a computer Ten animals were assigned to three groups.
The administration solution obtained in Preparation Example 2 was administered to each experimental group. The test substance in each experimental group, the concentration thereof, and the dose per day (once) are shown in Table 2. The administration was performed once a day for 28 days (when the administration start date of the test substance was calculated from the first day) using a disposable syringe and an oral sound. During the administration period, the mice were allowed to freely consume the high-fat diet and tap water obtained in Preparation Example 3, and were reared at 20 to 26 ° C. with a 12-hour light-dark cycle.
Figure JPOXMLDOC01-appb-T000004
　投与２８日目の夕方から絶食を行い、投与２９日目にエーテル麻酔下でマウスの腹部大動脈より、ヘパリン処理した注射筒を用いて全採血した。採取した血液は４℃、１５００×ｇで１５分間遠心して血漿を採取した。採取した血漿を用いて自動分析装置（7170形、株式会社日立製作所）によりトリグリセリド（FG消去法）、総コレステロール（CE・COD・POD法）およびLDLコレステロール（選択的可溶化法）を測定した。採血終了後、マウスの内臓脂肪（腸間膜脂肪）を採取して重量を測定した。 Fasting was performed on the evening of the 28th day of administration, and on the 29th day of administration, whole blood was collected from the abdominal aorta of the mouse under ether anesthesia using a heparinized syringe. The collected blood was centrifuged at 1500 × g for 15 minutes at 4 ° C. to collect plasma. Using collected blood plasma, triglyceride (FG elimination method), total cholesterol (CE. COD. POD method) and LDL cholesterol (selective solubilization method) were measured by an automatic analyzer (model 7170, Hitachi, Ltd.). After completion of blood collection, mouse visceral fat (mesenteric fat) was collected and weighed.
　測定結果を図２～４に示す。測定値は平均値±標準誤差で表した。ここで、対照群に対してのアドニキサンチン投与群またはアドニルビン投与群で２群間の検定を行った。２群間の検定は、Ｆ検定により分散に一様性が認められる場合にはStudent t検定を、分散に一様性が認められない場合にはAspin-Welch t検定を用いた。有意水準は５％または１％で表示した。（図中、*：P<0.05、**：P<0.01；対照群に対する有意差（Student t検定）、#：P<0.05；対照群に対する有意差（Aspin-Welch t検定））データの解析には、Office 2003およびOffice 2004（マイクロソフト株式会社）、SAS ver. 8.02（株式会社SASインスティチュートジャパン）、EXSAS ver. 7.14（株式会社サイエンティスト社）を使用した。 The measurement results are shown in FIGS. The measured values were expressed as mean ± standard error. Here, an assay between two groups was performed in the adonixanthin administration group or the adonirubin administration group relative to the control group. The test between the two groups used the Student t test when the variance showed uniformity, and the Aspin-Welch t test when the variance did not show uniformity. The significance level was displayed at 5% or 1%. (In the figure, *: P <0.05, **: P <0.01; significant difference from control group (Student t test), #: P <0.05; significant difference to control group (Aspin-Welch t test)) Data analysis For Office 2003 and Office 2004 (Microsoft Corporation), SAS ver. 8.02 (SAS Institute Japan Co., Ltd.) and EXSAS ver. 7.14 (Scientist Corporation) were used.
　図２は、血漿中のトリグリセリド濃度の測定結果を示す。図２に示される通り、アドニキサンチン投与群では、血漿中のトリグリセリド濃度が対照群と比較して有意に低減した。アドニルビン投与群でも、血漿中のトリグリセリド濃度が対照群と比較して低減した。
　図３は、血漿中の総コレステロール濃度の測定結果を示す。図３に示される通り、アドニルビン投与群では、血漿中の総コレステロール濃度が対照群と比較して有意に低減した。アドニキサンチン投与群でも、血漿中の総コレステロール濃度が対照群と比較して低減した。
　図４は、血漿中のＬＤＬコレステロール濃度の測定結果を示す。図４に示される通り、アドニルビン投与群では、血漿中のＬＤＬコレステロール濃度が対照群と比較して有意に低減した。アドニキサンチン投与群でも、血漿中のＬＤＬコレステロール濃度が対照群と比較して低減した。
　さらに、アドニキサンチン投与群およびアドニルビン投与群では、内臓脂肪量が対照群と比較して低減したことが確認された（対照群の内臓脂肪量の平均値：3.274g、アドニキサンチン投与群の内臓脂肪量の平均値：2.805g、アドニルビン投与群の内臓脂肪量の平均値：2.987g）。したがって、アドニキサンチンおよび／またはアドニルビンは内臓脂肪蓄積の抑制効果を有していると考えられた。 FIG. 2 shows the results of measurement of triglyceride concentration in plasma. As shown in FIG. 2, in the adonixanthin-administered group, the triglyceride concentration in the plasma was significantly reduced as compared to the control group. Also in the adonirubin administration group, the triglyceride concentration in plasma was reduced as compared with the control group.
FIG. 3 shows the measurement results of total cholesterol concentration in plasma. As shown in FIG. 3, in the adonirubin-administered group, the total cholesterol concentration in the plasma was significantly reduced as compared to the control group. Also in the adonixanthin administration group, the total cholesterol concentration in plasma was reduced as compared with the control group.
FIG. 4 shows the measurement results of LDL cholesterol concentration in plasma. As shown in FIG. 4, in the adonirubin-administered group, the LDL cholesterol concentration in the plasma was significantly reduced as compared to the control group. Also in the adonixanthin administration group, the LDL cholesterol concentration in the plasma was reduced as compared to the control group.
Furthermore, in the adonixanthin administration group and the adonirubin administration group, it was confirmed that the visceral fat content was reduced as compared to the control group (average visceral fat mass of the control group: 3.274 g, in the adonixanthin administration group) Average value of visceral fat mass: 2.805 g, average value of visceral fat mass of adonirubin administration group: 2.987 g). Therefore, adonixanthin and / or adonirubin were considered to have an inhibitory effect on visceral fat accumulation.

