JP2014118378A - Retinal endothelial cell damage inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a retinal endothelial cell damage inhibitor containing a novel component as an active ingredient.SOLUTION: The feature of the present invention for solving the above-mentioned subject is as follows: 1. the retinal endothelial cell damage inhibitor containing extract of black rice as an active ingredient; 2. the retinal endothelial cell damage inhibitor containing 2-hydroxy-5-[(3S)-3-hydroxybutyl] phenyl-β-D-glucoside as an active ingredient; 3. the retinal endothelial cell light-damage inhibitor containing cyanidin and/or cyanidin glycoside as an active ingredient; 4. the retinal endothelial cell damage inhibitor containing cyanidin-3-O-glucoside as the cyanidin glycoside in above-mentioned item 3.

Description

The present invention relates to a retinal endothelial cell damaging agent. The present invention is widely used for foods, pharmaceuticals, cosmetics and the like.

Macular edema is a major cause of vision loss in diabetic patients, and preretinal neovascularization (PDR) is a major cause of legal blindness. Diabetes is characterized by persistent hyperglycemia and causes reversible and irreversible pathological changes in the microvasculature of various organs. Thus, diabetic retinopathy (DR) is a retinal microvascular disease that manifests as a cascade of stages with increasing severity and worsening vision-related prognosis. The main risk factors for the development of diabetic retinopathy have been reported on the duration of diabetes, quality of glycemic control, and the presence of hypertension. This DR is broadly classified into two main clinical stages, nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) (in this case, “proliferative” refers to the retina described above) Refers to the presence of pre-angiogenesis).

Nonproliferative diabetic retinopathy (NPDR) and subsequent macular edema are partially associated with retinal ischemia due to retinal microangiopathy caused by persistent hyperglycemia. In NPDR, from the early “background” DR where multiple small lesions in the retina (eg, arteriole aneurysm, “dot-spotted” hemorrhage, and nerve fiber layer infarction) are observed, immediately before the onset of PNV A broad clinical subclass is included, including up to proliferative diabetic retinopathy. Characteristic histopathological findings of NPDR include reduction of endothelial cells in addition to thickening of retinal arterioles and capillary basement membranes. Thus, suppressing retinal endothelial cell damage is effective in the prevention and treatment of diabetic retinopathy.

Against this background, black rice extract and its component 2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glucoside
It was found that (HHPG) and cyanidin glycoside have an inhibitory effect on retinal endothelial cell injury, and the present invention was completed.
An object of the present invention is to provide a novel retinal endothelial cell disorder inhibitor.

The features of the present invention for solving the above-described problems are as follows.
1. Retinal endothelial cell disorder inhibitor comprising black rice extract as an active ingredient.
2. A retinal endothelial cell disorder inhibitor comprising 2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glucoside as an active ingredient.
3. A retinal endothelial cell disorder inhibitor comprising cyanidin and / or cyanidin glycoside as an active ingredient.
4). 2. The cyanidin glycoside described above is cyanidin-3-O-glucoside. An inhibitor of retinal endothelial cell damage according to claim 1.

It is a graph which shows the effect | action with respect to high glucose induced retinal endothelial cell damage of a black rice extract. 2 is a graph showing the effects of C3G and HHPG on high glucose-induced retinal endothelial cell injury. It is a graph which shows the effect | action with respect to high glucose induction ROS production of a black rice extract. It is a graph which shows the effect | action with respect to high glucose induction ROS production of C3G.

Hereinafter, the present invention will be described in detail.
The present invention is characterized by using black rice extract as an active ingredient.
Black rice is a kind of ancient rice native to Hanzhong Province, Shaanxi Province, China, and is also called purple black rice or purple rice. The surface of the brown rice is black and contains purple black pigment (anthocyanic pigment) in the pericarp, seed coat and germ. After 5 minutes (a little polished rice), the rice turns purple, and when all the rice cake is removed, it becomes a color close to white rice. There are two types of rice grains: japonica (short) and indica (long), and many of the latter are rice cakes. According to Kampo medicine, black rice has the effects of nourishing tonic and energizing, and is considered to have the effects of strengthening the gastrointestinal tract, supplementing and activating blood, strengthening lung function, and blackening hair.
As black rice varieties, Shikokuen, Kurodaen, Konan Kurome: Konan Kurome, Kuromasaki, Unnan Kuromome, Kohoku Murasaki Examples include black rice.

  In the present invention, the raw material for obtaining the black rice extract is not limited to black rice varieties, and only one of these varieties (including those listed above) may be used, or two or more. May be used in combination. The shape of the rice grain may be either Japonica (short grain) or Indica (long grain), or a mixture of these. As for the type of rice, either sticky rice or sticky rice may be used, or a mixture thereof may be used.

  Moreover, when extracting an active ingredient from black rice, it is desirable to use defatted rice bran as a raw material. This is because the active ingredient is efficiently extracted from this defatted product by removing the oil in the rice bran.

