Classifications

• • 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)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/75—Rutaceae (Rue family)
  • A61K36/752—Citrus, e.g. lime, orange or lemon
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • 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
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• • 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
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• PPAR Peroxisome proliferator-activated receptor
• the present invention relates to a peroxisome proliferator-activated receptor (PPAR) activator, and a medicament, a supplement, a functional food and a food additive using the same.
• PPAR peroxisome proliferator-activated receptor
• TNF-fibrils and free fatty acids which inhibit glucose uptake in muscle cells and liver cells, as well as adiponectin, which promotes the action of insulin. It is suppressed, resulting in insulin resistance.
• PPAR which is a nuclear receptor
• PPARa is mainly expressed in liver cells, and is also expressed in cardiomyocytes and gastrointestinal tract cells, and is involved in fatty acid oxidation, ketone body formation, apolipoprotein formation, and the like.
• PPAR ⁇ has no tissue specificity and is expressed throughout the body, but is significantly expressed in colorectal cancer cells.
• PPAR y can be divided into two subtypes, ⁇ 1 and ⁇ 2, where y1 is expressed in adipose tissue, immune tissue, adrenal gland, and small intestine, and y2 is specific in adipocytes It plays an important role in the induction of adipocyte differentiation and lipogenesis.
• PPAR is greatly involved in improving insulin resistance. It is also said to be involved in improving insulin, type 2 diabetes, obesity, hypertension, hyperlipidemia and arteriosclerosis. From this point of view, PPAR-activating substances have been studied, for example, fibrates, thiazolidine derivatives, fatty acids, leukotriene B4, indomethacin, ibuprofen, phenoprofen, 15_deoxy_ ⁇ -12, 14-PGJ2 Synthetic PPAR activators are known. However, synthetic PPAR activators have the problem of side effects due to long-term ingestion and are not suitable for ingestion in daily life to prevent or ameliorate diseases such as insulin resistance.
• PPAR activators derived from natural ingredients such as curcumin contained in Japanese pepper, monoacylglycerol which is a kind of fat and oil, and catechins contained in tea etc. are reported as PPAR activators. (See, for example, Patent Document 1).
• PPAR activators derived from natural ingredients such as curcumin contained in Japanese pepper, monoacylglycerol which is a kind of fat and oil, and catechins contained in tea etc.
• the present invention has been made in view of such circumstances, and provides a PPAR activator that can be taken for a long period of time without the problem of side effects and has no problem even when added to foods or the like. , Its purpose.
• the PPAR activator of the present invention is characterized in that it contains ⁇ -thaliptoxanthine.
• the present inventors have conducted a series of studies on PPAR activators as natural components in order to solve the above-mentioned problems, and found that cryptoxanthin, which is abundantly contained in mandarin citrus fruits such as Unshu mandarin orange, is capable of The inventors have found that they have an effect, and have reached the present invention. That is, Satsuma mandarin orange containing a large amount of ⁇ cryptoxanthin has been consumed for many years, and its safety has been confirmed. In addition, ⁇ -cributoxanthin has a low caloric value, so that there is no problem even if a diabetic patient or an obese patient takes it for a long time.
• ⁇ -Taributan xanthine is tasteless and odorless and does not impair the flavor of the food even when added to foods, so it can be added to foods and taken daily for a long time. It will be possible. Therefore, according to the present invention, ⁇ -cributoxanthin activates PPAR, thereby promoting the burning of fat, suppressing the secretion of TNF_ and free fatty acids, and promoting the secretion of adiponectin. Can normalize adipocyte status, improve insulin resistance, and improve other symptoms such as hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis and obesity. These are effective not only for humans but also for other animals.
• FIG. 1 is a graph showing the PPAR ⁇ ligand activity of ⁇ cryptoxanthin in one example of the present invention.
• the PPAR activator of the present invention may contain other components such as other PPAR activators, in addition to j3-cryptoxanthin, in addition to the 3- / 3-tryptoxanthine. Is also good.
• the activated PPAR may be, for example, either PPAR ⁇ or PPAR ⁇ , but preferably both.
• PPAR activator of the present invention for example, minute ⁇ system of TNF alpha and free fatty acids in adipocytes, the secretion of adiponectin in adipocytes It has at least one action such as promotion and promotion of fat oxidation in liver cells. Further, the PPAR activator of the present invention has, for example, an action of inducing at least one of apoptosis, differentiation and miniaturization of adipocytes.
