CN105837646A - Flavonoid new chemical entity, composition and use - Google Patents

Flavonoid new chemical entity, composition and use Download PDF

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CN105837646A
CN105837646A CN201510024470.6A CN201510024470A CN105837646A CN 105837646 A CN105837646 A CN 105837646A CN 201510024470 A CN201510024470 A CN 201510024470A CN 105837646 A CN105837646 A CN 105837646A
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hydrate
hesperidin
filter
filtrate
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刘力
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Abstract

The invention provides a flavonoid new chemical entity, which has little moisture absorption and good storage stability, and is applicable to preparation of food or health food or drugs for reduction of capillary fragility, treatment or prevention of chronic venous insufficiency, hemorrhoid, scurvy, venous lower limb ulcer, premenstrual syndrome, diabetics' microangiopathy and secondary upper limb lymphedema, cardiovascular diseases, blood glucose and lipid regulation, antisepsis and inflammation reduction, virus resisting, cancer resisting, immunity adjustment, radiation protection, liver protection, rheumatoid arthritis or arthritis resisting, ulcer resisting, phlegm eliminating, asthma relieving, black spots, freckles, free radical resistance, and oxidation resistance.

Description

The noval chemical compound entity of flavonoid and compositions and purposes
Technical field
The present invention relates to pharmaceutical technology field, be specifically to provide chromocor derivative, a kind of vitamin medicaments The noval chemical compound entity of Hesperidin and compositions and preparation thereof and purposes.
Background technology
The polymorphic of chemicals has critical role in drug research.At field of pharmacology, drug crystal forms and medicine The research work of hydrate or drug solvent compound has been listed in country 12 great new drug initiative science and technology key special subjects Research range.The solvated compounds of compound includes hydrate the most being produced and apply in medicine very early, Such as the antitumor drug cyclophosphamide that American Pharmacopeia 36 editions, European Pharmacopoeia 8.1 editions and Chinese Pharmacopoeia 2010 editions record Room temperature exists with monohydrate form at solid, and this chemical entities begins to lose water of crystallization at about 40 DEG C, 72 DEG C Left and right just loses whole water of crystallization.Since nearest more than 20 years, not only there is the different crystal forms of same molecular formula medicine Constantly it is found, and there is same parent but the research of different molecular formula drug solvent compound the most constantly obtains new Progress.Even regulation hypoglycemic medicament dapagliflozin is all studying the medicine system with dapagliflozin propylene glycol hydrate as core Agent, although the toxicity of propylene glycol is more than water.
Heat analysis method has important value and status in material science, chemistry or pharmaceutical analysis etc., can individually use Come detection compound polymorphic or during crystal formation change (Li Zengyu, " heat analyze ", publishing house of Tsing-Hua University, In August, 1987 first edition).Differential thermal analysis (DTA) is the analysis method more commonly used, and it can be not only used for determining of material Property differentiate it can also be used to quantitative analysis, in the international hot analysis meeting of Second Committee of nineteen sixty-eight, just by Barta etc. It is used for identifying unknown compound.The pharmacopeia of external many countries records differential thermal analysis already, and the method is particularly with tool The advantage that the discriminating of the same compound of different crystal forms has uniqueness.Before more than ten years, differential thermal analysis not only exists in China Chemical industry, pharmacy system are the most widely used, and also begin in complicated TCD identification application (Zhang Hanming, etc., The differential thermal analysis research of Margarita powder and adulterant thereof, Chinese patent medicine, 1999,21 (4): 173-175).In crystal formation is studied, differential Scanning (DSC) can complete the multinomial researchs such as pharmaceutical purity assessment, discriminating, polycrystalline state analysis, and (Zhu Bing, Liu Ji great waves .DSC exists Application in pharmaceutical analysis, process industry, 2008,15:64-66), (Lin Kejiang, Chen Wei, You Qidong. means of differential scanning calorimetry Method detection Nateglinide polymorphic, Acta Pharmaceutica Sinica, 2002,37 (1): 46-49).And the polymorphic of medicine not rare or Expensive solvent could be prepared, meaning can be exceeded by conventional solvent, temperature, time etc. or other trickle change Material obtain compound polymorphic (Du Qing, its energy flat. the polymorphic research of buspirone hydrochloride, China Medicine University is learned Report, 2000,31 (2): 102-104).At hot analysis field, dividing of compound is given in the combination of TG-DTA or TG-DSC especially Analysis brings more convenient.
Hesperidin had both belonged to vitamin drug, also served as the additive of food, Hesperidin energy hyaluronidase inhibitor, Reduce the saturating property of blood capillary and the fragility of capillary wall, protect blood capillary, prevent the effect that microvascular is hemorrhage； Can be used for multiple EXUDATIVE DISEASES, as edema, hemorrhage, hypertension, diabetes, chronic venous insufficiency, hemorrhoid, Vitamin C deficiency, various ulcer and blood vessel contusion etc.；Have simultaneously antiinflammatory, antioxidation, antibacterial, anticancer, regulation immunity, Radioprotective, protection cardiovascular system, the liver protecting, resisting rheumatoid arthritis or arthritis, antiviral (include list Pure property herpesvirus, simplex type I virus, parainfluenza 3 type virus, poliomyelitis I type virus, respiratory tract close spore Precursor virus, simplex type I virus, rotavirus etc. have inhibitory action), antiulcer, eliminate the phlegm, relieving asthma, blood pressure and blood lipoid Regulation, blood pressure regulating, blood circulation healthy, to Hydroxyl Radical Scavenging and antioxidation, body regulation, Treatment dermatosis aspect effect such as black speck, freckle.Presently disclosed document only report Hesperidin [molecular formula: C28H34O15,Molecular weight: 610.56, CAS:520-26-3], [list of references 1, Zhu Rongli, etc., Pericarpium Citri junoris in Pericarpium Citri Reticulatae The research of glycosides extraction process, food and fermentation industries, the 6th phase in 2012,57-60 page；Document 2, He Lina, leaf China, Guo Fang is powerful, Hesperidin analysis technique study, Chemical Industry in Guangzhou, and 2012,40 (14): 126-128；Document 3, Qian Junzhen Wang Baichu, the Advance on Pharmacological Activities of Hesperidin, research and development of natural products, CSCD the 1st phase-page in 2010, Page totally 5；Document 4, Dong Songgao Hui Yuanwuli army, the pharmacology activity research progress of Hesperidin, contemporary Chinese Chinese medicine, 2006,8(7):25-27；Document 5, Bears Li Lijun Wang Wen, etc., the Hesperidin therapeutical effect to collagen-induced arthritis in rats And Partial Mechanism, Medical University Of Anhui's journal, 2011,46 (10): 1013-1017；Document 6, Li Wei, Liu Juan, Liu Gan, Li Jun, Hesperidin to the protective effect of acute chemical hepatic injury mice and mechanism, Medical University Of Anhui's journal, 2010,45(3):346-350；] open source literature also reports that Hesperidin is used for preparing the flavonoid such as hesperidin methyl, diosmin Derivant；But up to the present, the most still there is no the hesperidin crystal hydrate of the disclosed document report present invention [C28H34O15·n H2O, wherein n=0.75,1.0] and its production and use.
Summary of the invention
Involved in the present invention is chromocor derivative, energy hyaluronidase inhibitor, reduces the saturating property of blood capillary and hair The fragility of thin blood vessel wall, protects blood capillary, prevents the effect that microvascular is hemorrhage；Can be used for multiple exudative disease Disease, such as edema, hemorrhage, hypertension, diabetes, chronic venous insufficiency, hemorrhoid, vitamin C deficiency, various ulcer With blood vessel contusion etc.；There is antiinflammatory, antioxidation, antibacterial, anticancer, regulation immunity, radioprotective, the protection heart simultaneously Vascular system, the liver protecting, resisting rheumatoid arthritis or arthritis, antiviral (include herpes simplex virus, Simplex type I virus, parainfluenza 3 type virus, poliomyelitis I type virus, respiratory tract close spore precursor virus, simplex type I disease Poison, rotavirus etc. have inhibitory action), antiulcer, eliminate the phlegm, relieving asthma, the regulation of blood pressure and blood lipoid, blood pressure regulating, Blood circulation is healthy, to Hydroxyl Radical Scavenging and antioxidation, body regulation, the treatment skin such as black speck, freckle The hesperidin derivative of skin disease aspect effect, i.e. hesperidin crystal hydrate and preparation thereof and purposes, its molecular formula is [C28H34O15·n H2O, wherein n=0.75,1.0].
The hesperidin crystal hydrate containing water of crystallization that the present invention obtains, it is surprising that the orange containing water of crystallization Skin glycosides hydrate low in hygroscopicity is in Hesperidin anhydride, and the Hesperidin hydrate containing water of crystallization is than Hesperidin anhydride more The existence that energy is stable, it is simple to store and transport, it is easy to make preparation.Additionally, the deliquescence of anhydride makes when processing Air to be completely cut off prevents adhesion etc., and crystalline hydrate has good sliding, thus improves grasping of preparation The property made.Furthermore, crystalline solid has higher than amorphous form and the chemical stability of low-crystallinity form and physically stable Property, they can also behave as hygroscopicity, bulk properties and or the mobility improved.
