JP2017066052A - Agent for inhibiting production of advanced glycation end product - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an agent for inhibiting the production of advanced glycation end products.SOLUTION: The present invention provides an agent for inhibiting the production of advanced glycation end products comprising a quercetin derivative as an active ingredient. The quercetin derivative has an action to inhibit the production of advanced glycation end products and therefore is suitably used for prevention of and/or treatment of diabetes or diabetic complication, and prevention of and/or treatment of skin aging.SELECTED DRAWING: None

Description

  The present invention relates to a terminal glycation product production inhibitor containing a specific quercetin derivative as an active ingredient. The present invention also relates to a pharmaceutical composition for preventing and / or treating diabetes or diabetic complications, which contains a specific quercetin derivative as an active ingredient. Furthermore, this invention relates to the pharmaceutical composition for non-human animals which contains a specific quercetin derivative as an active ingredient. In addition, the present invention relates to an external preparation for skin for preventing and / or improving skin aging, which contains a specific quercetin derivative as an active ingredient.

  The phenomenon of browning when a mixture of amino acid and reducing sugar is heated is generally called the Maillard reaction, and is known in the food field as a phenomenon that occurs during heat treatment and storage of food. The Maillard reaction also occurs in vivo, and it was clear that glycosylation hemoglobin (HbA1c) was identified in vivo in 1968, leading to the progress of protein glycation with the progress of diabetes and aging. It was done. In recent years, advanced glycation end products (hereinafter also referred to as “AGEs”) in protein glycation reactions have been reported to be involved in the onset of lifestyle-related diseases such as diabetic complications and arteriosclerosis and the progression of aging. (Non-Patent Documents 1 to 3).

  The details of the protein saccharification reaction in vivo are not clear, but the amino group present in the protein reacts with the aldehyde group present in the reducing sugar to form a Schiff base, which then passes through a stable Amadori compound. It is believed that the transition to AGEs will occur after a long-term reaction.

  AGEs do not refer to specific substances, and the whole of them has not yet been elucidated, but the presence of various substances such as pentosidine, pyropyridine, and pyralin has been confirmed depending on the presence of fluorescence and cross-linking structure. The physicochemical characteristics of AGEs include yellowish brown and fluorescence (mainly Ex: 370 nm, Em: 440 nm) and the formation of crosslinks between proteins. However, AGEs that do not show fluorescence like pyralin and do not have a crosslinked structure have also been confirmed.

  The accumulation of these AGEs is not only due to diabetic complications such as glomerular tissue sclerosis and renal arteriosclerosis, but also neurodegenerative diseases such as Alzheimer's disease, skin aging such as reduced skin elasticity and yellowing, It is reported to be deeply involved in aging, ocular aging, and albumin protein aging (Non-patent Documents 4 and 5).

  Therefore, blocking the glycation reaction in the living body is expected to have an effect of preventing the onset and progression of diseases such as diabetic complications, arteriosclerosis, osteoporosis, and osteoarthritis. In addition, inhibition of the saccharification reaction is expected to be effective in preventing and improving skin elasticity and yellowing. For this reason, various saccharification reaction inhibitors and AGEs production inhibitors have been developed and studied.

  Patent Document 1 discloses a Maillard reaction inhibitor containing a compound such as aminoguanidine. Aminoguanidine is a substance exhibiting an anti-glycation effect that has been most studied in the development of pharmaceuticals in this technical field, but has been confirmed to have side effects such as liver damage and has not yet been put into practical use.

  In addition, the Maillard reaction inhibitor by the extract of plants, such as a ganbei tree and a birch described in patent document 2, etc. are known, but problems remain in terms of effectiveness and safety.

  Therefore, there is a demand for highly safe drugs that can suppress the generation of AGEs involved in the onset and worsening of various diseases and skin aging, and that have no serious side effects.

Japanese Examined Patent Publication No. 6-67827 JP 2005-035911 A

The Journal of Clinical Investigation, 1993, vol.91, pp.2470-2478 The New England Journal of Medicine, 1991, vol.325, pp.836-842 The Biochemical Journal, 2000, vol.350, pp.381-387 New Food Industry, 2011, vol.53, No.6 Fragrance Journal, 2012, vol.40, No.4, pp.32-34

  An object of this invention is to provide the AGEs production inhibitor with few side effects. The present invention is also useful for the prevention and / or treatment of lifestyle-related diseases, particularly diabetes or diabetic complications, and has few side effects, as well as prevention of skin aging, particularly skin elasticity loss and yellowing. An object is to provide an external preparation for skin that is useful for improvement and / or has few side effects.