  Preferred degreasing solvents include N-hexane, acetone and the like. In particular, when N-hexane is used as a degreasing solvent, the extracted oil can be used as an edible oil, and the black rice extract can be easily used as a food material.

As the extraction solvent, polar solvents such as water, methanol, ethanol, isopropyl alcohol, 1,3-butylene glycol, ethylene glycol, propylene glycol, glycerin, and ethyl acetate can be used. Two or more of these solvents may be mixed.
Desirably, when water or ethanol is used as the extraction solvent, the active ingredient is efficiently extracted. In particular, hydrous ethanol is an extraction solvent that is less likely to reduce the activity of the active ingredient during extraction and is preferable from the standpoint of safety in the use of the extract in food. The kind of water for extraction is not particularly limited, and tap water, distilled water, mineral water, alkaline ionized water, deep water and the like can be used.

  As the extraction temperature, for example, when water-containing ethanol is used, the extraction temperature is 20 to 80 ° C., preferably about 40 to 50 ° C. This is because if the extraction temperature is too low, it becomes difficult to extract the active ingredient, and if the extraction temperature is too high, the activity of the active ingredient tends to decrease.

  The water-containing ethanol as the extraction solvent has an ethanol concentration of 40 to 90% (wt / wt), desirably an ethanol concentration of 60 to 80% (wt / wt). The reason why the ethanol concentration is 40% (wt / wt) or more is that if the ethanol content is too small, the extraction amount of the active ingredient tends to be insufficient. The reason why the ethanol concentration is 90% (wt / wt) or less is that if the ethanol concentration is too high, the oil content in the rice bran is likely to dissolve in the water-containing ethanol. In addition, in order to improve the content rate of the active ingredient, the water-containing ethanol extraction may be repeatedly performed while changing the ethanol concentration stepwise.

  As an extraction method, any method such as continuous extraction, immersion extraction, countercurrent extraction, and supercritical extraction can be adopted, and any apparatus can be used at room temperature or under reflux heating.

  Specifically, the raw material (defatted rice bran) is put into a treatment tank filled with the extraction solvent, and the active ingredient is eluted while stirring. For example, when water-containing ethanol is used as the extraction solvent, the extraction solvent is used in an amount of about 5 to 100 times (weight ratio) of the extraction raw material, and extraction is performed for about 30 minutes to 2 hours. The active ingredient is eluted in the solvent, and then filtered to remove the extraction residue to obtain an extract.

Thereafter, the extract is subjected to treatments such as dilution, concentration, drying, purification and the like according to a conventional method to obtain the retinal endothelial cell disorder inhibitor according to the present invention.
As a purification method, the extract is adsorbed through a synthetic adsorption resin, a gel filtration resin or the like and eluted with methanol, ethanol or the like, and concentrated under reduced pressure.

In addition, the present invention is characterized in that 2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glucoside is an active ingredient.
2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glucoside is a compound represented by the following chemical formula (1).

  2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glucoside is not particularly limited and can be extracted and purified from black rice extract.

In addition, the present invention is characterized in that cyanidin and / or a glycoside thereof (hereinafter, these are simply referred to as “cyanidine etc.”) as an active ingredient.
Cyanidin is a compound represented by the following chemical formula (2).

As for cyanidin, a commercially available product can be used. In other words, those manufactured by Extrasynthese can be used.
The glycoside of cyanidin is a compound in which a sugar is bonded to the compound of the above chemical formula (2).
The cyanidin glycoside used in the present invention is not particularly limited. For example, cyanidin-3-O-glucoside, cyanidin-3-rutinoid, cyanidin-3-sambubioside, cyanidin-3-sambubioside-5-glucoside or cyanidin-3, 5-diglucoside etc. are mentioned. In addition, these may use only 1 type and may use 2 or more types together. Of these, cyanidin-3-O-glucoside is particularly preferred.

  The inhibitor of retinal endothelial cell injury (referred to as black rice extract, cyanidin, peonidin, etc. The same shall apply hereinafter) of the present invention can be used as a material for various foods and drinks. Examples of food and drink include confectionery (gum, candy, caramel, chocolate, cookies, snacks, jelly, gummi, tablet confectionery, etc.), noodles (soba, udon, ramen, etc.), and dairy products (milk, ice cream, yogurt). ), Seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, tea, tea, carbonated drinks, sports drinks, etc.), health foods (tablets, capsules, etc.), nutrition Supplementary foods (such as energy drinks) are listed. The retinal endothelial cell injury inhibitor of the present invention may be appropriately blended with these foods and drinks.

These foods and drinks can be blended with various ingredients depending on the type, for example, glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid. Acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, gum arabic, Food materials such as carrageenan, casein, gelatin, pectin, agar, vitamin Bs, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, fragrances and preservatives can be used.