Distinctive, the heat of the hydrate of the present invention is analyzed (TG-DTA etc.) collection of illustrative plates and be can be seen that at about 50～130 DEG C Weightless platform there is strong corresponding endothermic peak, thermal analysis curue spectrum demonstrates hesperidin crystal hydrate [C28H34O15·0.75H2O]、[C28H34O15·H2O], measure moisture result and hot analysis result phase with Karl_Fischer method It coincide.
The polymorphic of chemicals has critical role in drug research, the useful chemical combination on the medicine of new crystal The discovery of thing provides new chance once improving the action characteristic of drug products, and it expands formulation science man design example The storehouse of the material obtained as having the pharmaceutical dosage form of the medicine of targeted release profile or other desired characteristic, this area Need hesperidin crystal hydrate or its polymorph.
It is surprising that distinctive, the heat of the hesperidin crystal hydrate of the present invention analyze (TG-DSC or TG-DTA) having the endothermic peak of correspondence under the weightless platform of collection of illustrative plates, thermal analysis curue spectrum demonstrates hesperidin crystal hydrate Corresponding characteristic etc..
The hesperidin crystal hydrate of the present invention, for off-white color to pale yellow powder, energy stable storage.The present invention is real Execute that hesperidin crystal hydrate sample prepared by example 1-3 method is the most airtight is accelerated stability test in cillin bottle, With reference to the content assaying method of the China National Drug Standard [WS-10001-(HD-0489)-2002] of Hesperidin, with Pericarpium Citri junoris Glycosides anhydride is reference substance, and mensuration is prepared by various embodiments of the invention 1, embodiment 2 and embodiment 3 method Hesperidin crystal hydrate, it was thus unexpectedly found that the content of the Hesperidin hydrate of the present invention was at 0 month to 6 months Not having significant change (30 DEG C, under RH75%) before and after in, be all higher than 98%, its color and outward appearance are also without significant change.Will Hesperidin crystal hydrate and Hesperidin anhydride sample carry out drawing moist test, take Hesperidin anhydride and the present invention Hydrate about 2g, is placed in the surface plate of dry constant weight, precise weighing, 25 DEG C, relative humidity be 75%, respectively In test 0h and 20h sampling, calculate the percentage rate drawing wet weightening finish, result display embodiment 1, embodiment 2 and enforcement The percentage rate of the sample weightening finish of example 3 is respectively 0.39%, 0.12%, 0.45%, and the percentage rate of anhydride weightening finish reaches 1.79%, its difference highly significant, result shows, Hesperidin anhydride draws moist more much higher than the hydrate of the present invention, The hesperidin crystal hydrate of the present invention can preferably storage-stable.
Hesperidin crystal hydrate preparation method is selected from:
Method A., in reaction vessel, adds the dry Pericarpium Citri junoris powder of the pulverizing of constant weight, adds 3-60 times amount (bulking value Than=gram: milliliter) water, C1-C6Low mass molecule alcohol (such as methanol, ethanol, isopropanol, butanol etc.), in acetone One or more soak and by ultrasonic extraction or microwave extraction 0.1-2 hour, then adds saturated limewater, hydroxide One or more in sodium solution, potassium hydroxide solution, sodium carbonate liquor, stirring, control pH and be about 9-13, so Extract or microwave extraction 0.1-3 hour in immersion and with ultrasonic assistant, filter separating solid substances, obtain the filter of Part I Liquid and Part I filtering residue；The filtrate of gained Part I is with mineral acid or organic acid such as dilute hydrochloric acid, sulphuric acid, phosphoric acid Solution, regulates pH to 4～7, places, makes precipitation fully separate out, and filters, the precipitate of Part I filtrate；Gained Part I filtering residue is again with the water of 2-30 times amount, C1-C6Low mass molecule alcohol (such as methanol, ethanol, isopropanol etc.), acetone In one or more in soak ultrasonic extraction or microwave extraction 0.1-2 hour, then add saturated limewater, hydroxide One or more in sodium solution, potassium hydroxide solution, sodium carbonate liquor, stirring, control pH and be about 9-13, so Soak and by ultrasonic extraction or microwave extraction 0.1-2 hour, filter, the filtrate of gained Part II with hydrochloric acid, sulphuric acid, The mineral acids such as phosphoric acid or organic acid soln, regulate pH to 4～7, places, makes precipitation fully separate out；Filter (sucking filtration or Centrifugal filtration etc.), obtain the precipitate of Part II filtrate；Collect Part I filtrate and the precipitate of Part II filtrate, It is washed to weakly acidic pH, obtains wet solids；
By in gained solids saturated limewater solution, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor One or more dissolve, add the 20 of 2-40 times amount～the C of 60%1-C6Low mass molecule alcohol (such as methanol, ethanol, isopropyl Alcohol), acetone or water, stirring, place, filter, gained filtrate is with mineral acids such as dilute hydrochloric acid, sulphuric acid, phosphoric acid or has Machine acid solution, regulate pH to 4～7,25 DEG C are arranged below, make precipitation fully separate out, gained precipitate is washed with water to Weakly acidic pH, then use C1-C6Low mass molecule alcohol, C2-C8Low molecule ether, C3-C8Low molecule ketone, C2-C8Low molecule ester, C4-C10Low molecule alkane or cycloalkane, petroleum ether, C1-C6Low molecule halogenated hydrocarbons, including dichloromethane, two chloroethenes The abundant rinse of one or more in alkane, chloroform etc. 1～10 times, filter, gained solid add appropriate organic solvent first In amide, DMF (DMF), one or more, after being stirred to dissolve, add proper amount of active carbon, Stir about 15-60 minute, crosses and filters to remove activated carbon, by gained filtrate water, C1-C6Low mass molecule alcohol, C2-C6Low Level nitrile, C3-C8Low molecule ketone in one or more carry out crystallization operation, 20～about-25 DEG C placements, be preferable over 10～ About-15 DEG C placements, make precipitation fully separate out, and filter, with water, C1-C6Low mass molecule alcohol washing solid 1-8 time, take out Filter, by gained solid with in appropriate Methanamide, DMF (DMF), DMSO one or more, After being stirred to dissolve, add proper amount of active carbon, stir about 15-60 minute, cross and filter to remove activated carbon, by gained filtrate water, C1-C6Low mass molecule alcohol, C2-C6Rudimentary nitrile, C3-C8Low molecule ketone in one or more carry out recrystallization operation, So can carry out one or many recrystallization operation, 20～about-25 DEG C placements further in accordance with the law, be preferable over 10～-10 DEG C Left and right is placed, and makes solid fully separate out, and filters, with water, C1-C6Low mass molecule alcohol, C3-C8Low molecule ketone, C2-C8 Low molecule ether, C2-C8Low molecule ester, C4-C10Low molecule alkane or cycloalkane, petroleum ether, C1-C6Low molecule halogen Wash solid 1-8 time for hydrocarbon, filter, gained solids is made thinner in being dried, obtain hesperidin crystal hydrate；Wherein, Frequency during supersound extraction can be between 10kHz-2000kHz, the power of microwave extraction can be Between 100W-1000W；Sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor concentration generally within 4M； The concentration of the mineral acids such as hydrochloric acid, sulphuric acid, phosphoric acid or organic acid soln is generally within 6M, more preferably within 3M.