  The inventors of the present invention have tried to screen from a plant that is a natural product and has a dietary experience with respect to a substance having an excellent anti-glycation effect and few side effects, and as a result of examining the plant extract and its components, a specific quercetin derivative Thus, the present invention was completed.

[式中のＲ_１およびＲ_２は、水素原子、水酸基、または単糖類、二糖類もしくは糖アルコールの糖残基を示し、Ｒ_３は水酸基または単糖類、二糖類もしくは糖アルコールの糖残基を示す。但し、Ｒ_１＝Ｒ_２＝水素原子、かつＲ_３＝水酸基である化合物は除く。]（以下、単に「ケルセチン誘導体」とも称する）を有効成分として含有する終末糖化産物生成抑制剤（以下、「本発明のＡＧＥｓ生成抑制剤」とも称する）を提供する。 That is, the present invention provides a quercetin derivative represented by the formula (1):

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide or sugar alcohol, and R ₃ represents a hydroxyl group or a sugar residue of a monosaccharide, disaccharide or sugar alcohol. Show. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ] (Hereinafter also referred to simply as “quercetin derivative”) as an active ingredient, a terminal glycation product production inhibitor (hereinafter also referred to as “AGEs production inhibitor of the present invention”) is provided.

  The present invention also includes a pharmaceutical composition for preventing and / or treating diabetes or diabetic complications containing a quercetin derivative as an active ingredient (hereinafter also referred to as “the pharmaceutical composition for preventing / treating diabetes of the present invention”). I will provide a.

  The present invention further provides a non-human animal pharmaceutical composition comprising a quercetin derivative as an active ingredient for the prevention and / or treatment of diabetes or diabetic complications in a non-human animal, the quercetin derivative being administered to a non-human animal. Including a method for preventing and / or treating diabetes or diabetic complications in a non-human animal, a method for producing a functional food or drink characterized by adding or adding a quercetin derivative to a food or drink, and a quercetin derivative and a carrier A composition for oral consumption is provided.

  The present invention further provides a skin external preparation for preventing and / or improving skin aging containing a quercetin derivative as an active ingredient (hereinafter also referred to as “the skin external preparation for skin aging prevention / amelioration of the present invention”). To do.

  AGEs are substances that have been suggested to be associated with various lifestyle-related diseases and skin aging, and in particular, the onset and / or progression of diabetes and its complications, as well as the occurrence of reduced skin elasticity and skin yellowing. And / or are deeply involved in progression. Therefore, the quercetin derivative, which has been found to have an action of suppressing the generation of AGEs by the present inventors, is a pharmaceutical composition for prevention and / or treatment of diabetes or diabetic complications, or skin elasticity reduction or yellowing. It is useful as an active ingredient with few side effects in an external preparation for skin for preventing and / or improving skin aging.

  The AGEs production inhibitor, the pharmaceutical composition for preventing / treating diabetes, the pharmaceutical composition for non-human animals, and the external preparation for skin aging prevention / amelioration of the present invention contain a quercetin derivative as an active ingredient.

  The quercetin derivative, which is an active ingredient of the AGEs production inhibitor of the present invention, may be a synthetic product or may be extracted and isolated from a plant.

  In the present specification and claims, the quercetin derivative represented by formula (1) includes both a single compound and a plurality of mixtures.

  When a quercetin derivative is extracted and isolated from a plant, the plant that can be used as a raw material is not limited, and examples thereof include onion (Allium cepa), African marigold (Tagetes erecta), Asian cotton (Gossypium herbaceum), Gerbera (Gerbera jamesonii), Hibiscus vitifolius, etc. are mentioned. In one embodiment, when 6-hydroxyquercetin, which is an active ingredient of the AGEs production inhibitor of the present invention, is extracted and isolated from a plant, it is preferable to use African marigold, and 8-hydroxyquercetin is extracted from the plant. In the case of isolation, Hibiscus vitifolius is preferably used, and when quercetin-4′-glucoside is extracted from a plant and isolated, onion is preferably used.

  The plant used as the raw material for extraction may be in the flowering period or in the vegetative period, and may be in the raw state or dried. Further, in order to increase the extraction efficiency, a plant body that has been appropriately shredded or pulverized, for example, a powdered one, may be used as an extraction raw material. Regarding the plant part used as a raw material, any of flowers, leaves, stems, roots, or whole plants containing these may be used as an extraction raw material.

