WO2018010170A1 - Nouveau mode de réalisation de flavonoïde, composition et application correspondantes - Google Patents

Nouveau mode de réalisation de flavonoïde, composition et application correspondantes Download PDF

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Publication number
WO2018010170A1
WO2018010170A1 PCT/CN2016/090190 CN2016090190W WO2018010170A1 WO 2018010170 A1 WO2018010170 A1 WO 2018010170A1 CN 2016090190 W CN2016090190 W CN 2016090190W WO 2018010170 A1 WO2018010170 A1 WO 2018010170A1
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hesperidin
hydrate
water
low molecular
filtrate
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PCT/CN2016/090190
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English (en)
Chinese (zh)
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刘力
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刘力
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Priority to PCT/CN2016/090190 priority Critical patent/WO2018010170A1/fr
Publication of WO2018010170A1 publication Critical patent/WO2018010170A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones

Definitions

  • the present invention relates to the field of medical technology, in particular to a novel compound entity which provides a flavonoid derivative, a vitamin drug, hesperidin. And compositions and their preparation and use.
  • Thermal analysis methods have important value and status in materials science, chemical or pharmaceutical analysis, and can be used alone to detect polymorphic changes in compounds or crystal forms in processes (Li Zengyu, Thermal Analysis, Tsinghua University Press, 1987 The first edition of August.)
  • Differential thermal analysis (DTA) is a more commonly used analytical method. It can be used for qualitative identification of substances as well as for quantitative analysis. As early as the second international thermal analysis conference in 1968, it was Barta Etc. used to identify unknown compounds. The pharmacopoeia of many countries abroad has already included differential thermal analysis, which has unique advantages especially for the identification of the same compound with different crystal forms.
  • the polymorphic form of the drug is not prepared in a rare or expensive solvent, and the polymorphic form of the compound can be unexpectedly obtained by conventional solvents, temperature, time, etc. or other subtle changes (Du Qing, Ping Neng . Polymorphism of buspirone hydrochloride, Journal of China Pharmaceutical University, 2000, 31(2): 102-104).
  • TG-DTA or TG-DSC The combination is more convenient for the analysis of compounds.
  • Hesperidin is both a vitamin and an additive for food. Hesperidin can inhibit hyaluronidase activity, reduce capillary permeability and brittleness of capillary wall, protect capillaries, and prevent microvascular rupture.
  • exudative diseases such as edema, hemorrhage, hypertension, diabetes, chronic venous insufficiency, hemorrhoids, scurvy, various ulcers and vascular contusions; at the same time, anti-inflammatory, anti-oxidant, anti-bacterial, anti-cancer, Regulates immunity, prevents radiation, protects the cardiovascular system, protects the liver, fights rheumatoid arthritis or arthritis, and is antiviral (including herpes simplex virus, herpes type I virus, parainfluenza type 3 virus, polio type I) Virus, respiratory syncytial virus, herpes type I virus, rotavirus, etc.), anti-ulcer, phlegm, asthma, blood sugar, etc.
  • Literature 2 He Lina, Ye Hua, Guo Fangqi, Research on Hesperidin Analysis Methods, Guangzhou Chemical, 2012, 40(14): 126-128
  • Literature 3 Qian Junxi, Wang Bochu, Research Progress in the Pharmacological Action of Hesperidin, Research and Development of Natural Products, CSCD No.1, 2010 - Page, 5 pages
  • Literature 4 Zhang Dongsong, Gao Huiyuan, Wu Lijun, Pharmacological Activity of Hesperidin Progress, Chinese Modern Chinese Medicine, 2006, 8(7): 25-27
  • Literature 5 Xiong Li, Li Jun, Wang Wen, et al.
  • the invention relates to a flavonoid derivative, which can inhibit hyaluronidase activity, reduce capillary permeability and brittleness of capillary wall, protect capillaries and prevent microvascular rupture and hemorrhage; and can be used for various exudative diseases, Such as edema, hemorrhage, hypertension, diabetes, chronic venous insufficiency, hemorrhoids, scurvy, various ulcers and vascular contusions; at the same time, anti-inflammatory, anti-oxidation, anti-bacterial, anti-cancer, immune regulation, radiation protection, protection Cardiovascular system, protection of liver, anti-rheumatic arthritis or arthritis, anti-virus (including herpes simplex virus, herpes type I virus, parainfluenza type 3 virus, poliovirus type I virus, respiratory syncytial virus, Herpes type I virus, rotavirus, etc.
  • various exudative diseases Such as edema, hemorrhage, hypertension, diabetes,
  • Hesperidin derivative which is an action of anti-oxidation, anti-oxidation, body regulation, treatment of dark spots, freckles and other skin diseases, namely hesperidin crystal water
  • the hesperidin crystal hydrate containing crystal water obtained by the present invention is surprisingly containing crystal water.
  • Hesperidin hydrate has lower wettability than hesperidin anhydrate, and hesperidin hydrate containing crystal water is more stable than hesperidin anhydride, which is convenient for storage and transportation, and is easy to prepare into a preparation.
  • the deliquescent of the anhydrate causes the air to be prevented from blocking or the like during the treatment, and the crystalline hydrate has good slidability, thereby improving the workability of the preparation.
  • crystalline solids have higher chemical stability and physical stability than amorphous forms and low crystallinity forms, and they may also exhibit improved hygroscopicity, bulk properties, and or flowability.
  • the thermal analysis (TG-DTA, etc.) spectrum of the hydrate of the present invention can be seen that the weight loss platform has a strong corresponding endothermic peak at about 50 to 130 ° C, and the thermal analysis spectrum shows hesperidin crystal hydration.
  • the results of the measurement [C 28 H 34 O 15 ⁇ 0.75H 2 O] and [ C 28 H 34 O 15 ⁇ H 2 O] by Karl Fischer method are in agreement with the results of thermal analysis.
  • Polymorphic forms of chemical drugs play an important role in drug research.
  • the discovery of useful compounds on the medicinal properties of the new crystals provides new opportunities to enhance the action characteristics of pharmaceutical products, and it expands the materials obtained by formulation scientists for designing pharmaceutical dosage forms such as drugs with target release profiles or other desirable properties.
  • a library of hesperidin crystal hydrates or polymorphs thereof is required in the art.
  • thermal analysis of the hesperidin crystal hydrate of the present invention (TG-DSC or TG-DTA)
  • the map has a corresponding endothermic peak under the weightless platform, and the thermal analysis map shows the corresponding characteristics of hesperidin crystal hydrate.