Or method B. is in reaction vessel, add the dry Pericarpium Citri junoris powder of the pulverizing of constant weight, add 3-60 times amount (weight Volume ratio=gram: milliliter) water, C1-C6Low mass molecule alcohol (as methanol, ethanol, isopropanol, butanol etc.) soak Extract 0.5-4 hour, then add in saturated limewater, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor One or more, stirring, control pH=10-13, such soak extraction 1-4 hour, filter separating solid substances, gained the The filtrate of a part, with mineral acid or organic acid solns such as dilute hydrochloric acid, sulphuric acid, phosphoric acid, regulates pH to 4～7, places, Precipitation is made fully to separate out；Gained Part I filtering residue extracts with the water soaking of 2-30 times amount again, then add saturated limewater, One or more in sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, stirring, control pH=10-13, So soak extraction 1-4 hour, filters, and the filtrate of gained Part II is with mineral acids such as dilute hydrochloric acid, sulphuric acid, phosphoric acid Or organic acid soln, regulate pH to 4～7, place, make precipitation fully separate out；Filter, collect Part I filtrate and The precipitate of Part II filtrate, is washed to weakly acidic pH, obtains wet solids；
By gained solids use, saturated limewater solution, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor In one or more dissolve, add the 20 of 2-60 times amount～the C of 60%1-C6Low mass molecule alcohol (such as methanol, ethanol, different Propanol), acetone or water, stirring, place, filter, gained filtrate adds up the activated carbon (body of the about 0.01-3% of amount of liquid Long-pending weight ratio=milliliter: gram), stir about 10-60 minute, sucking filtration, gained filtrate is with dilute hydrochloric acid, sulphuric acid, phosphoric acid Deng mineral acid or organic acid soln, regulating pH to 4～7,25 DEG C arranged below, makes precipitation fully separate out, and is sunk by gained Shallow lake thing washes with water to weakly acidic pH, then uses C1-C6Low mass molecule alcohol, C2-C8Low molecule ether, C3-C8Low molecule ketone, C2-C8Low molecule ester, C4-C10Low molecule alkane or cycloalkane, petroleum ether, C1-C6Low molecule halogenated hydrocarbons, including two One or more abundant rinses 1 in chloromethanes, dichloroethanes, chloroform etc.～10 times, filter, add suitable by gained solid The organic solvent DMSO (dimethyl sulfoxide) of amount, Methanamide, in DMF (DMF) a kind of or Several, after being stirred to dissolve, add activated carbon (weight of activated carbon and the liquor capacity of the about 0.01-3% of total amount of liquid Than=gram: milliliter), stir about 15-60 minute, cross and filter to remove activated carbon, by gained filtrate water, C1-C6Low point Sub-alcohol, C2-C6Rudimentary nitrile, C3-C8Low molecule ketone in one or more carry out crystallization operation, 20～-25 DEG C of left sides Right placement, is preferable over 10～about-15 DEG C placements, makes precipitation fully separate out, and filters, with water, C1-C6Low mass molecule alcohol Washing solid 1-8 time, filters, by gained solid appropriate DMSO, Methanamide, DMF (N, N-dimethyl methyl Amide) in one or more, after being stirred to dissolve, add the activated carbon (volume weight of the about 0.01-3% of total amount of liquid Ratio=milliliter: gram), stir about 15-60 minute, cross and filter to remove activated carbon, by gained filtrate water, C1-C6Low point Sub-alcohol, C2-C6Rudimentary nitrile, C3-C8Low molecule ketone in one or more carry out recrystallization operation, may be used the most in accordance with the law Carry out one or many recrystallization operation further, in 20～about-25 DEG C placements, be preferable over 10～about-10 DEG C placements, Make solid fully separate out, filter, with water, C1-C6Low mass molecule alcohol, C3-C8Low molecule ketone, C2-C8Low molecule Ether, C2-C8Low molecule ester, C4-C10Low molecule alkane or cycloalkane, petroleum ether, C1-C6In low molecule halogenated hydrocarbons One or more washing solids 1-10 time, filter, make thinner dry by gained solids, obtain hesperidin crystal hydrate. Wherein, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor concentration generally more preferably within 4M；Hydrochloric acid, The concentration of the mineral acid such as sulphuric acid, phosphoric acid or organic acid soln is generally within 6M, more preferably within 3M.
Crystallization or the recrystallization solvent of product of the present invention preferably are selected from: water and methanol, ethanol, isopropanol, acetonitrile, ether, Acetone, hexone, dichloromethane, DMSO (dimethyl sulfoxide), Methanamide, DMF (N, N-dimethyl formyl Amine) etc. in one or more.
Lower alcohol or the carbon number of low mass molecule alcohol in the present invention are defined as C1-C6(that is: the alcohol of 1-6 carbon atom), Such as methanol, ethanol, isopropanol, butanol etc.；C2-C6The carbon number of rudimentary nitrile be defined as C2-C6, as acetonitrile, Propionitrile etc.；C3-C8Low molecule ketone be defined as the ketone of 3-8 carbon atom, including acetone, butanone, pentanone, hexanone, Hexone etc.；The carbon number of rudimentary ether or low molecule ether is defined as C2-C8, such as ether, diisopropyl ether, butyl ether etc.；Close It is described as " low molecule ", " rudimentary " as long as the labeling method of the amount of carbon atom of compound is the application's in any kind Text occurs once, the carbon number of other any unmarked similar compound being described as " low molecule " with The quantity indicated is consistent.
The drying mode of the product of the present invention can be that (1 hour arrives in different temperatures (such as 10-80 DEG C), drying time A few days) or with other desiccant (including silica gel, phosphorus pentoxide, anhydrous calcium chloride, anhydrous sodium sulfate etc.) Under environmental condition or use the mode of normal pressure or decompression that last product is dried.Its baking temperature is preferably 78 Within DEG C.
The preparation of Hesperidin anhydride can be obtained through different drying meanss by the crystalline hydrate of the present invention, and its preparation can In different temperatures (such as 40-100 DEG C, preferably 60-95 DEG C), drying time (a few hours are to a few days) or do with other Drying prescription (include silica gel, molecular sieve, phosphorus pentoxide, sodium hydroxide, natrium carbonicum calcinatum, anhydrous calcium chloride, anhydrous Sodium sulfate, anhydrous magnesium sulfate etc.) environmental condition under or and use the mode of normal pressure or decompression that last product is entered Row is dried, it is possible to is first processed or the method for distillation band water by the anhydrous benzene mixing placement a few days, and combines described herein Other drying means obtains after drying so that its moisture is within 0.5%.
The determination of water of the present invention uses Karl_Fischer method, and solvent is methanol, Methanamide, DMF (N, N-dimethyl Methanamide), one or more in DMSO etc., be more preferably methanol and Methanamide mixed solvent.The Pericarpium Citri junoris of the present invention The fusing point of glycosides hydrate is measured at different time melting point apparatus, and melting point detector is not corrected.
Powder X-ray diffraction generally can be used to characterize and/or differentiate polymorph, is characterizing for powder X-ray diffraction and/or is differentiating Time, before report peak value, use modifier " about ".In view of the intrinsic change of peak value, this is the usual of solid-state chemical arts Way.The usual accuracy of 2 θ x-axle values of coatings spectral peak is in ± 0.2 ° of 2 θ rank, therefore, with " about 8.0 ° of 2 θ The powder X-ray diffraction maximum occurred means when measuring on most of x-ray diffractometers, and peak may be 7.8 ° of 2 θ and 8.2 ° Between 2 θ.The change of peak intensity is the result how each crystal is orientated relative to external X-ray source in shuttle, Orientation effect does not provide the structural information about crystal.
The present invention is on the one hand, it is provided that the different crystalline hydrate of Hesperidin and polymorphic.
The present invention is on the one hand, it is provided that the different crystalline hydrate more more stable than Hesperidin anhydride and polymorphic.
The present invention is on the other hand, it is provided that crystalline hydrate that Hesperidin is different and polymorphous preparation method.
The present invention provides a kind of Pharmaceutical composition on the other hand, including any one or more of by the side of the present invention Hesperidin hydrate prepared by method, and one or more pharmaceutically acceptable excipient.
It is an object of the invention to provide hesperidin crystal hydrate containing dose therapeutically effective as effective ingredient and The pharmaceutical composition of pharmaceutically acceptable carrier.
The method that the present invention further provides preparation pharmaceutical preparation, including any one or more of by the side of the present invention Hesperidin hydrate prepared by method and at least one or the merging of pharmaceutically acceptable excipient.
The present invention further provides Hesperidin hydrate, in preparation for treating the reduction blood capillary of people or mammal Property and the fragility of capillary wall thoroughly, protects blood capillary, prevents the effect that microvascular is hemorrhage；Can be used for multiple EXUDATIVE DISEASES, as edema, hemorrhage, hypertension, diabetes, chronic venous insufficiency, hemorrhoid, vitamin C deficiency, Various ulcer and blood vessel contusion etc.；Have simultaneously antiinflammatory, antioxidation, antibacterial, anticancer, regulation immunity, radioprotective, Protection cardiovascular system, the liver protecting, resisting rheumatoid arthritis or arthritis, antiviral (include herpes simplex Virus, simplex type I virus, parainfluenza 3 type virus, poliomyelitis I type virus, respiratory tract close spore precursor virus, bleb Rash I type virus, rotavirus etc. have inhibitory action), antiulcer, eliminate the phlegm, relieving asthma, the regulation of blood pressure and blood lipoid, blood Pressure regulation, blood circulation be healthy, to Hydroxyl Radical Scavenging and antioxidation, body regulation, treatment black speck, Purposes in the treatment such as dermatosis aspect effects such as freckle or the food of prevention or health food or pharmaceutical composition.
Hesperidin hydrate of the present invention have for preparation containing Hesperidin through gastrointestinal administration preparation, injection, eye By the purposes in preparation, external preparation etc., include tablet, capsule, granule, drop pill etc. through gastrointestinal administration； Injection includes little liquid drugs injection, freeze-dried powder, infusion solutions etc..
The Hesperidin hydrate of the present invention includes tablet, capsule, granule etc. for prepare through gastrointestinal administration； Tablet (include ordinary tablet, buccal tablet, speed disintegrating tablet, effervescent tablet etc.), capsule (including hard capsule, soft capsule etc.), Granule, drop pill etc., wherein can contain pharmaceutically acceptable filler, as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, aminoacid etc.；Pharmaceutically acceptable disintegrating agent, Such as starch, modified starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl Base cellulose, surfactant (sodium lauryl sulphate etc.)；Pharmaceutically acceptable wetting agent and binding agent, such as glue Change starch, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyvinylpyrrolidone, alginic acid and Salt；Pharmaceutically acceptable lubricant and fluidizer, as stearic acid, magnesium stearate, Macrogol 4000-8000, Pulvis Talci, micropowder silica gel, Stepanol MG etc.；Pharmaceutically acceptable sweeting agent and essence, as aspartame, Cyclamate, saccharin sodium, sucralose, edible essence etc..
Obtain compositions can prepared, in wet granulation mistake by wet granulation for preparing tablet or hard capsule implant Cheng Zhong, the excipient of some or all of active component or powder type is mixed, enters one the most again in the presence of liquid Step mixing, this causes powder grumeleuse to become particle.This particle is sieved and or grind, be dried, then sieve, expire The granularity hoped, then this particle can make tablet, or add before preparation other excipient, such as fluidizer and/ Or lubricant.