Claims (13)

  1. 　アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドを含んでなる、血中脂質の上昇抑制または低減用組成物。 A composition for suppressing or reducing blood lipids, comprising one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts.
  2. 　前記カロテノイドが、パラコッカス・カロティニファシエンス(Paracoccus carotinifaciens)由来である、請求項１に記載の組成物。 The composition according to claim 1, wherein the carotenoid is from Paracoccus carotinifaciens.
  3. 　前記血中脂質が、トリグリセリド、総コレステロール、およびＬＤＬコレステロールからなる群から選択される少なくとも一種である、請求項１または２に記載の組成物。 The composition according to claim 1 or 2, wherein the blood lipid is at least one selected from the group consisting of triglyceride, total cholesterol, and LDL cholesterol.
  4. 　脂質異常症の改善のための、請求項１～３のいずれか一項に記載の組成物。 A composition according to any one of claims 1 to 3 for the amelioration of dyslipidemia.
  5. 　前記脂質異常症が、高脂血症、高コレステロール血症、高トリグリセリド血症、および高ＬＤＬコレステロール血症からなる群から選択される少なくとも一種である、請求項４に記載の組成物。 The composition according to claim 4, wherein the dyslipidemia is at least one selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and hyper-LDL cholesterolemia.
  6. 　内臓脂肪の蓄積抑制または低減のための、請求項１～５のいずれか一項に記載の組成物。 The composition according to any one of claims 1 to 5, for the inhibition or reduction of visceral fat accumulation.
  7. 　肥満の改善または体重増加の抑制のための、請求項１～６のいずれか一項に記載の組成物。 The composition according to any one of claims 1 to 6, for the improvement of obesity or the suppression of weight gain.
  8. 　前記組成物が飲食品または食品添加物である、請求項１～７のいずれか一項に記載の組成物。 The composition according to any one of claims 1 to 7, wherein the composition is a food or drink or a food additive.
  9. 　前記組成物が機能性食品である、請求項１～８のいずれか一項に記載の組成物。 The composition according to any one of the preceding claims, wherein the composition is a functional food.
  10. 　前記組成物が医薬品である、請求項１～９のいずれか一項に記載の組成物。 The composition according to any one of the preceding claims, wherein said composition is a pharmaceutical.
  11. 　血中脂質の上昇抑制または低減用組成物の製造における、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの使用。 Use of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts in the manufacture of a composition for suppressing or reducing blood lipid elevation.
  12. 　アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイドの有効量を、それを必要とする対象に投与することまたは摂取させることを含んでなる、対象の血中脂質の低減または血中脂質の上昇の抑制方法。 Blood of a subject comprising administering to a subject in need thereof or ingesting an effective amount of one or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts A method of reducing middle lipid or suppressing elevation of blood lipid.
  13. 　血中脂質の上昇抑制または低減のための、アドニルビン、アドニキサンチンおよびそれらの薬学的に許容可能な塩から選択される一種以上のカロテノイド。 One or more carotenoids selected from adonirubin, adonixanthin and their pharmaceutically acceptable salts for the suppression or reduction of blood lipid elevation.
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WO2020095881A1 (en) * 2018-11-05 2020-05-14 Ｊｘｔｇエネルギー株式会社 Composition for increasing retention of carotenoid in blood
WO2021156145A1 (en) * 2020-02-03 2021-08-12 Dsm Ip Assets B.V. Adonirubin and dha for heart health

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