  • the hesperidin crystal hydrate of the present invention is an off-white to pale yellow powder and can be stably stored.
  • Hesperidin crystal hydrate samples were sealed and centrifuged for accelerated stability test, refer to the Chinese National Standard for Hesperidin [WS-10001-(HD-0489)-2002]
  • the method for determining the content, the hesperidin crystal hydrate prepared according to the different examples 1 , 2 and 3 of the present invention is determined by using hesperidin anhydrous as a control.
  • hesperidin hydrate of the present invention did not change significantly from 0 months to 6 months (30 ° C, RH 75%), and was greater than 98%, and the color and appearance thereof did not change significantly.
  • Hesperidin The crystallization hydrate and the hesperidin anhydrate sample were subjected to a wettability test, and about 2 g of hesperidin anhydride and the hydrate of the present invention were placed in a dry constant weight watch glass and accurately weighed at 25 ° C. Relative humidity is 75 %, samples were taken at 0h and 20h respectively, and the percentage of wetting gain was calculated. The results showed that the percentages of samples in Example 1, Example 2 and Example 3 were 0.39%, respectively.
  • the preparation method of hesperidin crystal hydrate is selected from the group consisting of:
  • the solid obtained is dissolved in one or more of a saturated aqueous solution of lime, sodium hydroxide, potassium hydroxide or sodium carbonate, and a 2-40 times amount of 20 to 60% of C 1 -C 6 is added .
  • Molecular alcohol such as methanol, ethanol, isopropanol
  • acetone or water stirred, placed, filtered, the filtrate obtained with dilute hydrochloric acid, sulfuric acid, phosphoric acid and other inorganic or organic acid solution, adjust the pH to 4 ⁇ 7, 25 °C Placed below, the precipitate is charged and analyzed, and the resulting precipitate is washed with water to near neutrality, and then a C 1 -C 6 low molecular alcohol, a C 2 -C 8 low molecular ether, a C 3 -C 8 low molecular ketone, a C 2 -C 8 low molecular ester, a C 4 -C 10 low molecular alkane or a cycloalkane,
  • Dissolving one or more of the obtained solids, saturated aqueous lime solution, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, and adding 2-60 times the amount of 20 to 60% of C 1 -C 6 Low molecular weight alcohol (such as methanol, ethanol, isopropanol), acetone or water, stirred, placed, filtered, and the resulting filtrate is added with a total amount of liquid of about 0.01-3% activated carbon (volume by weight ml: gram), stirred about After 10-60 minutes, suction filtration, the obtained filtrate is diluted with mineral acid or organic acid solution such as hydrochloric acid, sulfuric acid or phosphoric acid, and the pH is adjusted to 4 to 7 and placed below 25 °C to precipitate the precipitate.
  • mineral acid or organic acid solution such as hydrochloric acid, sulfuric acid or phosphoric acid
  • the concentration of the sodium hydroxide solution, the potassium hydroxide solution, and the sodium carbonate solution is usually preferably within 4 M; the concentration of the inorganic acid or organic acid solution such as hydrochloric acid, sulfuric acid, or phosphoric acid is usually within 6 M, and more preferably within 3 M.
  • the crystallization or recrystallization solvent of the product of the present invention is preferably selected from the group consisting of water and methanol, ethanol, isopropanol, acetonitrile, diethyl ether, acetone, isohexanone, dichloromethane, One or more of DMSO (dimethyl sulfoxide), formamide, DMF (N, N-dimethylformamide), and the like.
  • a lower alcohol or a lower alcohol is defined by the number of carbon atoms is C 1 -C 6 (i.e.: alcohols of 1 to 6 carbon atoms), such as methanol, ethanol, isopropanol, butanol and the like;
  • C 2 - The lower carbononitrile of C 6 is defined as C 2 -C 6 , such as acetonitrile, propionitrile, etc.
  • the low molecular ketone of C 3 -C 8 is defined as a ketone of 3-8 carbon atoms, including acetone, methyl ethyl ketone, Pentanone, ketone, isohexanone, etc.
  • the number of carbon atoms of lower ether or low molecular ether is defined as C 2 -C 8 , such as diethyl ether, diisopropyl ether, dibutyl ether, etc.; any class is described as 'low molecule', The labeling method for the number
  • the product of the invention can be dried at different temperatures (eg 10-80 ° C), drying time (1 Hours to several days), or with other desiccants (including silica gel, phosphorus pentoxide, anhydrous calcium chloride, anhydrous sodium sulfate, etc.) under ambient conditions, or using atmospheric or decompression methods for the final The product is dried. Its drying temperature is preferably Within 78 °C.
  • the preparation of hesperidin anhydride can be obtained by the different drying methods of the crystalline hydrate of the present invention, and can be prepared at different temperatures (for example, 40-100 ° C). , preferably 60-95 °C ), drying time (hours to days), or with other desiccant (including silica gel, molecular sieve, phosphorus pentoxide, sodium hydroxide, anhydrous sodium carbonate, anhydrous calcium chloride, anhydrous sodium sulfate, no
  • the final product may be dried under ambient conditions or under normal pressure or reduced pressure, or may be firstly mixed with anhydrous benzene for several days or distilled with water, and combined with Other drying methods described are obtained after drying, so that their moisture is Within 0.5%.
  • the moisture measurement of the present invention is carried out by Karl Fischer method, and the solvent is methanol, formamide, DMF (N, N-dimethylformamide), One or more of DMSO or the like is more preferably a mixed solvent of methanol and formamide.
  • the melting point of the hesperidin hydrate of the present invention was measured at a different time using a melting point apparatus, and the melting point analyzer was not corrected.
  • Powder X-ray diffraction is commonly used to characterize and/or identify polymorphs, for powder X-ray diffraction in characterization and / Or when identifying, use the modifier 'about' before reporting the peak. This is a common practice in the field of solid state chemistry due to the inherent variations in peaks.
  • the typical accuracy of the 2 ⁇ x-axis value of the powder peak is ⁇ 0.2° 2 ⁇ Level, therefore, the powder X diffraction peak appearing at 'about 8.0 ° 2 ⁇ means that when measured on most X-ray diffractometers, the peaks may be at 7.8 ° 2 ⁇ and 8.2 ° 2 ⁇ .
  • the change in peak intensity is the result of how each crystal is oriented in the sample container relative to the external X-ray source, and the orientation does not provide structural information about the crystal.
  • the invention provides different crystalline hydrates and polymorphs of hesperidin.
  • the invention provides different crystalline hydrates and polymorphs that are more stable than hesperidin anhydride.