The compositions being prepared as tablet generally can be prepared by being dry mixed.Such as, after active component and excipient mix Compositions can be compacted into small pieces or thin slice, be then comminuted into the granule of compacting, the granule of this compacting can be with After be suppressed into tablet.
As the replacement of dry granular method, mixed compositions can obtain evenly with dry method direct compression, direct compression Tablet.The excipient being particularly suitable for direct compression includes microcrystalline Cellulose, the lactose calcium phosphate of spray drying and colloid two Silicon oxide.These and other excipient is proper use of in direct compression is to the skill in this area with experience and technical ability Art personnel are known.
The capsule filling of the present invention can comprise any of above mixture and particle or granule, and it describes with reference to preparation Piece agent, but they do not carry out the last step being prepared as tablet.
Prepared by drop pill: the product of the present invention of 1 part of weight is dissolved in the melted pharmaceutically acceptable of 1-10 part weight In substrate, fully stir evenly, in coolant, prepare drop pill, throw away the refrigerant with dropping preparation method, be drying to obtain drop pill.This The pharmaceutically acceptable substrate of invention includes singly being not limited to poloxamer, glycerin gelatine, polyoxyethylene 40 monostearate Ester, stearic acid, octadecanol, hexadecanol, glyceryl monostearate, polyethylene glycol 6000, Macrogol 4000 etc.； Coolant includes but not limited to dimethicone, vegetable oil, liquid paraffin, ethanol, water etc..
The crystalline hydrate of the present invention is different from the deliquescence of anhydride and makes the air to be completely cut off when processing prevent adhesion etc., And crystalline hydrate has good sliding, thus improve the operability of preparation；And make the solid preparation of preparation have There is good dissolving out capability so that it is readily absorbed by entering blood circulation, improve bioavailability, and be conducive to fast Speed plays its effect.
Dosing eyes preparation or the preparation of ophthalmic preparation
In the preparation of hesperidin crystal hydrate eye drop, the parts by weight of each component can be: hesperidin crystal hydrate 0.1-1, cosolvent 0.1-1, antioxidant 0.02-0.5, metal chelating agent 0.01-0.2, osmotic pressure regulator 0.5-10, anti- Rotten agent 0.002-0.4, water is 10-200 part, separately adds pH adjusting agent appropriate.
Its preparation method may is that and added in appropriate water for injection by Hesperidin hydrate, adds cosolvent, stirring, examination Dissolve, add antioxidant, preservative, osmotic pressure regulator, stabilizer, pH adjusting agent, water, stir, Cheng Rong Aqueous, make pH=7.5～10.0, filter in the mode such as microporous filter membrane or ultrafiltration, detection, aseptic subpackaged in sterilized In clean plastics eyedrops bottle and get final product.
The injection of Hesperidin hydrate, its preparation method is:
The preparation method of freeze-dried powder is: take Hesperidin hydrate, can add pharmaceutically acceptable lyophilizing support Agent or auxiliary shape agent, inject with water, add pharmaceutically acceptable soda acid, be stirred to dissolve, and regulation pH is 7.5～10.0, Adding activated carbon 0.005～0.5% (W/V) and stir 15～45min, filter, moisturizing, aseptic filtration, by 20～600mg / bottle (in terms of principal agent) subpackage, lyophilization, tamponade, obtain finished product.
Hesperidin hydrate injection with small volume and preparation technology thereof: Hesperidin hydrate injects with water and pharmaceutically may be used The additives accepted, such as: pharmaceutically acceptable pH adjusting agent, pharmaceutically acceptable antioxidant, noble gas, Filtering, degerming make sterilizing injection with small volume, its pH value is between 7.5～10.0.
Pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable mineral acid or organic acid, inorganic base or organic Alkali, it is also possible to be lewis acid or the alkali of broad sense, can be contained one or several, can be hydrochloric acid, phosphoric acid, third Acid, acetic acid and acetate, such as sodium acetate etc., lactic acid and lactic acid pharmaceutical salts, citric acid pharmaceutical salts, sodium carbonate, carbonic acid Hydrogen sodium, potassium bicarbonate, sodium hydroxide, phosphate, tartaric acid and pharmaceutical salts thereof, Borax, boric acid, succinic acid, oneself Acid, adipic acid, fumaric acid, maleic acid, trihydroxy aminomethane, diethanolamine, ethanolamine, isopropyl Hydramine, diisopropanolamine (DIPA), 2-amino-2-(methylol) 1,3-PD amine, 1,2-hexamethylene diamine, N-methyl glucose amine, Diisopropylamine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts, as glucuronic acid, gluconic acid, lactobionic acid, One or several in malic acid, threonic acid THREONIC ACID., glucoheptonic acid, aminoacid and amino acid salts etc..
Pharmaceutically acceptable antioxidant and stabilizer can be sulfurous acid, sulphite, bisulfites, burnt sulfurous Hydrochlorate, dithionite, thiosulfate, organosulfur compound thiourea, glutathion, dimercaptopropanol, BAL, mercapto Guanidine-acetic acid and salt, 2-mercaptopropionic acid and pharmaceutical salts thereof, thio-2 acid and salt, phenol or derivatives thereof, such as gallic acid And pharmaceutical salts, caffeic acid and pharmaceutical salts thereof, ferulic acid and pharmaceutical salts thereof, di-t-butyl Pyrogentisinic Acid, 2,5-dihydroxy Benzoic acid, DHB salt, salicylic acid or its salt；Aminoacid and its salt；Ascorbic acid and Vitamin C Hydrochlorate, arabo-ascorbic acid and erythorbate, nicotiamide, tartaric acid, nitrate, phosphate, acetic acid pharmaceutical salts, Citrate, EDTA and edta salt, such as EDETATE SODIUM, Ethylenediaminetetraacetic Acid Calcium Salt, EDTA tetra-sodium, N-bis-(2 -ethoxy) one or several in glycine etc..
Pharmaceutically acceptable isoosmotic adjusting agent can be glucose, fructose, xylitol, sorbitol, mannitol, turn Change one or more in sugar, maltose, dextran, sodium chloride, potassium chloride, sodium lactate etc..
Go thermal source and degerming mode can be add dosing amount 0.005～3% activated carbon remove thermal source, microporous filter membrane is degerming And pressure sterilizing, it would however also be possible to employ heat sterilization, remove thermal source.In hyperfiltration process, ultrafilter can be selected for flat, volume Formula, tubular type, hollow fiber form or circle boxlike etc., preferably rolling and hollow fiber form ultrafilter, use to retain and relatively divide Protonatomic mass be 5 ten thousand to 30 ten thousand filter membrane remove major part heat generation material and antibacterial after, then use retain average molecular matter The ultrafilter membrane of amount 3000～60000 removes residue thermal source, the preferably ultrafilter membrane of relative molecular mass 3000～20000.
Consumption usage: generally, in the adult of 60-70kg body weight, take Hesperidin hydrate 0.020 of the present invention～ The freeze-dried powder of 0.2g or little liquid drugs injection in glucose 20～500 milliliter, are made quiet in 0.9% sodium chloride or 5～10% Arteries and veins is injected or instils, every day 1～2 times, 0.9% sodium chloride of Hesperidin hydrate or 5～10% glucose The route of administration of great transfusion preparation is intravenous injection, and dosage is the same；Intramuscular injection: take medicine 0.020 of the present invention～ 0.2g freeze-dried powder is dissolved in water for injection, intramuscular injection, every day 1～2 times；Child's amount of halving is used above. Through gastrointestinal administration dosage, it is generally oral: in the adult of 60-70kg body weight, 25-500mg/ time, 1-3 Times/day, child's amount of halving is used above.
The product of the present invention further provides for the purposes for preparing the chromocor derivative such as hesperidin methyl or diosmin. The present invention further provides the product of the preparation present invention for preparing Hesperidin hydrate and diosmin or its solvent chemical combination The purposes of the pharmaceutical composition of one or more compositions in thing or its pharmaceutical salts, wherein, Hesperidin hydrate and buchu Taking charge of bright or its solvated compounds or its pharmaceutical salts weight ratio is 2:1～1:20, wherein, and Hesperidin hydrate and buchu Take charge of bright or its solvated compounds or its pharmaceutical salts weight both to calculate according to its crystalline hydrate weight, it is possible to according to The weight of its anhydride calculates.