  In the case of extracting a quercetin derivative, which is an active ingredient of the AGEs production inhibitor of the present invention, a pharmaceutical composition for preventing / treating diabetes, a pharmaceutical composition for non-human animals, and a skin external agent for preventing / ameliorating skin aging, Any plant component extraction method can be used. Examples of the extraction method include a hot water extraction method, a boiling extraction method, a soaking extraction method, a shaking extraction method, a Soxhlet extraction method, and a steam distillation method.

  Extraction solvents include water, lower alcohols such as methanol and ethanol, polyhydric alcohols such as propylene glycol and 1,3-butylene glycol, ketones such as acetone, esters such as diethyl ether, acetonitrile, and ethyl acetate. These may be selected in consideration of the type of plant used as an extraction raw material, the processing to be performed later, the purpose of use of the extract, and the like. In one embodiment, methanol is used. In addition, in the case where it is not preferable to contain an organic solvent because the extract is used for food use etc., it is sufficient to use only water, ethanol alone that can be easily removed after extraction, or a mixture of water in any proportion with water. May be used as In one embodiment, the preferred extraction solvent is water or ethanol.

  The use amount of the extraction solvent is preferably from 1: 2 to 1:30 (plant raw material: extraction solvent), more preferably from 1: 3 to 1:25, and even more preferably from 1: 4 to 1:20 by weight.

  The extraction temperature may be appropriately determined depending on each solvent, but in the case of water extraction, it is preferably 4 to 130 ° C, more preferably 25 to 110 ° C, and further preferably 40 to 100 ° C. When the extraction temperature is less than 4 ° C, the active ingredient tends to be difficult to extract, and when it exceeds 130 ° C, the active ingredient tends to be easily decomposed. In the case of ethanol extraction, the extraction temperature is preferably 4 to 100 ° C, more preferably 10 to 80 ° C, further preferably 20 to 60 ° C. When the extraction temperature is less than 4 ° C., the active ingredient tends to be difficult to extract, and when it exceeds 100 ° C., the active ingredient tends to be easily decomposed.

  In the case of water extraction, the extraction time is preferably 1 minute to 15 days, more preferably 3 minutes to 1 day, and further preferably 5 minutes to 1 hour. When the extraction time is less than 1 minute, the active ingredient tends to be difficult to extract, and when it exceeds 15 days, the active ingredient tends to be easily decomposed. In the case of ethanol extraction, 1 hour to 15 days is preferable, 12 hours to 10 days is more preferable, and 1 to 8 days is more preferable. When the extraction time is less than 1 hour, the active ingredient tends to be difficult to extract, and when it exceeds 15 days, the active ingredient tends to be easily decomposed.

  In the present specification, the term “extract” includes an extract obtained by various extraction methods using a solvent, a concentrated solution obtained by concentrating the extract, a diluted solution obtained by diluting the extract with an appropriate solvent, and the extraction. Solid extract (for example, powdered or granular) obtained by removing the solvent from the liquid or its concentrated or diluted liquid by various methods such as heat drying, vacuum drying, freeze drying, etc., and solidifying agent or gel A solid or semi-solid extract obtained by addition of an agent is included.

  As an example of the extraction method, (1) 2 to 30 parts by weight, preferably 3 to 25 parts by weight of water is added to 1 part by weight of the plant material, and the mixture is allowed to stand at 40 to 90 ° C. for 10 to 120 minutes. Alternatively, a method of boiling at 100 ° C. for 5 to 15 minutes, or (2) 2 to 30 parts by weight, preferably 3 to 25 parts by weight of ethanol is added to 1 part by weight of the plant material, and 12 to 10 to 80 ° C. The method of leaving still for 10 days from time, Preferably leaving still at 20-60 degreeC for 1-8 days etc. are mentioned.