  • the invention provides a process for the preparation of different crystalline hydrates and polymorphs of hesperidin.
  • the present invention provides a pharmaceutical composition comprising any one or more of hesperidin hydrate prepared by the method of the present invention. And one or more pharmaceutically acceptable excipients.
  • the invention further provides a process for the preparation of a pharmaceutical formulation comprising any one or more of hesperidin hydrate prepared by the process of the invention Combination with at least one or a pharmaceutically acceptable excipient.
  • the present invention further provides hesperidin hydrate for reducing capillary permeability and brittleness of capillary walls in the preparation of a human or mammal for treatment, Protects capillaries and prevents microvascular rupture; can be used for a variety of exudative diseases such as edema, hemorrhage, hypertension, diabetes, chronic venous insufficiency, hemorrhoids, scurvy, various ulcers and vascular contusions; Anti-inflammatory, anti-oxidant, anti-bacterial, anti-cancer, immune-modulating, anti-radiation, protecting the cardiovascular system, protecting the liver, anti-rheumatic arthritis or arthritis, anti-virus (including Herpes simplex virus, herpes type I virus, parainfluenza type 3 virus, poliovirus type I virus, respiratory syncytial virus, herpes type I virus, rotavirus, etc.
  • exudative diseases such as edema, hemorrhage, hypertension, diabetes, chronic venous
  • the flavonoid entity of the present invention is used for the preparation of hesperidin Water-soluble hesperidin, hesperidin sodium, hesperetin, quercetin, dioxin, geranin, methyl hesperidin, hesperidin dihydrochalcone, luteolin, holy grass Flavonoids or flavonoid derivatives such as phenol, olopol and neohesperidin Application in .
  • the hesperidin hydrate of the invention has for the preparation of a preparation for transvaginal administration containing hesperidin, an injection, an ophthalmic preparation, an external preparation, and the like, the preparation for gastrointestinal administration includes a tablet, a capsule, a granule, a pill, etc.; an injection Including small water needles, freeze-dried powder needles, large infusions, etc.
  • the gastrointestinal administration of the hesperidin hydrate of the present invention includes tablets, capsules, granules and the like; tablets (including ordinary tablets, buccal tablets, rapid disintegrating tablets, effervescent tablets, etc.), Capsules (including hard capsules, soft capsules, etc.), granules, pills, etc., which may contain pharmaceutically acceptable fillers such as starch, modified starch, lactose, microcrystalline cellulose, cyclodextrin, sorbitol, mannose Alcohol, calcium phosphate, amino acid, etc.; pharmaceutically acceptable disintegrating agents, such as starch, modified starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substituted hydroxypropyl cellulose, surface active Agent (sodium dodecyl sulfate, etc.); pharmaceutically acceptable wetting agents and binders, such as gelatinized starch, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyvinyl
  • composition for preparing a tablet or a hard capsule filling may be prepared by wet granulation in which some or all of the active ingredient or the excipient in powder form is mixed and then in the presence of a liquid. Further mixing, this causes the powder to clot into particles. The particles are sieved and or ground, dried, and then sieved to the desired particle size, which can then be tableted, or other excipients such as a glidant and / or lubricant.
  • compositions prepared as tablets can generally be prepared by dry mixing.
  • the combined composition of the active ingredient and excipients can be compacted into small pieces or flakes which are then comminuted into compacted granules which can be subsequently compressed into tablets.
  • the mixed composition can be directly compressed by a dry method and directly compressed to obtain a more uniform tablet.
  • Excipients that are particularly suitable for direct compression include microcrystalline cellulose, spray dried calcium lactate phosphate, and colloidal silica. The proper use of these and other excipients in direct compression is well known to those skilled in the art.
  • the capsule filling of the present invention may comprise any of the above-mentioned mixtures and particles or granules, the description of which is prepared as a tablet, but they are not subjected to the final step of preparing into a tablet.
  • Pill preparation 1 part by weight of the product of the invention is dissolved in 1-10 The portion of the weight of the molten pharmaceutically acceptable matrix is thoroughly stirred, and the dropping pellet is prepared in a coolant by a dropping method, the coolant is removed, and the pellet is dried.
  • the pharmaceutically acceptable matrix of the present invention includes, but is not limited to, poloxamer, glycerin gelatin, polyoxyethylene. 40 monostearate, stearic acid, stearyl alcohol, cetyl alcohol, glyceryl monostearate, polyethylene glycol 6000, polyethylene glycol 4000 Etc.; coolants include, but are not limited to, dimethicone, vegetable oil, liquid paraffin, ethanol, water, and the like.
  • the crystalline hydrate of the present invention is different from The deliquescent of the anhydrate prevents the air from being blocked during the treatment, and the crystallization hydrate has good slidability, thereby improving the operability of the preparation; and preparing the solid preparation It has good dissolution properties, making it easy to be absorbed into the blood circulation, improving bioavailability, and facilitating its rapid function.
  • the parts by weight of each component may be: hesperidin crystal hydrate 0.1-1, cosolvent 0.1-1 , antioxidant 0.02-0.5, metal complexing agent 0.01-0.2, osmotic pressure regulator 0.5-10, preservative 0.002-0.4, water 10-200 parts, plus pH Adjust the amount of the agent.
  • the lyophilized powder preparation is prepared by taking hesperidin hydrate , can be added pharmaceutically acceptable lyophilized support or co-agent, add water for injection, add pharmaceutically acceptable acid and alkali, stir to dissolve, adjust the pH to 7.5 ⁇ 10.0, add activated carbon 0.005 ⁇ 0.5% (W / V) stirring for 15 ⁇ 45min, filtration, hydration, sterile filtration, according to 20 ⁇ 600mg / bottle (based on the main drug), lyophilized, tampon, to get the finished product.
  • Hesperidin hydrate small volume injection and preparation process thereof hesperidin hydrate Injectable water and a pharmaceutically acceptable additive, for example, a pharmaceutically acceptable pH adjuster, a pharmaceutically acceptable antioxidant, an inert gas, filtered, sterilized to prepare a sterile small volume injection, the pH thereof Value is 7.5 Between 10.0.
  • a pharmaceutically acceptable additive for example, a pharmaceutically acceptable pH adjuster, a pharmaceutically acceptable antioxidant, an inert gas, filtered, sterilized to prepare a sterile small volume injection, the pH thereof Value is 7.5 Between 10.0.