The weight ratio of pharmaceutical composition can be: Hesperidin hydrate and diosmin or diosmin hydrate weight ratio For 1:1～10 (said components all can convert with its hydrate or its hydrate be anhydride calculate two medicines weight or Weight ratio)；Such as, the medicine of 1g compositions or a unit dose can contain diosmin or diosmin hydrate 0.9g, Hesperidin hydrate 0.1g；The medicine of 0.5g compositions or a unit dose can contain diosmin 0.45g, Hesperidin 0.05g (said components can be all anhydride calculated weight according to hydrate or conversion)；Or 0.25g compositions With in the medicine of a unit dose containing diosmin or diosmin hydrate 0.45g, Hesperidin 0.025g (above-mentioned group Dividing can be all anhydride calculated weight according to hydrate or conversion)；The department Han buchu in the pharmaceutical composition of one unit dose Bright or diosmin hydrate 0.40g, Hesperidin 0.10g；Or the department Han buchu in the pharmaceutical composition of a unit dose Bright 0.30g, Hesperidin 0.20g；Or the 0.25g Han diosmin in the pharmaceutical composition of a unit dose, Hesperidin 0.25g；Or the 0.20g Han diosmin in the pharmaceutical composition of a unit dose, Hesperidin 0.40g；Above-mentioned each medicine Principal agent component in compositions the most all can be converted as anhydride calculated weight with its hydrate or its hydrate；At above-mentioned group Compound can contain pharmaceutically acceptable adjuvant or excipient.This pharmaceutical composition is mainly used in treating chronic venous Functional defect, hemorrhoid, hydrarthrosis, venous leg ulcers, premenstrual tension syndrome, the microangiopathy of diabetics Become and Secondary cases upper limb lymphedema etc..
Code name in the accompanying drawing of the present invention, if any the person of not indicating, can come according to entire content in this specification or performance data Carry out a volume judgement, determine that it belongs to which embodiment or which compound.If affiliated accompanying drawing diagram data has unintelligible Place with data in this specification for supplement according to or explanation, or accompanying drawing and description in data complement one another explanation. If collection of illustrative plates numbering fails clearly etc., to carry out reasoning according to specification and drawings and determine.
Accompanying drawing explanation
Fig. 1 is thermal analysis curue spectrum (embodiment 1) of Hesperidin 0.75 hydrate；
Fig. 2 is the X powder diffraction spectrum data (embodiment 1) of Hesperidin 0.75 hydrate；
Fig. 3 is the X powder diffraction spectrum data (embodiment 1) of Hesperidin 0.75 hydrate；
Fig. 4 is the X powder diffraction collection of illustrative plates (embodiment 1) of Hesperidin 0.75 hydrate；
Fig. 5 is thermal analysis curue spectrum (embodiment 2) of Hesperidin 1 hydrate；
Fig. 6 is the X powder diffraction spectrum data (embodiment 2) of Hesperidin 1 hydrate；
Fig. 7 is the X powder diffraction collection of illustrative plates (embodiment 2) of Hesperidin 1 hydrate；
Fig. 8 is thermal analysis curue spectrum (embodiment 3) of Hesperidin 0.75 hydrate；
Fig. 9 is the X powder diffraction spectrum data (embodiment 3) of Hesperidin 0.75 hydrate；
Figure 10 is the X powder diffraction collection of illustrative plates (embodiment 3) of Hesperidin 0.75 hydrate；
Detailed description of the invention
Except in an embodiment and indicated otherwise time, all of numerical value used in specification and claims should be by It is interpreted as modifying with term " about " in all of example, therefore, unless the contrary indication, this specification Being approximation with the numerical parameter gone out given in appending claims, it can be sought according to by present disclosure The required character asked and change, at least, and be not intended to limit the application of doctrine of equivalents right, Each numerical parameter is considered as the number of significant digits and the routine method of rounding up is explained.
Although the numerical range and the parameter that set the wide scope of disclosure are approximations.But institute in a particular embodiment The numerical value be given is reported as precisely as possible, and any number substantially comprises some and sent out by the test of each of which The error that existing standard deviation is necessarily led to.
It is pointed out that unless literary composition the most additionally illustrates, use in this specification and the appended claims Singulative " ", " a kind of " and " being somebody's turn to do " include the plural form that refers to thing, so, such as.If The mixture of two or more compound is included when mentioning the compositions containing " a kind of compound ", also note that , unless the most additionally illustrated, term "or" generally includes "and/or".
As used herein, term " obtains " referring to the compound of valuable purity level isolated, and described is pure Degree level includes but not limited to more than 90%, the purity level of 95%, 96%, 97%, 98% and 99%.Described is pure Degree level can pass through high-performance liquid chromatogram determination.
" pharmaceutical composition " used herein refers to the compositions of medicine, and described pharmaceutical composition can be containing at least one Plant pharmaceutically acceptable carrier.
" pharmaceutically acceptable excipient " used herein refers to the medicine that the compound being applicable to occasionally provide herein is administered With carrier or solvent, it includes well known to a person skilled in the art any examples of such carriers being applicable to specific administration mode, Such as, Sterile dilution can be included for parenteral, intradermal, the subcutaneous or solution of topical application or suspending agent Agent (such as, water for injection, saline solution, expressed oi etc.)；Fatty solvent (such as, the Polyethylene Glycol, sweet of synthesis Oil, propylene glycol etc.)；Antibacterial (such as, benzylalcohol, to hydroxyl the third methyl formate, to hydroxyl the third Ethyl formate etc.)； Antioxidant (such as, ascorbic acid, sodium sulfite etc.)；Chelating agen (such as, EDTA etc.)；Buffer agent (phosphorus Hydrochlorate, citrate etc.)；With or for tonicity-adjusting substances (e.g., sodium chloride, glucose etc.), or they Mixture.Other example includes, when intravenous administration, suitable carrier includes normal saline, phosphate-buffered Liquid and the solution containing thickening agent, such as glucose, Polyethylene Glycol etc. and their mixture.
As non-limiting example, Hesperidin hydrate can optionally and one or more pharmaceutically acceptable excipient Mixing, and can be with following form oral administration: tablet, capsule, dispersible powder, granule or containing such as The suspensoid of about 0.05-5% suspending agent or with the form parenteral of sterile solution agent or suspensoid, described suspensoid Suspending agent in isotonic medium and containing 0.05-5%, these pharmaceutical preparatioies can be containing e.g., from about 25% to about 90% Active component and carrier, more generally contain the active ingredient of 5% to 60% (weight).
In order to further appreciate that the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but Should be appreciated that these describe simply for further illustrating the features and advantages of the present invention rather than wanting right of the present invention The restriction asked, protection scope of the present invention is not limited by the following examples.
Infrared spectrum: pressing potassium bromide troche, measures sample ir data, and the instrument used includes that U.S.'s thermoelectricity is public Department NICOLET 5700FTIR Spectrometer, Nexus intelligent Fourier transformation infrared spectrometer (Thermo Nicolet) etc..
Heat analysis method
Hot analytical test strip part: Setaram company Setsys 16, about sample size 3-10mg, programming rate: 10K/min, N2Flow velocity: 50ml/min, temperature: room temperature～about 400 DEG C.
Surprisingly, distinctive, the heat of the hydrate of the present invention analyzes (TG-DTA or TG-DSC) figure Having the endothermic peak of correspondence under the weightless platform of spectrum, thermal analysis curue spectrum demonstrates hesperidin crystal hydrate；Karl Fischer Method test proves that this weightlessness is hydrone.
Powder X-ray diffraction approach
Utilize D/MX-III A X-ray diffractometer, voltage: 30-60kv, electric current: 30-100mA, scanning speed: 10 °/min, Step-length: 0.02 °/step；Copper target, monochromator: graphite monochromator；WavelengthThe angle of diffraction 2 θ, Sweep limits 3-60 °, measures the x-ray diffractogram of powder of sample, and whole peak positions are in ± 0.2 ° of 2 θ.Or utilize moral The D8Advance X-ray diffractometer of Bruker company of state, wavelengthThe angle of diffraction 2 θ, sweep limits 3-60 °, Other (index such as voltage, electric current) is about the same, measures sample.Each accompanying drawing in this specification and data Prove each other；The data of the embodiment in the description of the present invention are proved with data each other with each accompanying drawing in description.