  If desired, the extract obtained from the raw material plant may be subjected to a purification treatment before the operation of isolating the quercetin derivative. As the purification treatment, for example, a chromatographic method, an elution method using an ion exchange resin, partition extraction with a solvent, or the like can be employed alone or in combination. Examples of chromatographic methods include normal phase chromatography, reverse phase chromatography, adsorption chromatography, thin phase chromatography, centrifugal liquid chromatography, high performance liquid chromatography, etc., any of these or a combination thereof. The method to perform is mentioned. Solvents that can be used for partition extraction include ethyl acetate, hexane, 1-butanol and the like. In one embodiment, after the crude onion extract is subjected to adsorption chromatography, water, water: methanol = 1: 1 solution, methanol is passed through in this order, and the purified extract recovered in the methanol fraction is: EFFECT OF THE AGE GENERATION INHIBITOR OF THE INVENTION, PHARMACEUTICAL COMPOSITION FOR PREVENTION AND / OR TREATMENT OF DIABETIC OR DIABETIC COMPOUND, PHARMACEUTICAL COMPOSITION FOR NON-HUMAN Veterinary, AND EFFECT OF EXTERNAL SKIN It contains abundant quercetin-4′-glucoside as a component.

  The AGEs production inhibitor of the present invention only needs to contain a quercetin derivative as an active ingredient, and may further contain an excipient or the like as long as the AGEs production inhibitory effect of the quercetin derivative is not hindered.

  The ratio of the quercetin derivative in the AGE production inhibitor of the present invention is not particularly limited. For example, the AGEs production inhibitor of the present invention contains a quercetin derivative in an amount of 40% by weight, 45% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 85% by weight, 90% It may contain at least 95% by weight, 95% by weight or 98% by weight. Or the AGEs production | generation inhibitor of this invention may consist only of a quercetin derivative.

  The AGEs production inhibitor of the present invention can suppress the production of fluorescent AGEs such as pentosidine, croslin, pyropyridine, glyoxal-derived lysine dimer (GOLD), and methylglyoxal-derived lysine dimer (MOLD). In one embodiment, the AGEs production inhibitor of the present invention is used for inhibiting the production of pentosidine, which is a fluorescent AGE.

  The pharmaceutical composition for preventing / treating diabetes and the external preparation for skin aging prevention / amelioration of the present invention contain a quercetin derivative as an active ingredient, like the AGEs production inhibitor of the present invention.

  The amount of the quercetin derivative contained as an active ingredient in the pharmaceutical composition for preventing / treating diabetes according to the present invention can be appropriately set according to the intended dosage form and the like, but is usually about 1 to 98% by weight. What is necessary is just about 2-95 weight%, and it is more preferable that it is about 3-90 weight%.

  As used herein, “treatment” of diabetes or diabetic complications includes preventing the progression of symptoms in a patient already suffering from diabetes or diabetic complications.

  The method for administering the pharmaceutical composition for preventing / treating diabetes of the present invention may be either oral administration or parenteral administration. The administration time is not particularly limited and may be any of before, during, after, and between meals. For example, a meal having a saccharide content of 5 g or more, or an amino acid and / or protein content of 20 g or more. It is preferably administered before meal, during meal, after meal and between meals, and before meal, during meal, after meal and between meals of meal containing sugar and amino acid and / or protein above the above content. More preferably it is administered. Examples of the amino acid include lysine, arginine, and the like. Among them, lysine and / or arginine, which is easily converted to AGEs, is preferably administered before, during, after, and between meals. Examples of the protein include ovalbumin, milk albumin, gliadin, milk casein, soybean casein, and the like. Among them, one or more selected from ovalbumin, milk albumin, and milk casein which are easily converted to AGEs are contained in the above content. It is preferably administered before, during, after and between meals. Here, “meal” generally means eating (drinking action) or eating or drinking food as a daily habit for taking the nutrients necessary for survival, but “meal” as used herein. The term "" means a set of food and drink taken in a single eating and drinking act.

  As used herein, “saccharides” shall mean monosaccharides and / or disaccharides. On the other hand, “sugar” refers to carbohydrates other than dietary fiber, and includes oligosaccharides, polysaccharides, sugar alcohols and the like in addition to sugars.

  The dosage of the pharmaceutical composition for preventing / treating diabetes according to the present invention is appropriately selected according to conditions such as the degree of diabetes or its complications, the degree of other diseases, age, and sex, but suppresses the generation of AGEs. A quercetin derivative in an amount that can be used (hereinafter also referred to as an “AGEs suppression effective amount”) may be administered. An effective amount for inhibiting the generation of AGEs can be appropriately determined using methods well known to those skilled in the art (including various non-clinical and / or clinical trials).

  The pharmaceutical composition for preventing / treating diabetes according to the present invention may be one in which an effective amount of a quercetin derivative is administered at once, or may be administered in multiple portions at intervals. . When administered in multiple doses, the total amount of quercetin derivatives administered per day may be an effective amount for inhibiting the generation of AGEs and is preferably administered according to the number of meals.