As a specific production method, a retinal endothelial cell disorder inhibitor is spray-dried or freeze-dried together with powdered cellulose, and the resulting powder, granule, tablet or solution is easily contained in foods and drinks (instant foods, etc.). be able to. In addition, the retinal endothelial cell disorder inhibitor can be dissolved in, for example, fats and oils, ethanol, glycerin or a mixture thereof to be liquefied and added to beverages or added to solid foods. If necessary, it can be mixed with a binder such as gum arabic or dextrin to form a powder or granules and added to a beverage or a solid food.

When the retinal endothelial cell disorder inhibitor of the present invention is applied to foods and drinks, since the main purpose is disease prevention and health maintenance, the total content of active ingredients is 1 to 20 wt% with respect to the food and drinks. It is preferable that:

The retinal endothelial cell disorder inhibitor of the present invention may be used as a raw material for medicines (including pharmaceuticals and quasi drugs). It can be produced by appropriately blending the retinal endothelial cell disorder inhibitor of the present invention with a raw material for a pharmaceutical preparation. Examples of the raw material for preparation that can be blended in the retinal endothelial cell injury inhibitor of the present invention include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cacao butter, hydrogenated vegetable oil, kaolin , Talc, etc.), binder (distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrant (sodium alginate, agar) Sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption enhancers ( Quaternary ammonium base, sodium lauryl sulfate Um, etc.), adsorbents (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearates, polyethylene glycol, and the like) and the like.

The administration method of the retinal endothelial cell disorder inhibitor of the present invention can generally be orally administered in the form of tablets, pills, soft / hard capsules, fine granules, powders, granules, liquids, and the like. However, parenteral administration may also be used. When administered as a parenteral agent, it can be administered as a solution or with the addition of a dispersing agent, suspension, stabilizer, etc., by local tissue administration, intradermal, subcutaneous, intramuscular and intravenous injection, etc. it can. Moreover, it is good also as forms, such as a suppository. Furthermore, it can be administered as eye drops.

The dosage may vary depending on the administration method, medical condition, age of the patient, etc., but for adults, it can be generally administered as 0.5 to 5000 mg as an active ingredient per day, and usually about 0.5 to 3000 mg for children.
The mixing ratio of the retinal endothelial cell disorder inhibitor can be appropriately changed depending on the dosage form, but is usually about 0.3 to 15.0 wt% when administered orally or by mucosal absorption, depending on parenteral administration. In such a case, the content may be about 0.01 to 10 wt%. In addition, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or it may be necessary to administer beyond the range.

As the retinal endothelial cell disorder inhibitor of the present invention, a retinal endothelial cell disorder inhibitor can be expected as an external preparation for skin (including cosmetics, pharmaceuticals and quasi drugs).

Examples of cosmetics that can contain the retinal endothelial cell disorder inhibitor of the present invention include emulsions, soaps, facial cleansers, bath preparations, creams, emulsions, lotions, eau de cologne, shave creams, shave lotions, and makeup. Oil, sunscreen / sunscreen lotion, funny powder, foundation, perfume, pack, nail cream, enamel, enamel remover, eyebrow, blusher, eye cream, eye shadow, mascara, eyeliner, lipstick, lip balm, shampoo, rinse, Examples include hair dyes, dispersions, and cleaning materials.
Examples of the form of a pharmaceutical or quasi-drug that can contain the retinal endothelial cell disorder inhibitor of the present invention include ointments, creams, and liquids for external use.