• the ⁇ -cributoxanthin used is not particularly limited, and may be, for example, those derived from citrus, persimmon, papaya, vegetation, and red pepper. is there. Among them, citrus is more preferred and is preferably derived from mandarin citrus
• ⁇ -cributoxanthin may be, for example, one isolated and purified from the above-mentioned citrus fruits, or a commercially available product.
• the medicament of the present invention comprises, for example, at least one disease selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis and obesity.
• a medicament for preventing or treating the above which comprises the above-mentioned PPAR activator of the present invention.
• the medicament of the present invention may contain, for example, other PPAR activators and various additives in addition to the PPAR activator of the present invention.
• specific dosage forms include, for example, tablets, fine granules (including powders), capsules and liquids (including syrups).
• the medicament of the present invention can be produced according to a usual method described in the Japanese Pharmacopoeia and the like, by appropriately using a carotenoid and a base material suitable for each dosage form.
• the route of administration is not particularly limited, and includes, for example, oral administration and parenteral administration, and the parenteral administration includes, for example, oral administration, intratracheal administration, rectal administration, subcutaneous administration, and intramuscular administration. And intravenous administration.
• the supplement of the present invention comprises, for example, at least one supplement selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis, and obesity.
• a supplement for preventing or ameliorating a disease the supplement comprising the activator of the present invention.
• the supplement of the present invention may contain, for example, other PPAR activators, various additives, and other supplements in addition to the PPAR activator of the present invention. Examples include various vitamins such as C, amino acids, and oligosaccharides.
• the form of the supplement of the present invention is not particularly limited, and examples thereof include tablets, fine granules (including powders), capsules and liquids (including syrups).
• the functional food of the present invention comprises at least one disease selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis and obesity.
• the functional food of the present invention may contain, for example, other PPAR activators and various additives in addition to the PPAR activator of the present invention.
• the form of the functional food of the present invention is not particularly limited, and includes, for example, foods, confectioneries, functional drinks, and the like.
• the food additive of the present invention comprises at least one disease selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis, and obesity. It is a food additive for preventing or ameliorating the disease, which is the food additive containing the PPAR activator of the present invention.
• the food additive of the present invention may contain, for example, other PPAR activators and various additives in addition to the PPAR activator of the present invention.
• the form of the food additive of the present invention is not particularly limited, and examples thereof include a liquid, a paste, a powder, a flake, and a granule. Further, the food additive of the present invention includes, for example, for beverages.
• the PPAR activation method of the present invention is, for example, a method comprising bringing ⁇ -cryptoxanthin into contact with fat cells, liver cells and the like.
• the method of activating PPAR of the present invention has, for example, at least one effect such as suppression of secretion of TNF-a and free fatty acids in fat cells, promotion of secretion of adiponectin in fat cells, and promotion of oxidation of fat in liver cells.
• the PPAR activation method of the present invention is, for example, a method for inducing at least one of apoptosis, differentiation and miniaturization of adipocytes.
• the 3 / 3-cributoxanthin used is the same as that used for the PPAR activator of the present invention, for example, citrus, persimmon, papaya, beetle and the like. It is derived from red peppers. Among them, citrus fruits are more preferably derived from mandarin citrus fruits, and particularly preferably derived from Unshu mandarin orange. The raw material can be, for example, whole fruits, and it is particularly preferable to use pulp.
• the method for preventing, treating or ameliorating a disease of the present invention relates to a method for treating insulin, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis and obesity in mammals.
• a method for preventing, treating or ameliorating at least one disease selected from the group consisting of administering ⁇ -cributoxanthin examples include a human, a mouse, a rat, a rabbit, a dog, a cat, a rabbit, a pig, a pig, a monkey, and the like.
• the kit of the present invention comprises at least one disease selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis and obesity.
• a kit for prevention or treatment comprises at least one disease selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis and obesity.
• a second pharmaceutical composition comprising:
• a kit comprising a container for containing the ⁇ cryptoxanthin and the second pharmaceutical composition.
• the use of the present invention may be at least one selected from the group consisting of insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis, and obesity of the present invention in mammals. And the use of cryptoxanthin for the prevention, treatment or amelioration of two diseases.
• the mammal is as described above.
• ⁇ -cributoxanthin in the present invention is preferably produced from citrus fruits as described above.
• An example of this manufacturing method Japanese Patent No. 3359298, is shown below.