  The pharmaceutical composition for preventing / treating diabetes according to the present invention can be administered to either a person suffering from diabetes or diabetic complications or a healthy person, but suffering from diabetes having a high association with AGEs. It is preferably administered to a person. A person suffering from diabetes refers to a person whose hemoglobin A1c is 6.1% (JDS value) or more and falls under any of the following (1) to (3): (1) Fasting blood glucose level 126 mg / dL or more, (2) Adequate blood glucose level (whether fasting or after eating) is 200 mg / dL or more, and (3) 2 hours after glucose loading is 200 mg / dL or more. Details of the diagnostic criteria for diabetes are described in the “Report of the Committee on Diabetes Classification and Diagnostic Criteria” by the Japanese Diabetes Association (available from the association's website).

  Further, the pharmaceutical composition for preventing / treating diabetes of the present invention comprises diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic vascular complications, arteriosclerosis, renal failure, Alzheimer's disease, neurodegeneration, which develops with diabetes. It can be used for the prevention and / or treatment of diabetic complications such as diseases and cancer. Among these diabetic complications, it is preferably used for the prevention and / or treatment of diabetic retinopathy, diabetic nephropathy and / or diabetic neuropathy with a high incidence.

  Furthermore, diabetes and its complications can be effectively prevented by administering the pharmaceutical composition for preventing / treating diabetes of the present invention to healthy individuals.

  The pharmaceutical composition for preventing / treating diabetes according to the present invention has excipients, stabilizers, storages, in addition to the quercetin derivative, as long as the effect of preventing and / or treating diabetes or diabetic complications by the quercetin derivative is not hindered. Ingredients added to general pharmaceuticals such as agents, buffers, flavoring agents, suspending agents, emulsifiers, flavoring agents, solubilizing agents, coloring agents, thickeners, etc. are added to form various dosage forms be able to.

  Examples of the dosage form of the pharmaceutical composition for prevention / treatment of diabetes of the present invention include tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets), capsules, granules (expanded granules), powders, Oral solution (elixir, suspension, emulsion, limonade), syrup (syrup), oral jelly, oral tablet (troche, sublingual, buccal, adhesive tablet, gum), oral Spray, oral semi-solid preparation, mouthwash, injection (infusion solution, implantable injection, continuous injection), dialysis agent (peritoneal dialysis agent, hemodialysis agent), inhalant (inhalation powder) , Inhalants, aerosols), suppositories, rectal semisolids, enemas, eye drops, eye ointments, ear drops, nasal drops (nasal powders, nasal drops), vaginal tablets, Vaginal suppository, external solid preparation (external powder), external liquid (liniment, lotion), spray (External aerosols, pump sprays), ointments, creams, gels, patches (tape, cataplasms), and the like. Among these, tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, oral tablets, oral sprays, oral semisolids and mouthwashes are easy to administer. From the viewpoint of being easily absorbed in the living body, tablets, capsules, granules, and powders are more preferable.

  Further, the pharmaceutical composition for preventing / treating diabetes of the present invention can be applied to herbal medicine-related preparations such as extracts, pills, spirits, soaking agents, decoction, teas, tinctures, fragrances, and flow extracts. It can also be used in a dosage form to which an AGEs production inhibitor is added. These dosage forms are appropriately selected according to conditions such as the degree of diabetes or its complications, the degree of other diseases, age, and sex.

  Furthermore, the pharmaceutical composition for preventing / treating diabetes according to the present invention may further contain other drugs having an AGEs production inhibitory effect. Examples of these drugs include insulin resistance improving drugs, dyslipidemic drugs, angiotensin II type 1 receptor antagonists, angiotensin converting enzyme inhibitors, metformin, and the like.

  The AGEs production inhibitor of the present invention or a quercetin derivative that is an active ingredient thereof can also be used to prevent and / or treat diabetes or diabetic complications in non-human animals. Therefore, in one embodiment of the present invention, a non-human animal pharmaceutical composition comprising a quercetin derivative for preventing and / or treating diabetes or diabetic complications in a non-human animal (hereinafter referred to as the non-human animal pharmaceutical of the present invention). Also referred to as a composition). Also provided is a method for preventing and / or treating diabetes or diabetic complications in a non-human animal comprising administering a quercetin derivative to the non-human animal. Examples of non-human animals include livestock such as cows, horses, pigs, sheep, goats and chickens, and animals raised as pets such as dogs and cats.