  • the regulator may be a pharmaceutically acceptable inorganic or organic acid, an inorganic base or an organic base, or a Lewis acid or a base in a broad sense, and may contain one or more of them, and may be hydrochloric acid, phosphoric acid, propionic acid, acetic acid or the like.
  • Acetate such as sodium acetate, lactic acid and lactic acid pharmaceutically acceptable salts, citric acid pharmaceutically acceptable salts, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, phosphate, tartaric acid and its pharmaceutically acceptable salts, borax, Boric acid, succinic acid, hexanoic acid, adipic acid, fumaric acid, maleic acid, trishydroxyaminomethane, diethanolamine, ethanolamine, isopropanolamine, diisopropanolamine, 2-Amino-2-(hydroxymethyl) 1 ,3-propanediolamine, 1,2-hexanediamine, N- Methylglucamine, diisopropylamine and salts thereof, polyhydroxycarboxylic acids and pharmaceutically acceptable salts such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic acid, amino acids and amino acid salts, etc. One or several of them.
  • the pharmaceutically acceptable antioxidants and stabilizers may be sulfurous acid, sulfite, bisulfite, pyrosulfite, dithionite, thiosulfate, organic sulfur compound thiourea, glutathione. Peptide, dimercaptopropanol, thioglycolic acid and salt, thiolactic acid and pharmaceutically acceptable salt thereof, thiodipropionic acid and salt, phenol or a derivative thereof, such as gallic acid and its pharmaceutically acceptable salt, caffeic acid and its medicinal use Salt, ferulic acid and its pharmaceutically acceptable salt, di-tert-butyl-p-phenol, 2 , 5-dihydroxybenzoic acid, 2 , 5- Dihydroxybenzoate, salicylic acid or a salt thereof; amino acid and a salt thereof; ascorbic acid and ascorbate, isoascorbic acid and isoascorbate, nicotinamide, tartaric acid, nitrate, phosphate, pharmaceutically
  • the pharmaceutically acceptable isotonicity adjusting agent may be one or more of glucose, fructose, xylitol, sorbitol, mannitol, invert sugar, maltose, dextran, sodium chloride, potassium chloride, sodium lactate, and the like.
  • the ultrafilter may be a flat plate type, a coil type, a tube type, a hollow fiber type or a round box type, etc., preferably a roll type and a hollow fiber type ultrafilter, and the molecular weight of the interception is 50,000 to 300,000.
  • the filter removes the remaining heat source by using an ultrafiltration membrane with a molecular weight of 3,000 to 60,000, preferably an ultrafiltration membrane having a molecular weight of 3,000 to 20,000.
  • Dosage Usage Under normal circumstances, in the adult of 60-70kg body weight, take the hesperidin hydrate of the present invention 0.005 ⁇ 0.2g Lyophilized powder preparation or small water needle in 0.9% sodium chloride or 5 to 10% glucose 20 to 500 liters, for intravenous bolus injection or infusion, 1 to 2 times a day, hesperidin hydrate hydrate Object 0.9% sodium chloride or 5 to 10% glucose infusion preparation is administered intravenously at the same dose as before; intramuscular injection: taking the drug of the present invention 0.020 to 0.2g The lyophilized powder preparation is dissolved in water for injection, intramuscularly, 1 to 2 times a day; the child is used in half or more.
  • the dose administered by the gastrointestinal tract is usually taken orally: in an adult of 60-70 kg body weight, 5-500mg / time, 1-3 times / day, children use more than half of the amount.
  • the products of the invention further provide for the use of a flavone derivative such as methyl hesperidin or diosmin.
  • the invention further provides for the preparation of the product of the invention for the preparation of hesperidin hydrate and diosmin or its solvent combination
  • composition comprising one or more of the compounds or a pharmaceutically acceptable salt thereof, wherein the hesperidin hydrate and the dioxin
  • the weight ratio of Siming or its solvent compound or its pharmaceutically acceptable salt is 2:1 to 1:20, among which hesperidin hydrate and dioxin
  • the weight of Siming or its solvent compound or its pharmaceutically acceptable salt can be calculated according to the weight of its crystalline hydrate or
  • the weight of its anhydrate is calculated.
  • the weight ratio of the pharmaceutical composition may be: the weight ratio of hesperidin hydrate to diosmin or diosmin hydrate is 1:1 to 10 (The above components can be converted into an anhydrate by the hydrate or its hydrate to calculate the weight or weight ratio of the two drugs); for example, 1 g of the composition or a unit dose of the pharmaceutical composition may contain diosmin or Diosmin monohydrate 0.9 g, hesperidin hydrate 0.1 g; 0.5 g of the composition or a unit dose of the pharmaceutical composition may contain diosmin 0.45 g, hesperidin 0.05 g (The above components can be calculated according to the hydrate or converted to an anhydrate); or 0.25g of the composition and a unit dose of the drug containing diosmin or diosmin hydrate 0.45g, hesperidin 0.025g (The above components can be calculated according to the hydrate or converted to an anhydrate); a unit dose of the pharmaceutical composition contains diosmin or diosmin hydrate 0.40g
  • the product of the present invention further provides a pharmaceutical composition for preparing an entity containing the compound, which is one or more of hesperidin hydrate and neohesperidin or a solvent compound thereof or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition wherein the weight ratio of hesperidin hydrate to neohesperidin or a solvent compound thereof or a pharmaceutically acceptable salt thereof is 1 : 2 ⁇ 10 : 1
  • the weight of hesperidin hydrate and neohesperidin or a solvent compound thereof or a pharmaceutically acceptable salt thereof may be calculated according to the weight of the crystalline hydrate or the weight of the anhydrous substance, and the pharmaceutical composition is divided
  • the composition can also be used for the preparation of an antidepressant health food or medicine.
  • a unit dose of the pharmaceutical composition may contain neohesperidin or a solvent compound thereof 0.45 g, hesperidin 0.45 g (The above components can be calculated according to the hydrate or converted to an anhydrate); or a unit dose of the pharmaceutical composition contains neohesperidin or its solvent compound 0.25g, hesperidin 0.25g (The above components can be calculated according to the hydrate or converted to an anhydrate); or a unit dose of the pharmaceutical composition contains neohesperidin or its solvent compound 0.1g, hesperidin 0.1g (The above components can be calculated according to the hydrate or converted to an anhydrate); or a unit dose of the pharmaceutical composition contains neohesperidin or its solvent compound 0.1g, hesperidin 0.4g (The above components can be calculated according to the hydrate or converted to an anhydrate); or a unit dose of the pharmaceutical composition contains neohesperidin or its solvent compound 0.05g, hesperidin 0.2g (The above components can
  • a unit dose of the pharmaceutical composition contains the flavonoid compound of the present invention.