In addition to the retinal endothelial cell disorder inhibitor according to the present invention, the external preparation for skin of the above form is a component blended in a skin external preparation such as cosmetics and quasi-drugs as long as the retinal endothelial cell disorder inhibitory effect is not impaired. , Oils, higher alcohols, fatty acids, UV absorbers, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active ingredients, solvents, antioxidants, fragrances, preservatives, etc. it can.
Examples are listed below, but the present invention is not limited to these examples.
(1) Examples of oil [ester-based oil phase components]: glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, Isocetyl isostearate, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate , Diisopropyl adipate, isoaralkyl neopentanoate, glyceryl tri (capryl / caprate), trimethylolpropane tri-2-ethylhexanoate, trimethylotriisostearate Propane, tetra-2-ethylhexanoate pentaerythritol, cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isolaurate Stearyl, isotridecyl myristate, isocetyl myristate, isostearyl myristate, isocetyl palmitate, isostearyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl linoleate, octyldodecyl isoleate, isopropyl isostearate Cetostearyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, ethylene glycol dioctanoate Cole, ethylene glycol dioleate, propylene glycol dicaprate, propylene glycol di (capryl / capric acid), propylene glycol dicaprylate, neopentyl glycol dicaprate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, triisopalmitine Glyceryl acid, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyl decyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerin oleic acid Ester, polyglycerol isostearate, dipropyl carbonate Dialkyl carbonate (C12-18), triisocetyl citrate, triisoaralkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyl decyl lactate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate , Trioctyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, di-2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, Cholesteryl oleate, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, 12-stearoylhydroxystearin Isocetyl, 12-stearoyl-hydroxystearic acid stearyl 12-stearoyl-hydroxystearic acid isostearate, and the like.
[Hydrocarbon-based oil phase component]: Squalane, liquid paraffin, α-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybutene, microcrystalline wax, petrolatum and the like.
[Animal and vegetable oil and its hardened oil, and naturally derived wax]: beef tallow, hardened beef tallow, pork tallow, hardened tallow, horse oil, hardened horse oil, mink oil, orange luffy oil, fish oil, hardened fish oil, egg yolk oil, etc. Animal oil and its hardened oil, avocado oil, almond oil, olive oil, cacao butter, apricot oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, soybean oil, evening primrose oil, Perilla oil, tea seed oil, camellia oil, corn oil, rapeseed oil, hardened rapeseed oil, palm kernel oil, hardened palm kernel oil, palm oil, hardened palm oil, peanut oil, hardened peanut oil, castor oil, hardened castor oil, Vegetable oil such as sunflower oil, grape seed oil, jojoba oil, hardened jojoba oil, macadamia nut oil, medhome oil, cottonseed oil, hardened cottonseed oil, palm oil, hardened palm oil and the hardened oil thereof, beeswax High acid value beeswax, lanolin, reduced lanolin, hydrogenated lanolin, liquid lanolin, carnauba wax and montan wax.
[Silicone-based oil phase component]: dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane , Dimethylsiloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel , Acrylic silicone, trimethylsiloxysilicic acid, silicone RTV rubber and the like.
[Fluorine oil phase component]: Perfluoropolyether, fluorine-modified organopolysiloxane, fluorinated pitch, fluorocarbon, fluoroalcohol, fluoroalkyl / polyoxyalkylene co-modified organopolysiloxane, and the like.
(2) Examples of higher alcohols include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol, octyldodecanol and the like.
(3) Examples of fatty acids Caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid , Erucic acid, 2-ethylhexanoic acid and the like.
(4) Examples of UV absorbers Paraaminobenzoic acid, amyl paraaminobenzoate, ethyldihydroxypropyl paraaminobenzoate, glyceryl paraaminobenzoate, ethyl paraaminobenzoate, octyl paraaminobenzoate, octyldimethyl paraaminobenzoate, ethylene glycol salicylate, salicylic acid Octyl, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomenthyl salicylate, benzyl cinnamate, octyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate, mono-2-diparamethoxycinnamate Glyceryl ethylhexanoate, isopropyl paramethoxycinnamate, diethanolamine salt of paramethoxyhydrocinnamic acid, diisopropyl diisopropylcinnamic acid Stealth mixture, urocanic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its salts, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, dihydroxydimethoxybenzophenone, hydroxyoctoxybenzophenone, tetrahydroxybenzophenone, Butylmethoxydibenzoylmethane, 2,4,6-trianilino-p- (carbo-2-ethylhexyl-1-oxy) -1,3,5-triazine, 2- (2-hydroxy-5-methylphenyl) benzotriazole , Methyl-O-aminobenzoate, 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate, phenylbenzimidazole sulfate, 3- (4-methylbenzylidene) camphor, Isopropyl dibenzoylmethane, 4- (3,4-dimethoxyphenyl methylene) 2-ethylhexyl-2,5-dioxo-1-imidazolidin propionate, and the like these polymeric derivatives and silane derivatives thereof.
(5) Examples of powders and pigments Red 104, Red 201, Yellow 4, Blue 1, Black 401 and other dyes, Yellow 4 AL lake, Yellow 203 BA lake and other lake dyes, nylon powder , Silk powder, urethane powder, Teflon (registered trademark) powder, silicone powder, polymethyl methacrylate powder, cellulose powder, starch, silicone elastomer spherical powder, polyethylene powder, yellow iron oxide, red iron oxide, black Colored pigments such as iron oxide, chromium oxide, carbon black, ultramarine and bitumen, white pigments such as zinc oxide, titanium oxide and cerium oxide, extender pigments such as talc, mica, sericite, kaolin and barium sulfate plate, titanium mica Pearl pigments such as barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate, metal salts such as magnesium silicate, Inorganic powders such as Rica and alumina, metal soaps such as aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, zinc undecylenate, bentonite, smectite, boron nitride, etc. It is done. There are no particular restrictions on the shape of these powders (spherical, rod-like, needle-like, plate-like, irregular shape, flake-like, spindle-like, etc.) and particle diameter. These powders are conventionally known surface treatments such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, silane coupling agent treatment, titanium coupling agent treatment, oil agent treatment, N-acylated lysine treatment, The surface treatment may or may not be performed in advance by polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment, mechanochemical treatment or the like.
(6) Examples of surfactant [anionic surfactant]: fatty acid soap, α-acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether Sulfates, alkylamide sulfates, alkyl phosphates, POE alkyl phosphates, alkylamide phosphates, alkyloyl alkyl taurine salts, N-acyl amino acid salts, POE alkyl ether carboxylates, alkyl sulfosuccinates, alkyls Examples include sodium sulfoacetate, acylated hydrolyzed collagen peptide salt, and perfluoroalkyl phosphate.
[Cationic surfactant]: alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, benzaza chloride Examples thereof include luconium, amidopropyldimethylhydroxypropylammonium chloride behenate, diethylaminoethylamide stearate, dimethylaminopropylamide stearate, and lanolin derivative quaternary ammonium salts.
[Amphoteric surfactant]: Carboxybetaine type, amide betaine type, sulfobetaine type, hydroxysulfobetaine type, amide sulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, amidoamine type and the like.
[Nonionic surfactant]: Propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE sorbitol fatty acid ester, POE glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE Examples thereof include hydrogenated castor oil, POE castor oil, POE / POP copolymer, POE / POP alkyl ether, polyether-modified silicone lauric acid alkanolamide, alkylamine oxide, and hydrogenated soybean phospholipid.