  The amount of the quercetin derivative to be contained in the pharmaceutical composition for non-human animals of the present invention, the method of administering the pharmaceutical composition, the timing of administration, the dosage and the dosage form, other drugs that can be used in combination with the quercetin derivative in the pharmaceutical composition, Regarding the administration method, administration time, dosage, etc. in the case of administering the natural product and the naturally-derived substance and the AGEs production inhibitor of the present invention to a non-human animal, the “pharmaceutical composition for diabetes prevention / treatment of the present invention” This is the same as described above. Or you may mix and administer the pharmaceutical composition for non-human animals of this invention in feed or drinking water.

  Moreover, the AGEs production | generation inhibitor of this invention can also be used as a food additive. By adding or adding a quercetin derivative to a food or drink, a functional food or drink that suppresses the generation of AGEs can be provided. In addition, a composition for oral consumption containing a quercetin derivative and a carrier can be used as a supplement that suppresses the generation of AGEs. In the present application, “carrier” means a physiologically acceptable medium capable of dissolving or suspending a quercetin derivative for producing a liquid preparation or an excipient for producing a solid preparation. The carrier may be appropriately selected from components that are usually used in the production of pharmaceuticals and supplements according to the dosage form of the composition. In addition to the carrier, the composition contains a stabilizer, a preservative, a buffering agent, a corrigent, a suspending agent, an emulsifier, a flavoring agent, a solubilizing agent, a colorant, a viscous agent, as long as it does not interfere with the AGEs formation inhibiting action You may add the component normally used for pharmaceuticals and supplements, such as an agent.

  The total amount of the quercetin derivative to be contained in the composition for oral consumption of the present invention can be appropriately set according to the target dosage form and the like, but is usually about 1 to 98% by weight. It is preferably about 95% by weight, and more preferably about 3 to 90% by weight.

  As the dosage form of the composition for oral intake, any of those listed above as dosage forms of the pharmaceutical composition may be used as long as it can be taken orally, and tablets, capsules, granules, powders, oral liquids, Syrups, oral jelly preparations, oral tablets, oral sprays, oral semisolid preparations and gargles are preferred, and tablets, capsules, granules and powders are more preferred in that they are easily absorbed in vivo.

  The composition for oral intake of the present invention can be ingested as a supplement intended to maintain health. The ingestion method, ingestion time, ingestion amount and the like of the composition for oral intake are the same as those described above for the “pharmaceutical composition for prevention / treatment of diabetes of the present invention” as the administration method, administration time, dosage and the like.

  Furthermore, the quercetin derivative can also be used as an active ingredient of an external preparation for skin for preventing / improving skin aging. The amount of the quercetin derivative contained in the skin external preparation for skin aging prevention / improvement according to the present invention can be appropriately set according to the intended dosage form and the like, but is usually about 0.01 to 20% by weight. What is necessary is just about 0.05 to 15 weight%, and it is more preferable that it is about 0.1 to 10 weight%.

  The applied amount of the external preparation for skin aging prevention / improvement of the present invention to the skin is appropriately selected according to conditions such as the degree of skin aging, the degree of other skin troubles, age, and sex, but the generation of AGEs It is sufficient to apply an amount that can suppress the amount (AGEs generation suppression effective amount). An effective amount for inhibiting the generation of AGEs can be appropriately determined using methods well known to those skilled in the art (including various non-clinical and / or clinical trials).

  The skin external preparation for skin aging prevention / improvement according to the present invention may be one in which an AGEs production-inhibiting effective amount of quercetin derivative may be applied at once, or may be applied multiple times at intervals. good. In the case where it is applied in a plurality of times, the total amount of quercetin derivatives applied in one day may be an effective AGE generation suppression amount.

  The skin external preparation for skin aging prevention / improvement of the present invention can effectively prevent skin aging, for example, skin elasticity reduction or yellowing, by applying to the skin by a method such as application. It can improve skin aging or prevent the progression of skin aging.

  The skin external preparation for skin aging prevention / improvement of the present invention has a stabilizer, preservative, buffer, oxidation, in addition to the quercetin derivative, as long as the effect of preventing and / or improving skin aging by the quercetin derivative is not disturbed. Components such as an inhibitor, a suspending agent, a surfactant, a solubilizing agent, a colorant, a thickener, and a fragrance can be added to form various dosage forms.