  • the weight of the entity is preferably 1-1000 mg.
  • the code numbers in the drawings of the present invention may be judged based on the overall contents or characteristic data in the present specification to determine which embodiment or which compound they belong to. If the data in the attached drawing is unclear, the data in this manual is used as a supplementary basis or explanation, or the data in the drawing and the specification are mutually supplementary. If the map number is not clear, etc., it can be determined by logical inference according to the specification and the drawing.
  • Figure 1 is a thermogram of hesperidin 0.75 hydrate (Example 1);
  • Figure 2 is X powder diffraction pattern data of hesperidin 0.75 hydrate (Example 1);
  • Figure 3 is X powder diffraction pattern data of hesperidin 0.75 hydrate (Example 1);
  • Figure 4 is an X powder diffraction pattern of hesperidin 0.75 hydrate (Example 1);
  • Figure 5 is a thermogram of hesperidin 1 hydrate (Example 2);
  • Figure 6 is X powder diffraction pattern data of hesperidin 1 hydrate (Example 2);
  • Figure 7 is an X powder diffraction pattern of hesperidin 1 hydrate (Example 2);
  • Figure 8 is a thermogram of hesperidin 0.75 hydrate (Example 3);
  • Figure 9 is X powder diffraction pattern data of hesperidin 0.75 hydrate (Example 3);
  • Figure 10 is an X powder diffraction pattern of hesperidin 0.75 hydrate (Example 3);
  • the term 'obtained' refers to a compound isolated at a valuable level of purity, including but not limited to greater than 90%, 95%, 96%, 97%, 98%, and 99% purity levels.
  • the purity level can be determined by high performance liquid chromatography.
  • composition refers to a composition of a drug, which may contain at least one pharmaceutically acceptable carrier.
  • 'pharmaceutically acceptable excipient' refers to a pharmaceutically acceptable carrier or vehicle suitable for administration of a compound as provided herein, which includes any such carrier known to those skilled in the art to be employed in a particular mode of administration.
  • solutions or suspensions for parenteral, intradermal, subcutaneous, or topical application may include sterile diluents (eg, water for injection, saline solutions, fixed oils, and the like); synthetic fatty vehicles (eg, Polyethylene glycol, glycerin, propylene glycol, etc.; antibacterial agents (for example, benzyl alcohol, methyl p-hydroxypropionate, ethyl p-hydroxypropionate, etc.); antioxidants (for example, ascorbic acid, sodium hydrogen sulfite, etc.); Mixture (for example, EDTA And so on; buffers (phosphate, citrate, etc.); and or for osmotic pressure regulating substances (eg, sodium chloride, glucose, etc.
  • hesperidin hydrate may optionally be admixed with one or more pharmaceutically acceptable excipients and may be administered orally in the form of tablets, capsules, dispersible powders, granules. Or contain, for example, A suspension of 0.05-5% suspending agent, or parenterally in the form of a sterile solution or suspension, in an isotonic medium containing 0.05-5% suspending agent.
  • These pharmaceutical preparations may contain, for example, about From 25% to about 90% of the active ingredient together with the carrier, more usually from 5% to 60% by weight of active ingredient.
  • Infrared spectroscopy Potassium bromide tablets were used to determine the infrared spectrum data of the samples.
  • the instruments used included the American thermoelectric company NICOLET 5700 FTIR Spectrometer, Nexus intelligent Fourier transform infrared spectrometer (Thermo Nicolet) and so on.
  • Thermal analysis test conditions Setaram Setsys 16, sample volume of about 3-10mg, heating rate: 10K / min, N 2 flow rate: 50ml / min, temperature: room temperature ⁇ 400 °C or so.
  • Example 1 Preparation of hesperidin 0.75 hydrate In a stainless steel barrel, 2 kg of dry orange peel powder was added, 12 times of water was added, 1 time of ethanol was immersed, and ultrasonic assisted extraction was carried out at a frequency between 25 kHz and 50 kHz.
  • the obtained solid is stirred with an appropriate amount of DMF (N, N-dimethylformamide), dissolved, about 400 ml with water, about 20 ml of acetonitrile, and about 20 ml of isopropanol, and recrystallized, suction filtered, and the obtained solid is used in an appropriate amount.
  • DMF N, N-dimethylformamide N-dimethylformamide
  • the solid was washed three times with ethanol, the solid was washed three times with isopropyl alcohol, washed five times with water, and filtered with suction.
  • the solid obtained was diluted by air at about 30 ° C for about 4 hours, and then dried at about 71 ° C for 3 hours to obtain white color.
  • UV is taken from the product of the invention (calculated as anhydrate), accurately weighed, dissolved in 50% ethanol solution and quantitatively diluted to prepare a solution containing about 20 mg per 1 ml, according to spectrophotometry (Chinese Pharmacopoeia 2000) The second edition of Appendix II A), the absorbance is measured at a wavelength of 285 nm, and the absorption coefficient ( E 1% 1 cm) is in the range of 318 to 338; ESI-MS: m/z: 611 [M+1] + ; infrared spectrum ( ⁇ KBr max cm -1 ): 3546.2 , 3475.7 , 3425.7 , 2979.9 , 2938.6 , 2917.3 , 1648.2 , 1607.3 , 1520.1 , 1467.7 , 1443.7 , 1402.3 , 1359.5 , 1300.1 , 1277.8 , 1241.5 , 1205.2 , 1184.4 , 1156.1 , 113
  • Example 2 Preparation of Hesperidin 1 Hydrate
  • the first part of the filtrate is precipitated; the first part of the obtained filter residue is further immersed in 10 times of water, saturated lime water is added, stirred, and the pH is controlled to about 11.5, soaked for 2 hours, filtered, and the residue is discarded, and the second part is obtained.
  • the filtrate was adjusted to pH 4.5 with 3M hydrochloric acid solution, placed, and the precipitate was analyzed to obtain a precipitate of the second portion of the filtrate; suction filtration was performed to separately collect the precipitate of the first portion of the filtrate and the precipitate of the second portion of the filtrate, and washed to near the middle.
  • organic solvent DMF N, N-dimethylformamide
  • the mixture was allowed to stand, and the precipitate was analyzed by suction.
  • the solid was washed twice with ethanol and twice with isopropanol.
  • the mixture was thoroughly washed twice with acetone and filtered with suction.