[Natural surfactant]: Examples include lecithin, saponin, and sugar surfactant.
(7) Examples of polyhydric alcohols and sugars Ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1,3 -Butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fructose, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose, pullulan and the like. These chemically modified compounds can also be used.
(8) Examples of polymers Acrylic ester / methacrylic acid ester copolymer (plus size, manufactured by Kyoyo Chemical), vinyl acetate / crotonic acid copolymer (resin 28-1310, manufactured by NSC), vinyl acetate / croton Acid / vinyl neodecanate copolymer (28-2930, manufactured by NSC), methyl vinyl ether maleic acid half ester (Gantrez ES, manufactured by ISP), T-butyl acrylate / ethyl acrylate / methacrylic acid copolymer (rubymer) , BASF), vinyl pyrrolidone / vinyl acetate / vinyl propionate copolymer (Rubicol VAP, BASF), vinyl acetate / crotonic acid copolymer (Rubiset CA, BASF), vinyl acetate / croton Acid / vinyl pyrrolidone copolymer (Rubiset CAP, manufactured by BASF), vinyl pyrrolidone / acrylate copolymer (Rubiflex, BAS) F), acrylate / acrylamide copolymer (Ultrahold, BASF), vinyl acetate / butyl maleate / isobornyl acrylate copolymer (Advantage, ISP), carboxyvinyl polymer (Carbopol, BF Goodrich), anionic polymer compounds such as acrylic acid / alkyl methacrylate copolymer (Pemulene, BF Goodrich), and acetic acid amphoteric products of dialkylaminoethyl methacrylate polymers (Yukaformer, Mitsubishi Chemical) Amphoteric polymer compounds such as octyl acrylate acrylate / hydroxypropyl acrylate / butylaminoethyl methacrylate copolymer (AMPHOMER, NSC), quaternized vinylpyrrolidone / dimethylaminoethyl methacrylate (GAFQUAT, ISP) , Methyl vinyl imidazolium chloride / Cationic polymer compounds such as vinylpyrrolidone copolymer (rubicoat, manufactured by BASF), polyvinylpyrrolidone (rubiscol K, manufactured by BASF), vinylpyrrolidone / vinyl acetate copolymer (rubiscol VA, manufactured by BASF) Nonionic polymer compounds such as vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer (copolymer 937, manufactured by ISP), vinylcaprolactam / vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer (copolymer VC713, manufactured by ISP), etc. is there. Cellulose or derivatives thereof, keratin and collagen or derivatives thereof, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharide, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, gum arabic, crystalline cellulose, arabino Naturally derived polymer compounds such as galactan, gum karaya, gum tragacanth, alginic acid, albumin, casein, curdlan, gellan gum and dextran can also be suitably used.
(9) Examples of physiologically active ingredients Examples of physiologically active ingredients include substances that impart some physiological activity to the skin when applied to the skin. For example, whitening ingredients, anti-inflammatory agents, anti-aging agents, UV protection agents, slimming agents, tanning agents, antioxidants, hair growth agents, hair restorers, moisturizers, blood circulation promoters, antibacterial agents, bactericides, desiccants, A cooling sensation agent, a warming sensation agent, vitamins, an amino acid, a wound healing promoter, an irritation relaxation agent, an analgesic agent, a cell activator, an enzyme component, etc. are mentioned. Examples of these suitable ingredients include, for example, ashitaba extract, avocado extract, amateur extract, altea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, ginkgo biloba extract, fennel extract, turmeric extract, oolong tea extract, ages Extract, Echinacea leaf extract, Ogon extract, Oat extract, Oen extract, Barley extract, Hypericum extract, Oyster extract, Dutch mustard extract, Orange extract, Seawater dried product, Seaweed extract, Hydrolyzed elastin, Hydrolyzed wheat powder, Hydrolyzed silk , Chamomile extract, carrot extract, cormorant extract, licorice extract, calcade extract, oyster extract, kiwi extract, kina extract, cucumber extract, guanosine, gardenia extract, kumazasae Kiss, Clara extract, Walnut extract, Grapefruit extract, Clematis extract, Chlorella extract, Mulberry extract, Gentian extract, Black tea extract, Yeast extract, Burdock extract, Rice bran ferment extract, Rice germ oil, Comfrey extract, Collagen, Cowberry extract, Saisin extract , Psycho extract, Saitai extract, Salvia extract, Soybean extract, Sasa extract, Hawthorn extract, Salamander extract, Shiitake extract, Giant extract, Shikon extract, Perilla extract, Linden extract, Shimotake extract, Japanese peony extract, Ginger root extract, Birch extract, Japanese cedar Extract, Kizuta extract, Hawthorn extract, Elderberry extract, Achillea millefolium extract, Atlantic mint extract, Sage extract, Zeni mallow Extract, Senkyu Extract, Assembly Extract, Soybean Extract, Taiso Extract, Thyme Extract, Tea Extract, Fresh Coffee Bean Extract, Clove Extract, Chigaya Extract, Chimpi Extract, Toki Extract, Tokinsenka Extract, Tonin Extract, Spruce Extract, Dokudami Extract, Tomato Extract, Natto Extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, buckwheat extract, parsley extract, honey, hamamelis extract, parietaria extract, toad extract, bisabolol, loquat extract, dandelion extract, burdock extract, butterfly extract, butcher bloom extract, Grape extract, propolis, loofah extract, safflower extract, peppermint extract, bodaiju extract, button extract, hop extract, matsue , Maronnier extract, Citrus extract, Mukuroji extract, Melissa extract, Peach extract, Cornflower extract, Eucalyptus extract, Yukinoshita extract, Yuzu extract, Yakuinin extract, Artemisia extract, Lavender extract, Apple extract, Lettuce extract, Lemon extract, Forsythia extract, Rose extract , Rosemary extract, roman chamomile extract, royal jelly extract and the like.
Biopolymers such as deoxyribonucleic acid, mucopolysaccharide, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, hydrolyzed eggshell membranes, amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidonecarboxylate , Moisturizing ingredients such as betaine, whey, trimethylglycine, oily ingredients such as sphingolipid, ceramide, phytosphingosine, cholesterol, cholesterol derivatives, phospholipids, ε-aminocaproic acid, glycyrrhizic acid, β-glycyrrhetinic acid, lysozyme chloride, guaiazulene, Anti-inflammatory agents such as hydrocortisone, vitamin A, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E, calcium pantothenate, biotin, nicotinamide, vitamin C ester, etc. Active ingredients such as vitamins, allantoin, diisopropylamine dichloroacetate, 4-aminomethylcyclohexanecarboxylic acid, antioxidants such as tocopherol, carotenoid, flavonoid, tannin, lignan, saponin, α-hydroxy acid, β-hydroxy acid, etc. Cell activators, blood circulation promoters such as γ-oryzanol and vitamin E derivatives, wound healing agents such as retinol and retinol derivatives, whitening such as arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, glutathione Agent, cephalanthin, licorice extract, red pepper tincture, hinokitiol, garlic iodide extract, pyridoxine hydrochloride, DL-α-tocopherol, DL-α-tocopherol acetate, nicotinic acid, nicotinic acid derivative, calcium pantothenate, D-pan Tenenyl alcohol, acetyl pantothenyl ethyl ether, biotin, allantoin, isopropylmethylphenol, estradiol, ethinyl estradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, takanal, camphor, salicylic acid, nonylic acid vanillylamide, nonanoic acid vanillylamide, piroctone ola Mines, glyceryl pentadecanoate, L-menthol, mononitroguaiacol, resorcin, γ-aminobutyric acid, benzethonium chloride, mexiletine hydrochloride, auxin, female hormone, cantalis tincture, cyclosporine, zinc pyrithione, hydrocortisone, minoxidil, polymonostearate Examples include hair restorers such as oxyethylene sorbitan, mint oil, and Sasanishiki extract.
(10) Examples of antioxidants: sodium bisulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, tolylbiguanide, nordihydroguaiaretic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxy Examples include plant extracts having an antioxidant effect such as toluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoid, flavonoid, tannin, lignan, saponin, apple extract and clove extract.
(11) Examples of solvents Examples include purified water, ethanol, lower alcohol, ethers, LPG, fluorocarbon, N-methylpyrrolidone, fluoroalcohol, volatile linear silicone, and next-generation fluorocarbon.