Specific embodiment
The preparation of embodiment 1 Hesperidin 0.75 hydrate, in stainless steel cask, adds 2kg dry Pericarpium Citri junoris fine powder, adds The water of 12 times amount, 1 times amount soak with ethanol after extract 30 points with frequency ultrasonic assistant between 25kHz-50kHz Clock, adds enough saturated limewaters, stirring, controls about the pH=11.5-12 of solution, and under agitation soaks 2 Hour, filter separating solid substances, obtain the filtrate of Part I filtering residue and Part I；The filtrate of gained Part I is used The hydrochloric acid solution regulation pH to 4-6 of 3M, places, makes precipitation fully separate out；Gained Part I filtering residue is again with 6 times The water of amount, the soak with ethanol of 0.1 times amount are also extracted 30 minutes with frequency ultrasonic assistant between 25kHz-50kHz, Add saturated limewater, stirring, control about pH=11.5, so soak 2 hours, filter, gained Part II The hydrochloric acid solution of filtrate 2M, regulates pH to 5, places, makes precipitation fully separate out；Sucking filtration, collects Part I Filtrate and the precipitate of Part II filtrate, be washed to weakly acidic pH, by the sodium hydroxide solution of gained solids 1M Dissolve, add 15 times amount 50% ethanol water, stirring, place, sucking filtration, gained filtrate add up amount of liquid about 1% Activated carbon (envelope-bulk to weight ratio=milliliter: gram), stir about 30 minutes, sucking filtration, the hydrochloric acid of gained filtrate 3M Solution, regulates pH to 5, and 4 DEG C are arranged below, make precipitation fully separate out, and wash gained precipitate to weakly acidic pH with water, With the abundant rinse of ether and petroleum ether 3 times, sucking filtration, then with the abundant rinse of ethanol 3 times, sucking filtration, gained solid is added After appropriate organic solvent DMF (DMF) is stirred to dissolve, the work of about the 1% of totalling amount of liquid Property charcoal (envelope-bulk to weight ratio=milliliter: gram), stir about 30 minutes, cross and filter to remove activated carbon, by gained filtrate water About 400ml, ethanol about 20ml carries out crystallization operation, places, make precipitation fully separate out between 0～-10 DEG C, sucking filtration, With washing with alcohol solid 3 times, with isopropanol washing solid 5 times, sucking filtration, by gained solid with appropriate DMF (N, Dinethylformamide) be stirred to dissolve after, with water about 400ml, acetonitrile about 20ml, isopropanol about 20ml, carry out Recrystallization operation, sucking filtration, after gained solid is stirred to dissolve with appropriate DMF (DMF), With water about 400ml, ethanol about 20ml, the most in accordance with the law recrystallization 2 times, place 1 day in 0～about-10 DEG C, make solid Body fully separates out, sucking filtration, with washing with alcohol solid 3 times, washs solid 3 times, washing 5 times with isopropanol, sucking filtration, Gained solids is made thinner about 30 DEG C forced air dryings about 4 hours, then is placed in about 71 DEG C and is dried 3 hours, obtains class white Color powder 6.32g；Fusing point: 258.4～262.2 DEG C, (melting point apparatus does not corrects) is decomposed in variable color；Differentiate: (1) takes this Bright product about 5mg (calculates quality by anhydride), after adding ethanol 5ml heating for dissolving, lets cool, adds magnesium powder 0.2g, edge Tube wall is slowly added dropwise hydrochloric acid about 2ml, displaing amaranth.(2) ultraviolet takes product of the present invention (calculating quality by anhydride), Accurately weighed, add 50% ethanol solution and dissolve and quantitatively dilution makes in every 1ml the solution containing about 20 μ g, according to light splitting light Degree method (Chinese Pharmacopoeia two annex IV A of version in 2000), measures trap, absorptance at the wavelength of 285nmIn the range of 318～338；ESI-MS:m/z:611 [M+1]+；Infrared spectrum (νKBr 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、1132.4、1096.8、 1069.1、1033.1、973.8、891.2、846.8、817.0、767.3；It is 2.32% that Ka Shi method measures moisture, heat point Analysis collection of illustrative plates: platform weightlessness about 2.18%, this contains the result (theoretical value 2.17%) of 0.75 water of crystallization by mistake with sample (see accompanying drawing 1) in the range of difference；X-ray powder diffraction spectrum (see accompanying drawing 2,3,4), is including following 2 θ values Position there is corresponding eigenvalue, be about: 3.84,5.31,7.14,7.81,8.13,8.59,11.40,12.23, 13.27、13.72、15.63、16.04、16.31、17.20、18.31、18.66、19.28、19.67、20.85、21.26、 21.46、22.35、22.62、23.31、23.85、24.02、24.28、24.59、24.92、25.44、25.77、25.90、 26.20、26.63、26.88、27.62、28.07、28.42、28.80、29.23、29.75、30.57、31.20、32.05、 32.94、34.73、35.08、36.19、37.28、38.24、39.68、40.13、40.72、42.79、44.29；Element Analysis theories value: C 53.89%, H5.73%；Measured value: C 53.78%, H5.65%.
The preparation of embodiment 2 Hesperidin 1 hydrate, in stainless steel cask, adds 3kg dry Pericarpium Citri junoris fine powder, adds 12 times amount Water soaking 1 hour, add enough saturated limewaters, stirring, control about the pH=11.5-12 of solution, and stirring Mix lower immersion 2 hours, filter separating solid substances, obtain the filtrate of Part I filtering residue and Part I；Gained Part I The hydrochloric acid solution regulation pH to 4-6 of filtrate 3M, place, make precipitation fully separate out, obtain the heavy of Part I filtrate Shallow lake thing；Gained Part I filtering residue with the water soaking of 10 times amount, adds saturated limewater again, stirring, controls pH=11.5 left The right side, so soaks 2 hours, filters, discards filtering residue, the hydrochloric acid solution regulation pH of the filtrate 3M of gained Part II To 4.5, place, make precipitation fully separate out, obtain the precipitate of Part II filtrate；Sucking filtration, collects Part I respectively The precipitate of filtrate and the precipitate of Part II filtrate, be washed to weakly acidic pH, then will extract two parts of gained Solids merging is placed in flask, adds the water of 3 times of volumes, and makes it dissolve with the sodium hydroxide solution of 1M, adds 12 times The ethanol water of the 51% of amount, stirring, to place, sucking filtration, gained filtrate adds up the activated carbon (volume of about the 1% of amount of liquid Weight ratio=milliliter: gram), stir about 30 minutes, sucking filtration, the hydrochloric acid solution regulation pH to 5-6 of gained filtrate 3M, 4 DEG C are arranged below, make precipitation fully separate out, and wash gained precipitate to weakly acidic pH with water, then with the abundant rinse of ethanol 2 Secondary, with the abundant rinse of ether and hexamethylene 3 times, sucking filtration, the abundant rinse of methanol 2 times, with the abundant rinse of acetone 1 time, take out Filter, adds gained solid after appropriate organic solvent DMF (DMF) is stirred to dissolve, adds up The activated carbon of amount of liquid about 1% (envelope-bulk to weight ratio=milliliter: gram), stir about 30 minutes, cross and filter to remove activated carbon, Gained filtrate is carried out crystallization operation with ethanol about 20ml, acetonitrile about 10ml, acetone about 10ml, water about 400ml, in 0～ Placing between-10 DEG C, make precipitation fully separate out, sucking filtration, gained solid washing with alcohol solid 2 times, isopropanol is abundant Rinse 2 times, with the abundant rinse of acetone 2 times, sucking filtration, by gained solid with appropriate DMF (N, N-dimethyl formyl Amine) be stirred to dissolve after, with ethanol about 20ml, acetone about 20ml, water about 400ml, carry out recrystallization operation, as These recrystallization three times the most again, place 2 days in 0～about-10 DEG C, make solid fully separate out, and sucking filtration uses washing with alcohol Solid 2 times, sucking filtration；Again with water abundant rinse solid, sucking filtration, such 8 times；Gained solids is made thinner about 30 DEG C drums Air-dry dry about 6 hours, then be placed in 50 DEG C dry 4 hours, obtain off-white powder 7.26g；Fusing point: 258.2～261.7 DEG C, (melting point apparatus does not corrects) is decomposed in variable color；Differentiate: (1) takes product of the present invention about 5mg (calculating quality by anhydride), adds After ethanol 5ml heating for dissolving, let cool, add magnesium powder 0.2g, be slowly added dropwise hydrochloric acid about 2ml, displaing amaranth along tube wall.(2) Ultraviolet takes product of the present invention (calculating quality by anhydride), accurately weighed, adds 50% ethanol solution and dissolves and the dilutest Release the solution made in every 1ml containing about 20 μ g, according to spectrophotography (Chinese Pharmacopoeia two annex IV A of version in 2000), Trap, absorptance is measured at the wavelength of 285nmIn the range of 318～338；ESI-MS:m/z: 611[M+1]+；Infrared spectrum (νKBr 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、1132.2、1096.6、1068.6、1032.8、973.6、911.2、891.2、846.5、 816.5、767.2；It is 3.01% that Ka Shi method measures moisture, and heat analyzes TG-DTA: platform weightlessness about 2.85%, this and sample Product contain the result (theoretical value 2.87%) of 1 water of crystallization in range of error (see accompanying drawing 5)；X-ray powder diffraction 5.27,7.12 collection of illustrative plates (see accompanying drawing 6, accompanying drawing 7), has corresponding eigenvalue in the position including following 2 θ values, is about:, 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、25.89、26.18、26.59、26.88、27.62、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；Elementary analysis, theoretical value: C 53.50%, H5.77%；Measured value: C 53.57%, H5.68%.