  The skin external preparation for preventing / ameliorating skin aging according to the present invention may be a cosmetic or a pharmaceutical composition. The cosmetics can be usually provided as cosmetics or quasi drugs.

  The form of the external preparation for skin aging prevention / improvement of the present invention includes basic cosmetics such as milky lotion, cosmetic liquid, lotion, pack, cream and hand cream, makeup makeup such as foundation, makeup base, lip balm and lipstick. Cosmetics, facial cleansers, soaps, makeup removers, body cosmetics such as body shampoos, hair cosmetics such as hair nicks and hair lotions, and bath preparations.

  In addition, the pharmaceutical composition for preventing / treating diabetes, the pharmaceutical composition for non-human animals, the food additive, and the external preparation for skin aging prevention / amelioration of the present invention are natural products or naturally derived substances having an AGEs production inhibitory effect. It can also be included. Examples of these natural products or naturally-derived substances include herbs such as dokudami, hawthorn, chamomile, grape leaves, cherry blossoms, corn stigma and stigmas, plantain seeds, maronier, peonies, rose flowers, plum fruit , Mountain grape, purple chrysanthemum flower, wheat germ, wheat germ-derived polyamine, mangosteen and the like.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these description.

Example 1
Measurement of fluorescent AGE intensity Using 6-hydroxy quercetin (manufactured by Santa Cruz Biotechnology), 8-hydroxy quercetin (manufactured by ChromaDex), quercetin-4'-glucoside (manufactured by ChromaDex) to confirm the AGEs production inhibitory effect Therefore, the fluorescence AGE intensity was measured by the following method. 0.5 ml phosphate buffer solution (pH 7.2) (hereinafter referred to as amino acid solution) containing 7.5 mg / ml Boc-lysine and 7.5 mg / ml Boc-arginine 1.0 ml, 54 mg / ml DL-glyceraldehyde solution 0.25 ml (hereinafter referred to as a sugar solution) and 0.25 ml of a sample solution having the composition shown in Table 1 were mixed and allowed to stand at 37 ° C. for 7 days. The fluorescence intensity (excitation wavelength: 380 nm, fluorescence wavelength: 400-600 nm) of the reaction solution was measured using a 96-well microplate reader, and this value was defined as a2 in the fluorescent AGEs intensity calculation formula shown below. Regarding b2 to d2 in the calculation formula, the fluorescence intensity was measured by reacting under the same conditions, and the fluorescence AGEs intensity was calculated. The blank was measured by adding a solvent instead of adding the sample solution.

Fluorescence AGE intensity = a2-b2-c2-d2
a2: 0.25 mL of sample solution in each test group + 1.0 mL of amino acid solution + 0.25 mL of sugar solution
b2: 0.25 ml of sample solution of each test group + 1.25 ml of 0.5 M phosphate buffer (pH 7.2)
c2: Amino acid solution 1.0 ml + 0.5 M phosphate buffer (pH 7.2) 0.5 ml
d2: 1.25 ml of sugar solution 0.25 ml + 0.5 M phosphate buffer (pH 7.2)

  In the test group using the quercetin derivative, the intensity of the fluorescent AGEs was lower than that of the blank, and it was confirmed that the quercetin derivative suppressed the production of the fluorescent AGEs. The results are shown in Table 2.

Example 2
Production of powder The raw materials were mixed in the proportions shown in Table 3 to produce a powder. The powder is one form of the AGEs production inhibitor of the present invention, the pharmaceutical composition for preventing / treating diabetes of the present invention, or the composition for oral consumption of the present invention.

Example 3
Preparation of tablets After mixing the raw materials in the proportions shown in Table 4, using a continuous tableting machine (Piccola B-10 / RIVA), a die (φ8mm, R12mm), weight 150-200mg per tablet Tablets were manufactured directly by tableting under the tableting conditions of 12 rpm and a tableting pressure of 4 kN. The tablet is a form of the AGE production inhibitor of the present invention, the pharmaceutical composition for preventing / treating diabetes of the present invention, or the oral composition of the present invention.

Example 4
Production of Oral Solution The raw material was dissolved in distilled water at the ratio shown in Table 5 to produce an oral solution. The oral solution is one form of the pharmaceutical composition for preventing / treating diabetes or the composition for oral intake of the present invention.