Examples of the present invention will be described below. The following examples are described for confirming various actions and effects of the retinal endothelial cell disorder inhibitor obtained by the present invention, and the scope of the present invention is limited to these products and production methods. It is not something.

Examples Example 1: Variety "Shokukuen" was used for black rice as a raw material for black rice extract.
Black rice bran (400 g) was degreased with 5 times the weight ratio of n-hexane, and then the rice bran was air-dried. Next, stirring extraction was performed at room temperature using 50% ethanol. Thereafter, the extract was adsorbed on a synthetic adsorbent and eluted with 70% ethanol. The eluate was concentrated under reduced pressure at 40 ° C. or lower to obtain 11 g of black rice extract (Example 1). As a result of analyzing the black rice extract of Example 1 by HPLC, it was confirmed that it contained 2.9% cyanidin-3-O-glucoside.
Example 2: Cyanidin-3-O-glucoside As Example 2, cyanidin-3-O-glucoside (manufactured by Extrasynthese) was used.
Example 3: Isolation of 2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glc from black rice extract 2-hydroxy-5- [ (3S) -3-hydroxybutyl] phenyl-β-D-glc was isolated.
Black rice extract (150 g) was adsorbed on a filter aid to obtain a non-adsorbed fraction. Thereafter, the non-adsorbed fraction was adsorbed on the ODS column and eluted with hydrous ethanol. The eluted fraction was concentrated to obtain a crude fraction (3 g). The crude fraction was isolated and purified by preparative HPLC to obtain 2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glc. 2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glc was identified by NMR.