  • the obtained solid was applied with an appropriate amount of DMF (N. N-dimethylformamide)
  • DMF N. N-dimethylformamide
  • UV is taken from the product of the invention (calculated as anhydrate), accurately weighed, dissolved in 50% ethanol solution and quantitatively diluted to prepare a solution containing about 20 mg per 1 ml, according to spectrophotometry (Chinese Pharmacopoeia 2000) The second edition of Appendix II A), the absorbance is measured at a wavelength of 285 nm, and the absorption coefficient ( E 1% 1 cm) is in the range of 318 to 338; ESI-MS: m/z: 611 [M+1] + ; infrared spectrum ( ⁇ KBr max cm -1 ) : 3546.6 , 3474.8 , 3425 , 3081.7 , 2980.2 , 2938.8 , 2916.9 , 1647.9 , 1607.4 , 1519.9 , 1467.3 , 1443.6 , 1402.2 , 1359 , 1299.7 , 1277.8 , 1241 , 1204.9 , 1184.2 , 1156
  • the X-ray powder diffraction pattern (see Figure 6 and Figure 7) has corresponding characteristics at locations including the following 2 ⁇ values , approximately: 5.27, 7.12, 7.78, 8.11, 8.56, 11.39, 12.23, 13.24, 13.70, 15.61, 15.88, 16.29, 17.18, 18.29, 18.66, 19.67, 20.82, 21.23, 21.42, 21.73, 22.33, 22.60, 23.30, 23.81, 24.29, 24.55, 24.91, 25.44, 26.88, 26.62, 28.47, 28.77, 29.18, 29.72, 30.55, 31.15, 32.05, 32.92, 34.69, 35.06, 36.19, 37.28, 38.19, 38.51, 39.63, 40.21, 44.04, 46.42, 47.58; Elemental analysis, theoretical value: C 53.50%, H5.77%; measured values: C
  • Example 3 Preparation of hesperidin 0.75 hydrate In a stainless steel bucket, add 2.2 kg of dry orange peel powder, add 8 times the amount of ethanol, 3 times the amount of water, soak for 3 hours and then use the frequency between 25 kHz and 50 kHz.
  • the solid was washed with ethanol three times, thoroughly washed with acetone twice, suction filtered, washed with water until near neutral, and suction filtered to obtain a precipitate of the first and second portions of the filtrate;
  • the filtrate of the third part is adjusted to pH 5 with 3M hydrochloric acid solution.
  • the precipitate was charged and analyzed by suction filtration, and the solid obtained was washed with ethanol three times, thoroughly washed with acetone twice, suction filtered, washed with water until near neutral, and suction filtered to obtain a precipitate of the third portion of the filtrate; A portion of the precipitate of the second portion of the filtrate and the precipitate of the third portion of the filtrate are placed in a flask, and 8 times the amount of water is added and stirred for about 1 hour, saturated lime water is added, pH is adjusted to 10 - 11.5, stirred, and filtered. 2M hydrochloric acid solution was added to the filtrate, the pH was adjusted to 3, and the precipitate was allowed to be analyzed.
  • the solid was washed with ethanol three times, and washed thoroughly with diethyl ether, ethyl acetate, petroleum ether and chloroform. Fully rinsing twice with acetone, suction filtration, adding appropriate amount of DMF and DMSO to the obtained solid, heating and stirring to dissolve, adding appropriate amount of activated carbon, stirring for about 30 minutes, filtering, and filtering the obtained filtrate with water about 60 ml, isopropanol About 30ml, about 30ml of acetone, crystallization operation, left at 0 ⁇ -10 °C for 2 days, the solid is fully analyzed, the solid is filtered and washed with ethanol three times, and thoroughly rinsed twice with acetone, water 3 times, suction filtration, the obtained solid was recrystallized from about 100 ml of DMF, about 500 ml of water, and about 30 ml of isopropanol, and recrystallized three times according to the law, and the solid was subjected to analysis
  • the solid was washed three times with acetone, washed twice with acetone, washed with water, washed three times, and filtered with suction.
  • the solid obtained was recrystallized twice according to the law, and left at 0 to -10 °C for 2 days to allow the solid to be analyzed and pumped.
  • the product of the present invention is about 5 mg (calculated as anhydrate), and added with 5 ml of ethanol to dissolve, and then allowed to cool, and 0.2 g of magnesium powder is added, and about 2 ml of hydrochloric acid is slowly added dropwise along the tube wall to obtain a purple-red color.
  • UV is taken according to the product of the invention (calculated as anhydrate), accurately weighed, dissolved in 50% ethanol solution and quantitatively diluted to prepare a solution containing about 20 mg per 1 ml, according to spectrophotometry (Chinese Pharmacopoeia 2000) The second edition of Appendix II A), the absorbance is measured at a wavelength of 285 nm, the absorption coefficient ( E 1% 1 cm) is in the range of 318 to 338; the infrared spectrum ( ⁇ KBr max cm -1 ): 3545.0, 3476.3, 3423.2, 2938.0 , 2917.7, 2850.4, 1648.1, 1607.1, 1519.9, 1467.3, 1443.6, 1402.1, 1359.8, 1300.2, 1277.5, 1241.7, 1205.2, 1184.2, 1155.9, 1132.3, 1096.7, 1069.2, 1033.0, 972.9, 877.8, 846.8, 817.2, 767, 743
  • Example 4 Preparation of freeze-dried powder preparation 10 g of hesperidin hydrate (Example 1 method or Example 2 method or Example 3) Method), adding xylitol 2.0 to 5g, adding fresh water for injection 500ml, stirring, adjusting the pH to 8.5 ⁇ 10.0 with phosphoric acid and 1M sodium hydroxide solution. Solubilize into a solution, add activated carbon 0.01 ⁇ 0.5% (W / V) for 15 ⁇ 45min, filter, hydrate to 600ml, filter with 0.22 micron microporous membrane, press 50mg / bottle, 100mg / bottle or 200mg / bottle (based on the main drug anhydrate) divided, freeze-dried, tampon, to get the finished product.
  • W / V activated carbon 0.01 ⁇ 0.5%
  • Example 5 Preparation of Injections Hesperidin hydrate 10 g (Prepared according to Example 1 or Example 2 or Example 3 Method prepared), add mannitol 40g, add 40-60 ° C water for injection 500ml, stir, adjust the pH with 8.0 ⁇ 9.5 with 1M citric acid and sodium hydroxide Soluble into a solution, add activated carbon 0.01 ⁇ 0.5% (W / V) for 15 ⁇ 45min, filter, hydrate to 600ml, with 0.22 Filtration by micron microfiltration membrane or filtration with ultrafiltration membrane with molecular weight of 6000-20000, according to 50, 100mg / bottle or 200mg / bottle (by hesperidin 1 Hydrate meter) Packing, freeze-drying, tamping, and finished product.