Example 5
Manufacture of lotion The raw materials were dissolved in distilled water at the ratio shown in Table 6 to produce lotion. The lotion is one form of the external preparation for skin aging prevention / amelioration of the present invention.

Example 6
Production of emulsion The raw materials were mixed in the proportions shown in Table 7 to produce an emulsion. The emulsion is one form of the external preparation for skin aging prevention / amelioration of the present invention.

Claims (19)

Quercetin derivative represented by formula (1):

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol, and R ₃ represents a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol. Indicates. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ]
A terminal glycation product production inhibitor containing as an active ingredient.   The terminal glycation product production inhibitor according to claim 1, wherein the quercetin derivative represented by the formula (1) is at least one selected from 6-hydroxyquercetin, 8-hydroxyquercetin, and quercetin-4'-glucoside. Quercetin derivative represented by formula (1):

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol, and R ₃ represents a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol. Indicates. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ]
A pharmaceutical composition for the prevention and / or treatment of diabetes or diabetic complications.   The pharmaceutical composition according to claim 3, wherein the quercetin derivative represented by the formula (1) is one or more selected from 6-hydroxyquercetin, 8-hydroxyquercetin, and quercetin-4'-glucoside.   The pharmaceutical composition according to claim 3 or 4, wherein the diabetic complication is one or more diseases selected from the group consisting of diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic vascular complication and arteriosclerosis. .   The saccharide content is 5 g or more, and the amino acid and / or protein content is 20 g or more, which is administered before, during, after or between meals. A pharmaceutical composition according to claim 1.   An agent selected from the group consisting of tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, oral tablets, oral sprays, oral semisolids, mouthwashes, injections and inhalants The pharmaceutical composition according to any of claims 3 to 6, which is in the form. Quercetin derivative represented by formula (1) for the prevention and / or treatment of diabetes or diabetic complications in non-human animals:

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol, and R ₃ represents a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol. Indicates. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ]
A pharmaceutical composition for non-human animals, containing as an active ingredient.   The pharmaceutical composition for non-human animals according to claim 8, wherein the quercetin derivative represented by the formula (1) is one or more selected from 6-hydroxyquercetin, 8-hydroxyquercetin, and quercetin-4'-glucoside. . Quercetin derivative represented by formula (1):

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol, and R ₃ represents a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol. Indicates. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ]
A method for preventing and / or treating diabetes or diabetic complications in a non-human animal, comprising administering to the non-human animal.   The method according to claim 10, wherein the quercetin derivative represented by the formula (1) is at least one selected from 6-hydroxyquercetin, 8-hydroxyquercetin, and quercetin-4'-glucoside. Quercetin derivative represented by formula (1):

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol, and R ₃ represents a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol. Indicates. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ]
A method for producing a functional food or drink, comprising blending or adding to the food or drink.   The method for producing a functional beverage according to claim 12, wherein the quercetin derivative represented by the formula (1) is at least one selected from 6-hydroxyquercetin, 8-hydroxyquercetin, and quercetin-4'-glucoside. Quercetin derivative represented by formula (1):

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol, and R ₃ represents a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol. Indicates. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ]
And a carrier, and an agent selected from the group consisting of tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, oral tablets, oral sprays, oral semisolids, and mouthwashes A composition for oral consumption provided in a form.   The composition for oral inoculation according to claim 14, wherein the quercetin derivative represented by the formula (1) is one or more selected from 6-hydroxyquercetin, 8-hydroxyquercetin, and quercetin-4'-glucoside. Quercetin derivative represented by formula (1):

[Wherein R ₁ and R ₂ represent a hydrogen atom, a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol, and R ₃ represents a hydroxyl group, or a sugar residue of a monosaccharide, disaccharide, or sugar alcohol. Indicates. However, compounds in which R ₁ = R ₂ = hydrogen atom and R ₃ = hydroxyl group are excluded. ]
A topical skin preparation for the prevention and / or improvement of skin aging.   The skin external preparation according to claim 16, wherein the quercetin derivative represented by the formula (1) is at least one selected from 6-hydroxyquercetin, 8-hydroxyquercetin, and quercetin-4'-glucoside.   The external preparation for skin according to claim 16 or 17, which is a cosmetic.   The skin external preparation of Claim 18 which is a thing of the form chosen from the group which consists of a milky lotion, a cosmetic liquid, a lotion, a pack, a cream, a hand cream, a foundation, a makeup base, a lip balm, and a lipstick.