Test Example 1: Effects of black rice extract, HHPG and cyanidin-3-O-glucoside (C3G) on high glucose-induced retinal endothelial cell injury (1) Test method Human retinal capillary endothelial cells have an effect on high glucose-induced retinal injury (HRMEC: Human Retinal Microvascular Endothelial Cell) A culture system was used. That is, HRMEC was seeded in a 96-well plate at a concentration of 5000 cells / well and cultured for 24 hours. After incubation, 50 mM glucose and each sample were added to HRMEC. After 24 hours of incubation, WST-8 was added to each well, incubated for 3 hours at 37 ° C and 5% CO2, and then directly measured for absorbance at 492 nm (reference wavelength: 660 nm) to measure viable cells . The results are shown in FIG. 1 (black rice extract) and FIG. 2 (HHPG and C3G).

(2) Results and Effects of Examples in Test Example 1 As shown in FIG. 1, a significant high glucose-induced retinal endothelial cell injury inhibitory action was observed in black rice extract. In addition, as shown in Fig. 2, HHPG and C3G, which are contained components, also showed a significant inhibitory effect. From the above results, the black rice extract has a high glucose-induced high glucose-induced retinal endothelial cell injury-inhibiting action, and the black rice extract has high glucose-induced high glucose-induced retinal endothelial cell damage-inhibiting active ingredients HHPG and It was confirmed to be C3G.

Test Example 2: Effects of black rice extract and cyanidin 3-O-glucoside (C3G) on high glucose-induced reactive oxygen (ROS) production (2) Test method Mechanism of inhibitory action of black rice extract and C3G on high glucose-induced HRMEC injury As an elucidation, we investigated the effect on active oxygen (ROS) that is increased by high glucose. HRMEC was seeded in a 96-well plate at a concentration of 5000 cells / well and cultured for 24 hours. After incubation, 50 mM glucose and each sample were added to HRMEC. After 24 hours of incubation, CM-H2DCFDA (10 μM), a ROS detection probe, was added and incubated at 37 ° C for 1 hour. Fluorescence is measured using a spectrophotometer (Varioskan; Thermo Electron Corporation, Vantaa,
Finland) was used to calculate the ROS production rate. The results are shown in FIG. 3 (black rice extract) and FIG. 4 (C3G).

As a result, as shown in FIG. 3, a significant ROS production inhibitory effect was observed in the black rice extract. In addition, as shown in FIG. 4, the similar inhibitory action was also observed in the contained component C3G. From the above results, it was confirmed that ROS production inhibitory action was involved as a mechanism of inhibitory action of black rice extract and C3G on high glucose-induced HRMEC injury.