  • Example 6 Preparation of a small water needle preparation Hesperidin hydrate 10.2 g (Prepared according to Example 1 or Example 2 Method or the preparation of Example 3), adding L-arginine 0.8g, EDTA disodium 0.1g, adding 400ml of water for injection, 2M sodium lactate to adjust the pH to 7.5 ⁇ 9.0, add activated carbon 0.01% (W / V), stir for 15 ⁇ 45min, filter, hydrate to 500ml, filter with 0.22 micron microporous membrane, press 5ml / The bottles are packed and sterilized to obtain finished products.
  • Example 7 Hesperidin 1 hydrate 10 g (prepared according to the method of Example 1 or the method of Example 2 or the method of Example 3) Add 400ml of water for injection, stir, adjust the pH to 7.6 ⁇ 9.0 with 1M sodium hydroxide solution and sodium dihydrogen phosphate solution, dissolve into solution, add activated carbon 0.01% ( W / V Stir for 15 to 45 minutes, filter, replenish water to 500ml, filter with 0.22 micron microporous membrane or filter with ultrafiltration membrane with molecular weight of 6000-10000. 5ml / bottle parts, freeze-dried, tampon, to get the finished product.
  • Example 8 Hesperidin hydrate Preparation of sodium chloride infusion: 10 g of hesperidin hydrate (Example 1 Preparation or Example 2 Method or Example 3 method), sodium chloride 85g, sodium tartrate 1.1g, EDTA disodium 0.2g, added to the water for injection, stirred, adjusted with 2M sodium citrate solution In the range of 7.2-8.5, dissolve, add water for injection to 10000ml, add 0.05% activated carbon, stir for about 10-30 minutes, filter for decarbonization, and then pass 0.22um. Fine filtration of microporous membrane, potted in 50ml or 100ml infusion bottle, sterilized, packaged.
  • hesperidin hydrate prepared according to the method of Example 1
  • microcrystalline cellulose sodium carboxymethyl starch over 100 mesh sieve
  • the solution is made into soft material, granulated through 18 - 24 mesh, dried, over 14 - 20
  • hesperidin hydrate prepared according to the method of Example 1
  • microcrystalline cellulose sodium carboxymethyl starch over 100 mesh sieve
  • the solution is made into soft material, granulated through 18 - 24 mesh, dried, over 14 - 20
  • the solution is made into soft material, granulated through 18 - 24 mesh, dried, over 14 - 20 After sieving the whole granules, add the micro-silica gel to mix, compress, inspect and package.
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 1 or the method of Example 2 or Example 3), microcrystalline cellulose, starch 100 mesh sieve, using 10% gelatinized starch to make soft material, granulate through 18 - 24 mesh, dry, sieve through 14 - 20 mesh, add magnesium stearate and fill the capsule.
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 1 or the method of Example 2 or Example 3), microcrystalline cellulose, lactose 100 mesh sieve, using 10% gelatinized starch to make soft material, granulate through 18 - 24 mesh, dry, sieve through 14 - 20 mesh, add magnesium stearate and fill the capsule.
  • Example 14 Granules of hesperidin hydrate (100 mg/pack)
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 1 or the method of Example 2 or Example 3) , mannitol, lactose, cyclamate, food flavor through a 100 mesh sieve, using 8 % povidone K-30 ethanol aqueous solution (ethanol 8 : water 2 ) to make a soft material, through 18 - 24 mesh sieve granulation, Dry at 60 °C, add 100 mesh sieve of xanthan gum, sieve through 14 - 20 mesh, mix well, add 100 mesh sieve of xanthan gum, and pack.
  • Prescription amount of hesperidin hydrate 1g (prepared according to the method of Example 2), 400ml of water for injection, plus 10ml of glycerin , Povidone K-30 0.5g, sodium hydrogen sulfite 0.6g, EDTA disodium 0.3g, borax 2.5g, sodium chloride 3.1g, adjusted to sodium hydrogen phosphate and disodium hydrogen phosphate solution 7.1-8.0, stir to dissolve, then add water for injection to 500ml, stir evenly, test, filter with 0.22-0.45 ⁇ m microporous membrane to clear, Dispense in a sterilized clean eye drops bottle, sterilize, let cool, that is.
  • Example 16 Pharmaceutical composition of hesperidin hydrate and diosmin (50 mg/450 mg/tablet)
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 2), diosmin, microcrystalline cellulose, sodium carboxymethyl starch over 100 Mesh sieve, use 10% gelatinized starch solution to make soft material, sieve through 18 - 24 mesh, dry, pass through 14 - 20 mesh sieve, add 100
  • the magnesium stearate of the mesh sieve is mixed, compressed, inspected and packaged.
  • a prescribed amount of hesperidin hydrate (prepared as in Example 1), diosmin, microcrystalline cellulose, sodium carboxymethyl starch over 100 Mesh sieve, use 10% gelatinized starch solution to make soft material, sieve through 18 - 24 mesh, dry, pass through 14 - 20 mesh sieve, add 100
  • the magnesium stearate of the mesh sieve is mixed, compressed, inspected and packaged.
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 2), diosmin, microcrystalline cellulose, sodium carboxymethyl starch over 100 Mesh sieve, use 10% povidone K-30 ethanol water (ethanol 8 : water 2 ) solution to make soft materials, sieve through 18 - 24 mesh, dry, after 14 - 20 mesh sieve, add Mix 100 mg of magnesium stearate, compress, test, and package.
  • Hesperidin hydrate (weight calculated as anhydrate) 50g
  • Diosmin (weight based on anhydrous) 450g
  • a prescribed amount of hesperidin hydrate (prepared according to Example 1 or Example 2 or Example 3 Prepared by the method), diosmin, microcrystalline cellulose, sodium carboxymethyl starch over 100 mesh sieve, soft material with 10% gelatinized starch solution, granulated through 18 - 24 mesh, dried, over 14 - 20 After sieving the whole granules, the magnesium stearate added with a 100 mesh sieve is mixed, compressed, inspected and packaged.
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 1 or the method of Example 2 or Example 3) was passed over 100. After meshing, add to the molten poloxamer, polyethylene glycol 6000 matrix, stir well, use dimethyl silicone oil as a coolant, drop the pellets, dry, and package.