The preparation of embodiment 3 Hesperidin 0.75 hydrate, in stainless steel cask, adds 2.2kg dry Pericarpium Citri junoris fine powder, adds 8 times The ethanol of amount, the water of 3 times amount, use frequency ultrasonic assistant between 25kHz-50kHz to extract 30 after soaking 3 hours Minute, filtering, the filtrate of Part I and part 1 filtering residue, filtering residue adds the water soaking 1 hour of 12 times amount, adds Saturated limewater, stirring, control about the pH=11.0-12 of solution, and under agitation soak 2 hours, filter separation solid Body thing, obtains the filtrate of part 2 filtering residue and Part II；The filtrate of gained Part I and the filtrate of Part II are used The hydrochloric acid solution regulation pH to 4-6 of 2M, places, makes precipitation fully separate out, and sucking filtration, gained solid is solid by washing with alcohol Body 3 times, with the abundant rinse of acetone 2 times, sucking filtration, is washed to weakly acidic pH, sucking filtration, obtains the first and second portion filtrate Precipitate；Gained Part II filtering residue with the water soaking of 6 times amount, adds saturated limewater again, stirring, controls pH=11.5 Left and right, so soaks 2 hours, filters, discards filtering residue, the hydrochloric acid solution regulation of the filtrate 3M of gained Part III PH to 5, places, makes precipitation fully separate out, sucking filtration, gained solid washing with alcohol solid 3 times, fully moistens with acetone Wash 2 times, sucking filtration, be washed to weakly acidic pH, sucking filtration, obtain the precipitate of Part III filtrate；Part I will be collected respectively Merging with the precipitate of Part II filtrate and the precipitate of Part III filtrate and be placed in flask, the water adding 8 times amount stirs Mixing about 1 hour, add saturated limewater, regulate pH=10-11.5, stirring, filter, filtrate adds the hydrochloric acid solution of 2M, Regulation pH to 3, places, makes precipitation fully separate out, and filters, gained solid washing with alcohol solid 3 times, uses second respectively The abundant rinse of ether, ethyl acetate, petroleum ether, chloroform 1 time, sucking filtration, with the abundant rinse of acetone 2 times, sucking filtration, by institute Solid adds appropriate DMF and DMSO, after heated and stirred makes dissolving, add proper amount of active carbon, stir about 30 minutes, Filter, gained filtrate water about 60ml, isopropanol about 30ml, acetone about 30ml are carried out crystallization operation, in 0～-10 DEG C Left and right is placed 2 days, makes solid fully separate out, and filters to obtain solid washing with alcohol solid 3 times, with the abundant rinse of acetone 2 times, Wash 3 times, sucking filtration, by gained solid DMF about 100ml, water about 500ml, isopropanol about 30ml, heavily tie Crystalline substance, and so recrystallization three times in accordance with the law, place and make solid fully separate out, sucking filtration, gained solid washing with alcohol solid 3 Secondary, with the abundant rinse of acetone 2 times, sucking filtration, wash 3 times, sucking filtration, so recrystallization 2 times the most again of gained solid, Place 2 days in 0～about-10 DEG C, make solid fully separate out, sucking filtration, filter to obtain solid washing with alcohol solid 3 times,
With the abundant rinse of acetone 2 times, washing 3 times, sucking filtration, gained solids is made thinner about 25 DEG C and is dried about 1 day, then 40 DEG C Left and right vacuum (the vacuum meter reading of vacuum drying oven is about about 0.08MPa) be dried 2 hours, then be placed in 70 DEG C do Dry 2 hours, obtain class color powder 7.58g；Fusing point: 258.4～261.6 DEG C, (melting point apparatus does not corrects) is decomposed in variable color；Differentiate: (1) take product of the present invention about 5mg (calculating quality by anhydride), after adding ethanol 5ml heating for dissolving, let cool, add magnesium Powder 0.2g, is slowly added dropwise hydrochloric acid about 2ml, displaing amaranth along tube wall.(2) ultraviolet takes product of the present invention (by anhydride Calculate quality), accurately weighed, add 50% ethanol solution and dissolve and quantitatively the solution containing about 20 μ g is made in every 1ml in dilution, According to spectrophotography (Chinese Pharmacopoeia two annex IV A of version in 2000), at the wavelength of 285nm, measure trap, inhale Receive coefficientIn the range of 318～338；Infrared spectrum (νKBr 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；It is 2.35% that Ka Shi method measures moisture, heat analysis TG-DTA: Platform weightlessness about 2.10% (see accompanying drawing 8), this result (theoretical value 2.17%) containing 0.75 water of crystallization with sample exists In range of error；Elementary analysis, theoretical value: C 53.50%, H5.77%；Measured value: C 53.59%, H5.71%； Powder X-ray diffraction (see accompanying drawing 9,10), has corresponding eigenvalue in the position including following 2 θ values, is about: 5.29、7.13、7.78、8.11、8.55、11.39、12.21、13.24、13.69、15.59、16.00、16.29、17.16、 18.31、18.62、19.65、20.82、21.21、21.42、22.31、22.59、23.30、23.81、24.29、24.55、 24.88、25.41、25.87、26.16、26.61、26.86、27.72、28.42、28.78、29.72、30.54、31.12、 32.03、32.96、34.72、35.06、36.24、37.29、38.21。
The preparation of embodiment 4 freeze-dried powder takes Hesperidin hydrate 10g (preparation of embodiment 1 method or embodiment 2 method Or embodiment 3 method), add xylitol 2.0～5g and add fresh water for injection 500ml stirring, by phosphoric acid and the hydroxide of 1M Sodium solution regulation pH is 8.5～10.0, makes to be dissolved into solution, adds activated carbon 0.01～0.5% (W/V) and stir 15～45min, Filter, moisturizing to 600ml, with 0.22 micrometer Millipore membrane filtration, by 50mg/ bottle, 100mg/ bottle or 200mg/ bottle (with Principal agent anhydride meter) subpackage, lyophilization, tamponade, obtain finished product.
The preparation of embodiment 5 injection takes Hesperidin hydrate 10g (by the preparation of embodiment 1 method or embodiment 2 method or reality Execute example 3 method to prepare), with mannitol 40g, add 40-60 DEG C of water for injection 500ml stirring, by citric acid and the hydroxide of 1M Sodium regulation pH is 8.0～9.5, makes to be dissolved into solution, adds activated carbon 0.01～0.5% (W/V) and stir 15～45min, mistake Filter, moisturizing to 600ml, retain relative molecular mass 6000-20000's with 0.22 micrometer Millipore membrane filtration or employing Ultrafiltration membrance filter, by 50,100mg/ bottle or 200mg/ bottle (by Hesperidin 1 hydrated basis) subpackage, lyophilization, pressure Plug, obtains finished product.
The Hesperidin hydrate 10.2g for preparing of the little hydro-acupuncture preparation of embodiment 6 (is prepared or embodiment 2 method by embodiment 1 method Or prepared by embodiment 3 method), add L-arginine 0.8g, EDETATE SODIUM 0.1g, inject and stir with water 400ml, 2M breast Acid sodium regulation pH is 7.5～9.0, adds activated carbon 0.01% (W/V) and stirs 15～45min, filters, moisturizing to 500ml, With 0.22 micrometer Millipore membrane filtration, by 5ml/ bottle subpackage, sterilizing obtains finished product.
Embodiment 7 Hesperidin 1 hydrate 10g (is prepared by the preparation of embodiment 1 method or embodiment 2 method or embodiment 3 method), adds Water for injection 400ml stirs, and sodium hydroxide solution and sodium dihydrogen phosphate regulation pH with 1M are 7.6～9.0, make molten Solution becomes solution, adds activated carbon 0.01% (W/V) and stirs 15～45min, filters, moisturizing to 500ml, micro-with 0.22 micron Hole membrane filtration or employing retain the ultrafiltration membrance filter of relative molecular mass 6000-10000, by 5ml/ bottle subpackage, freezing It is dried, tamponade, obtains finished product.
The preparation of embodiment 8 Hesperidin hydrate sodium chloride transfusion: (prepared by embodiment 1 method by Hesperidin hydrate 10g Or embodiment 2 method or embodiment 3 method), sodium chloride 85g, sodium tartrate 1.1g, EDETATE SODIUM 0.2g, add injection In water, stirring, with the liquor sodii citratis regulation pH value of 2M in the range of 7.2-8.5, make dissolving, inject and use water To 10000ml, add the activated carbon of dosing amount 0.05%, about heated and stirred 10-30 minute, filtering decarbonization, then warp 0.22um microporous filter membrane fine straining, embedding in the infusion bottle of 50ml or 100ml, sterilizing, pack and get final product.
Embodiment 9 Hesperidin 0.75 hydrate tablet (25mg/ sheet)
The Hesperidin hydrate (preparing by embodiment 1 method) of recipe quantity, microcrystalline Cellulose, carboxymethyl starch sodium are crossed 100 Mesh sieve, PVP K-30 ethanol water (ethanol: the volume ratio=8:2 of water) the solution soft material the most processed with 10%, cross 18 -24 mesh sieves are pelletized, and are dried, and cross after 14-20 mesh sieve granulate, add micropowder silica gel mixing, tabletting, check, pack.
Embodiment 10 Hesperidin hydrate tablet (50mg/ sheet)
The Hesperidin hydrate (preparing by embodiment 1 method or embodiment 2 method) of recipe quantity, microcrystalline Cellulose, carboxymethyl are formed sediment Powder sodium crosses 100 mesh sieves, and PVP K-30 ethanol water (ethanol: the volume ratio=8:2 of the water) solution with 10% is made in right amount Soft material, crosses 18-24 mesh sieve and pelletizes, be dried, after crossing 14-20 mesh sieve granulate, add micropowder silica gel mixing, tabletting, inspection Test, pack.
Embodiment 11 Hesperidin hydrate tablet (200mg/ sheet)
The Hesperidin hydrate (preparing by embodiment 1 method or embodiment 2 method) of recipe quantity, microcrystalline Cellulose, carboxymethyl are formed sediment Powder sodium crosses 100 mesh sieves, and PVP K-30 ethanol water (ethanol: the volume ratio=8:2 of the water) solution with 10% is made in right amount Soft material, crosses 18-24 mesh sieve and pelletizes, be dried, after crossing 14-20 mesh sieve granulate, add micropowder silica gel mixing, tabletting, inspection Test, pack.
Embodiment 12 Hesperidin hydrate capsule (100mg/ grain)
By the Hesperidin hydrate of recipe quantity (preparing by the preparation of embodiment 1 method or embodiment 2 method or embodiment 3 method), micro- Crystalline cellulose, starch cross 100 mesh sieves, the gelling starch soft material the most processed with 10%, cross 18-24 mesh sieve and pelletize, are dried, After crossing 14-20 mesh sieve granulate, add magnesium stearate mixing, fill capsule.