The compounding example of the retinal endothelial cell disorder inhibitor by this invention is shown.
Formulation Example 1: Chewing gum
53.0wt% sugar
Gum base 20.0
Glucose 10.0
Minamata 16.0
Fragrance 0.5
Retinal endothelial cell disorder inhibitor 0.5
100.0wt%

Formulation Example 2: Gummy
Reduced water tank 40.0wt%
Granulated sugar 20.0
Buto sugar 20.0
Gelatin 4.7
Water 9.68
Yuzu fruit juice 4.0
Yuzu Flavor 0.6
Dye 0.02
Retinal endothelial cell disorder inhibitor 1.0
100.0wt%

Formulation Example 3: Candy
50.0 wt% sugar
Minamata 33.0
Water 14.4
Organic acid 2.0
Fragrance 0.2
Retinal endothelial cell disorder inhibitor 0.4
100.0wt%

Formulation Example 4: Yogurt (hard / soft)
Milk 41.5wt%
Nonfat dry milk 5.8
Sugar 8.0
Agar 0.15
Gelatin 0.1
Lactic acid bacteria 0.005
Retinal endothelial cell disorder inhibitor 0.4
Perfume
Water residue
100.0wt%

Formulation Example 5: Soft drink
Fructose glucose liquid sugar 30.0wt%
Emulsifier 0.5
Retinal endothelial cell disorder inhibitor 0.3
Perfume
Purified water residue
100.0wt%

Formulation Example 6: Tablets
76.4 wt% sugar
Glucose 19.0
Sucrose fatty acid ester 0.2
Retinal endothelial cell disorder inhibitor 0.5
Purified water 3.9
100.0wt%

Formulation Example 7: Soft capsule
Brown rice germ oil 47.0wt%
Yuzu seed oil 40.0
Emulsifier 12.0
Retinal endothelial cell disorder inhibitor 1.0
100.0wt%

Formulation Example 8: Tablet
Lactose 54.0wt%
Crystalline cellulose 30.0
Starch degradation product 10.0
Glycerin fatty acid ester 5.0
Retinal endothelial cell disorder inhibitor 1.0
100.0wt%

Formulation Example 9: Eye drops Ketotifen fumarate 0.7 wt%
Sodium azulene sulfonate 0.2
Cromoglycate sodium 9.8
L-potassium aspartate 8.5
Allantoin 3.0
Tetrahydrozoline hydrochloride 0.5
Methyl sulfate neostigmine 0.05
Benzalkonium chloride solution 0.1
Glycerin 25.0
Retinal endothelial cell disorder inhibitor 1.0
pH regulator
Purified water balance
100.0wt%

Formulation Example 10: Cosmetic cream
Squalane 20.0wt%
Beeswax 5.0
Refined jojoba oil 5.0
Glycerin 5.0
Glycerol monostearate 2.0
Polyoxyethylene (20) sorbitan
Monostearate 2.0
Retinal endothelial cell disorder inhibitor 2.0
Preservative appropriate amount
Perfume
Purified water residue
100.0wt%

Formulation Example 11: Lotion
Ethanol 5.0wt%
Glycerin 2.0
1,3-butylene glycol 2.0
Polyethylene oleyl ether 0.5
Sodium citrate 0.1
Citric acid 0.1
Retinal endothelial cell disorder inhibitor 0.1
Purified water residue
100.0wt%

Formulation Example 12: Body gel
Macadamia nut oil 2.0wt%
Octyldodecyl myristate 10.0
Methylphenylpolysiloxane 5.0
Behenyl alcohol 3.0
Stearic acid 3.0
Batyl alcohol 1.0
Glyceryl monostearate 1.0
Tetraoleic acid polyoxyethylene sorbit
2.0
Hydrogenated soybean phospholipid 1.0
Ceramide 0.1
Retinol palmitate 0.1
Preservative appropriate amount
Camellia extract 1.0
Retinal endothelial cell disorder inhibitor 1.0
1,3-butylene glycol 5.0
Purified water residue
100.0wt%

Formulation Example 13: Latex
Squalane 4.0wt%
Vaseline 2.5
Cetanol 2.0
Glycerin 2.0
Lipophilic glyceryl monostearate
1.0
Stearic acid 1.0
L-Arginine 1.0
Retinal endothelial cell disorder inhibitor 0.5
Potassium hydroxide 0.1
Aroma
Purified water residue
100.0wt%

Formulation Example 14: Bath agent (liquid)
Propylene glycol 50.0wt%
Ethanol 20.0
Sodium sulfate 5.0
Retinal endothelial cell disorder inhibitor 0.5
Lanolin 0.5
Avocado oil 0.5
Dye 1.5
Fragrance 22.0
100.0wt%

  As described above, the present invention can provide a retinal endothelial cell disorder inhibitor containing a novel component as an active ingredient and an ophthalmic disease preventive / therapeutic agent using the same.

Claims (4)

Retinal endothelial cell disorder inhibitor comprising black rice extract as an active ingredient. A retinal endothelial cell disorder inhibitor comprising 2-hydroxy-5-[(3S) -3-hydroxybutyl] phenyl-β-D-glucoside as an active ingredient. A photoretinal endothelial cell disorder inhibitor comprising cyanidin and / or cyanidin glycoside as an active ingredient. The retinal endothelial cell disorder inhibitor according to claim 3, wherein the cyanidin glycoside is cyanidin-3-O-glucoside.

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