• the production of ⁇ -cributoxanthin from citrus fruits can be carried out by a method including the following steps (1) to (4).
• Citrus fruits are squeezed and filtered or sieved.
• Examples of the citrus used in the production method include Unshu mandarin orange, Iyo citrus, summer mikan, Hassaku, bonkan, navel orange, lemon, Valencia orange, grapefruit, and the like.
• Mandarin citrus with a large amount is preferred, more preferably Unshu Mandarin orange.
• the whole citrus fruit can be used as a raw material, but it is particularly preferable to use pulp.
• the citrus fruits are usually squeezed after sorting and washing.
• the juice extractor include an in-line juice extractor, a chopper pulper extractor, and a brown juice extractor.
• the juice obtained is usually contaminated with small pieces of carcinoma skin and coarse pulp, and is filtered or sifted to remove these.
• a paddle type or screw type finisher can be used, and the size of the screen is, for example, 0.3 to 0.5 mm.
• the juice is treated by centrifugation.
• This centrifugation treatment includes light centrifugation and heavy centrifugation under the following conditions.
• the light centrifugation means a level of centrifugation capable of separating large particles of pulp.
• the heavy centrifugation refers to centrifugation at a level at which small particles of pulp can be centrifuged.
• the centrifugal strength of the light centrifugation is, for example, 3000 X g.min or less, and the centrifugal strength of the heavy centrifugation is, for example, 1500 X g- Min, and set the centrifugal strength for light centrifugation to be lower than that for heavy centrifugation.
• the squeezed juice is subjected to light centrifugation, and the supernatant is further subjected to heavy centrifugation to collect a precipitate.
• a solubilized enzyme is added to the precipitate obtained by the heavy centrifugation.
• the solubilizing enzyme for example, actinase, cellulase, hemicellulase, protease, lipase, maceration enzyme, protease, and the like can be used. These enzymes may be used alone or in combination of two or more.
• the addition ratio of the solubilized enzyme is in the range of 0.5 to 10 g per 1 kg of the precipitate.
• the precipitate to which the solubilized enzyme has been added is filled in a container, and frozen without heating. Subsequently, the frozen precipitate is thawed. Thawing may be left at room temperature. The thawed precipitate is subjected to solid-liquid separation and dehydrated by centrifugation to obtain a solid (sediment). This solid content contains a high concentration of ⁇ -cributoxanthin. By repeating the operation of adding purified water to the solid content and centrifuging the solid content, the concentration of the cryptoxanthin in the solid content can be further improved.
• CV-1 cells (cultured cells derived from male African midori kidney kidney) were inoculated into a 24-well culture plate at a concentration of 0.2 zg / well at 37 ° C and 5% CO 2. The cells were cultured under the following conditions for 24 hours.
• DMEM Dulbecco's Modified Eagle Medium: GIBCO
• FBS ⁇ fetal serum
• penicillin'streptomycin solution was used as a medium.
• pM-hPPARy and p4XUASg-tk-luc were transfected into cultured CV-1 cells using a lipofectamine system (Invitrogen).
• the activity of PPARy was improved by ⁇ -tallipoxanthin, and the activity was increased as the concentration of ⁇ -cributoxanthin was increased.
• the PPAR activator of the present invention has excellent PPAR activity, can be taken for a long period of time without any problem of side effects, and can be preferably used for foods and the like. Therefore, the PPAR activator of the present invention is useful for preventing or preventing diseases such as insulin resistance, hyperinsulinemia, type 2 diabetes, hypertension, hyperlipidemia, arteriosclerosis and obesity. Can be used as medicines, supplements, functional foods and food additives for improvement. These are effective not only for humans but also for other animals.

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• 2005
  • 2005-05-20 WO PCT/JP2005/009258 patent/WO2005112904A1/ja not_active Ceased
  • 2005-05-20 CN CN2005800160315A patent/CN1956711B/zh not_active Expired - Lifetime
  • 2005-05-20 JP JP2006513743A patent/JPWO2005112904A1/ja active Pending
  • 2005-05-20 US US11/569,381 patent/US20070218147A1/en not_active Abandoned
  • 2005-05-20 EP EP05741624A patent/EP1772143A4/en not_active Ceased
• 2012
  • 2012-06-22 JP JP2012140693A patent/JP2012214488A/ja active Pending
• 2014
  • 2014-03-31 JP JP2014073014A patent/JP2014122247A/ja active Pending

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