  • Diosmin (weight based on anhydrate) 45g
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 1 or prepared by the method of Example 2 or Example 3) and dioxin After 100 mesh sieve, add to the molten poloxamer, polyethylene glycol 6000 matrix, stir well, use dimethyl silicone oil as the coolant, drop the pellet, dry, and package.
  • Hesperidin hydrate (weight calculated as anhydrate) 50g
  • Neohesperidin weight calculated as anhydrate 50g
  • a prescribed amount of hesperidin hydrate (prepared according to the method of Example 2), diosmin, microcrystalline cellulose, sodium carboxymethyl starch was passed through a 100 mesh sieve, 10% povidone K-30 ethanol water (ethanol 9 : water 1 ) solution is made into soft material, sieved through 18 - 24 mesh, dried, filtered through 14 - 20 mesh sieve, added 100 The magnesium stearate of the mesh sieve is mixed, compressed, inspected and packaged.
  • Hesperidin hydrate (weight calculated as anhydrate) 50g
  • Neohesperidin weight calculated as anhydrate
  • hesperidin hydrate a prescribed amount of hesperidin hydrate (as in Example 1 Preparation of the method), diosmin, microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose over 100 mesh sieve, using 10% gelatinized starch solution to make soft material, over 18 - 24 mesh Sieve granules, dry, over After 14 - 20 mesh sieving, the micro-silica gel with 100 mesh sieve is mixed, compressed, inspected and packaged.
  • Hesperidin hydrate (weight calculated as anhydrous) 250g
  • Neohesperidin (calculated as anhydrate) 250g
  • a prescribed amount of hesperidin hydrate (prepared according to Example 1 or Example 2 or Example 3 Preparation, diosmin, microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose over 100 mesh sieve, with 10% povidone K-30 aqueous ethanol solution (ethanol 9 : water 1
  • ethanol 9 water 1
  • Appropriate amount of soft material granulated by 18 - 24 mesh, dried, sieved through 14 - 20 mesh, and then mixed with 100 mesh sieve of magnesium stearate, compressed, inspected and packaged.
  • Hesperidin hydrate (weight calculated as anhydrous) 250g
  • Neohesperidin weight calculated as anhydrate 50g
  • a prescribed amount of hesperidin hydrate (prepared according to Example 1 or Example 2 or Example 3 Preparation, diosmin, microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose over 100 mesh sieve, with 10% povidone K-30 aqueous ethanol solution (ethanol 9 : water 1
  • ethanol 9 water 1
  • Appropriate amount of soft material granulated by 18 - 24 mesh, dried, sieved through 14 - 20 mesh, and then mixed with 100 mesh sieve of magnesium stearate, compressed, inspected and packaged.
  • Hesperidin hydrate (weight calculated as anhydrous) 500g
  • Neohesperidin weight calculated as anhydrate 50g
  • a prescribed amount of hesperidin hydrate (prepared according to Example 1 or Example 2 or Example 3 Preparation, diosmin, microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose over 100 mesh sieve, with 10% povidone K-30 aqueous ethanol solution (ethanol 9 : water 1
  • ethanol 9 water 1
  • Appropriate amount of soft material granulated by 18 - 24 mesh, dried, sieved through 14 - 20 mesh, and then mixed with 100 mesh sieve of magnesium stearate, compressed, inspected and packaged.

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Abstract

L'invention concerne un nouveau mode de réalisation d'un flavonoïde présentant une hygroscopicité réduite et une stabilité au stockage améliorée. Le flavonoïde est applicable pour la préparation d'un aliment, d'un aliment naturel ou d'un produit pharmaceutique ou d'une composition correspondante pour conférer des effets préventifs ou un traitement d'états de santé, y compris : la fragilité capillaire, l'insuffisance veineuse chronique, les hémorroïdes, le scorbut, l'ulcère veineux du membre inférieur, le syndrome prémenstruel, la microangiopathie et le lymphoedème de membre supérieur secondaire chez un patient diabétique, les maladies cardiovasculaires, la modulation du sucre sanguin et des lipides sanguins, un effet antimicrobien et anti-inflammatoire, antiviral, anticancéreux, la modulation de l'immunité, un effet antirayonnement, un effet de protection du foie, un effet antipolyarthrite rhumatoïde ou antiarthrite, anti-ulcère, l'élimination des mucosités, la distension abdominale, l'indigestion, la perte d'appétit, un effet antidépresseur, les taches noires, les taches de rousseur, un effet antiradicalaire et antioxydant.
PCT/CN2016/090190 2016-07-15 2016-07-15 Nouveau mode de réalisation de flavonoïde, composition et application correspondantes WO2018010170A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2021210925A1 (fr) * 2020-04-14 2021-10-21 재단법인 경기도경제과학진흥원 Composition pour le traitement, la prévention ou l'amélioration du lymphœdème
CN115671120A (zh) * 2022-11-18 2023-02-03 广东省科学院动物研究所 一种二氢查尔酮在制备祛痰和/或治疗慢性阻塞性肺疾病的药物中的应用

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CN101704867A (zh) * 2009-11-03 2010-05-12 国家海洋局第三海洋研究所 一种柚皮苷或橙皮苷的制备方法
CN104119411A (zh) * 2014-08-12 2014-10-29 四川天予植物药业有限公司 一种高纯度橙皮苷的制备方法
CN105418705A (zh) * 2015-12-08 2016-03-23 桂林三宝生物科技有限公司 从柑橘皮、果中提取橙皮苷和新橙皮苷的方法
CN105837646A (zh) * 2015-01-16 2016-08-10 刘力 黄酮类的新化合物实体及组合物和用途

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CN101704867A (zh) * 2009-11-03 2010-05-12 国家海洋局第三海洋研究所 一种柚皮苷或橙皮苷的制备方法
CN104119411A (zh) * 2014-08-12 2014-10-29 四川天予植物药业有限公司 一种高纯度橙皮苷的制备方法
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CN105418705A (zh) * 2015-12-08 2016-03-23 桂林三宝生物科技有限公司 从柑橘皮、果中提取橙皮苷和新橙皮苷的方法

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WO2021210925A1 (fr) * 2020-04-14 2021-10-21 재단법인 경기도경제과학진흥원 Composition pour le traitement, la prévention ou l'amélioration du lymphœdème
CN115671120A (zh) * 2022-11-18 2023-02-03 广东省科学院动物研究所 一种二氢查尔酮在制备祛痰和/或治疗慢性阻塞性肺疾病的药物中的应用

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