Embodiment 13 Hesperidin hydrate capsule (200mg/ grain)
By the Hesperidin hydrate of recipe quantity (preparing by the preparation of embodiment 1 method or embodiment 2 method or embodiment 3 method), micro- 100 mesh sieves crossed by crystalline cellulose, lactose, the gelling starch soft material the most processed with 10%, cross 18-24 mesh sieve and pelletize, are dried, After crossing 14-20 mesh sieve granulate, add magnesium stearate mixing, fill capsule.
The granule (100mg/ bag) of embodiment 14 Hesperidin hydrate
By the Hesperidin hydrate (preparing by the preparation of embodiment 1 method or embodiment 2 method or embodiment 3 method) of recipe quantity, manna Alcohol, lactose, cyclamate, edible essence cross 100 mesh sieves, with the PVP K-30 ethanol water soft material the most processed of 8%, Crossing 18-24 mesh sieve to pelletize, less than 60 DEG C are dried, and add the xanthan gum of 100 mesh sieves, after crossing 14-20 mesh sieve granulate, mixed Even, added the xanthan gum of 100 mesh sieves, subpackage fills.
The eye drop of embodiment 15 Hesperidin hydrate
By the Hesperidin hydrate 1g (preparing by embodiment 1 method or embodiment 2 method) of recipe quantity, inject and use water 400ml, Glycerol adding 10ml, PVP K-30 0.5g, add sodium sulfite 0.6g, EDETATE SODIUM 0.3g, Borax 2.5g, chlorination Sodium 3.1g, is adjusted to 7.1-8.0 with dibastic sodium phosphate and disodium phosphate soln, is stirred to dissolve, and then adds people's water for injection extremely 500ml, stirs, detection, with 0.22-0.45 μm filtering with microporous membrane to clear and bright, is sub-packed in sterilized clean eye In liquid medicine bottle, sterilizing, let cool, to obtain final product.
Embodiment 16 Hesperidin hydrate and the pharmaceutical composition of diosmin (50mg/450mg/ sheet)
By the Hesperidin hydrate (preparing by embodiment 1 method or embodiment 2 method) of recipe quantity, diosmin, microcrystalline Cellulose, Carboxymethyl starch sodium crosses 100 mesh sieves, with the gelling starch solution soft material the most processed of 10%, crosses 18-24 mesh sieve and pelletizes, dry Dry, cross after 14-20 mesh sieve granulate, added the magnesium stearate mixing of 100 mesh sieves, tabletting, and checked, pack.
Embodiment 17 Hesperidin hydrate and diosmin (25mg/225mg/ sheet, by anhydride calculated weight) group The preparation of compound
By the Hesperidin hydrate (preparing by embodiment 1 method or embodiment 2 method) of recipe quantity, diosmin, microcrystalline Cellulose, Carboxymethyl starch sodium crosses 100 mesh sieves, with the gelling starch solution soft material the most processed of 10%, crosses 18-24 mesh sieve and pelletizes, dry Dry, cross after 14-20 mesh sieve granulate, added the magnesium stearate mixing of 100 mesh sieves, tabletting, and checked, pack.
Embodiment 18 pharmaceutical composition prepare Hesperidin hydrate and diosmin (100mg/400mg/ sheet)
By the Hesperidin hydrate (preparing by embodiment 1 method or embodiment 2 method) of recipe quantity, diosmin, microcrystalline Cellulose, Carboxymethyl starch sodium crosses 100 mesh sieves, with 10% PVP K-30 ethanol water (8:2) solution soft material the most processed, crosses 18- 24 mesh sieves are pelletized, and are dried, and cross after 14-20 mesh sieve granulate, added the magnesium stearate mixing of 100 mesh sieves, tabletting, inspection, Packaging.
(50mg/450mg/ sheet, by nothing with diosmin for the Hesperidin hydrate of preparing of embodiment 19 pharmaceutical composition Water thing calculates the weight of principal agent-Hesperidin and diosmin)
By the Hesperidin hydrate of recipe quantity (preparing by the preparation of embodiment 1 method or embodiment 2 method or embodiment 3 method), Ao Siming, microcrystalline Cellulose, carboxymethyl starch sodium cross 100 mesh sieves, with the gelling starch solution soft material the most processed of 10%, Cross 18-24 mesh sieve to pelletize, be dried, cross after 14-20 mesh sieve granulate, added the magnesium stearate mixing of 100 mesh sieves, tabletting, Inspection, packaging.
The preparation (10000) of embodiment 20 Hesperidin hydrate drop pill
Prescription: Hesperidin hydrate 25g
Poloxamer 20g
Polyethylene glycol 6000 60g
The Hesperidin hydrate (preparing by the preparation of embodiment 1 method or embodiment 2 method or embodiment 3 method) of recipe quantity is crossed 100 After mesh sieve, in the poloxamer that is added to melt, polyethylene glycol 6000 substrate, fully stir evenly, be cold with dimethicone But agent, dropping preparation method pill, it is dried, packaging.
(50mg/450mg/ bag is calculated by anhydride in the preparation (1000) of the drop pill of embodiment 21 pharmaceutical composition Principal agent-Hesperidin and the weight of diosmin)
By the Hesperidin hydrate of recipe quantity (preparing by the preparation of embodiment 1 method or embodiment 2 method or embodiment 3 method), After diosmin crosses 100 mesh sieves, in the poloxamer that is added to melt, polyethylene glycol 6000 substrate, fully stir evenly, with two Methyl-silicone oil is coolant, dropping preparation method pill, is dried, packaging.
Industrial applicibility etc. and explanation etc. thereof:
Above by detailed description of the invention and embodiment, the present invention is described in detail, it will nevertheless be understood that these are said Bright to the scope of the present invention any restriction of composition, in the case of without departing from the spirit and scope of protection of the present invention, Technical solutions and their implementation methods of the present invention can be carried out multiple modification, improve and replace or suitably change and combine, Realizing the technology of the present invention, these are all because falling within the scope of protection of the present invention；It is appreciated that the change of a lot of details Being possible, this is also not so limited the scope of the invention, spirit and content, and the present invention is not limited to above-described embodiment.

Claims (13)

1. a flavone compound entity, it is characterised in that: for hesperidin crystal hydrate, molecular formula is C28H34O15·nH2O, n=0.75,1.0.
Flavone compound entity the most according to claim 1, it is characterised in that: for Hesperidin 1 hydrate.
nullFlavone compound entity the most according to claim 2，It is characterized in that: utilize powder X-ray diffractometry to measure，At the angle of diffraction 2 θ、In the range of the measurement of 3-60 °，There is corresponding eigenvalue in the position of following 2 θ values: 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、25.89、26.18、26.59、26.88、27.62、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.
Flavone compound entity the most according to claim 1, it is characterised in that: for Hesperidin 0.75 hydrate.
nullFlavone compound entity the most according to claim 4，It is characterized in that: utilize powder X-ray diffractometry to measure，At the angle of diffraction 2 θ、In the range of the measurement of 3-60 °，There is corresponding eigenvalue in the position of following 2 θ values: 3.84、5.31、7.14、7.81、8.13、8.59、11.40、12.23、13.27、13.72、15.63、16.04、16.31、17.20、18.31、18.66、19.28、19.67、20.85、21.26、21.46、22.35、22.62、23.31、23.85、24.02、24.28、24.59、24.92、25.44、25.77、25.90、26.20、26.63、26.88、27.62、28.07、28.42、28.80、29.23、29.75、30.57、31.20、32.05、32.94、34.73、35.08、36.19、37.28、38.24、39.68、40.13、40.72、42.79、44.29.
nullFlavone compound entity the most according to claim 4，It is characterized in that: utilize powder X-ray diffractometry to measure，At the angle of diffraction 2 θ、In the range of the measurement of 3-60 °，There is corresponding eigenvalue in the position of following 2 θ values: 5.29、7.13、7.78、8.11、8.55、11.39、12.21、13.24、13.69、15.59、16.00、16.29、17.16、18.31、18.62、19.65、20.82、21.21、21.42、22.31、22.59、23.30、23.81、24.29、24.55、24.88、25.41、25.87、26.16、26.61、26.86、27.72、28.42、28.78、29.72、30.54、31.12、32.03、32.96、34.72、35.06、36.24、37.29、38.21.
7. according to the flavone compound entity described in claim 1-5, it is characterised in that: there is under the weightless platform of 50～130 DEG C of heat analysis TG-DTA collection of illustrative plates the endothermic peak of correspondence.
8. according to the purposes of the flavone compound entity described in claim 1-5, it is characterized in that: the compositions containing this chemical entities for preparation for preparation, this pharmaceutical composition shows as solid preparation, preparation for external application to skin, suppository, injection, solid preparation selected from tablet, capsule, granule or dry suspension.
Flavone compound entity the most according to claim 1, it is characterized in that: the pharmaceutical composition containing this chemical entities for preparation, this pharmaceutical composition is the pharmaceutical composition of Hesperidin hydrate and one or more compositions in diosmin or its solvated compounds or its pharmaceutical salts, wherein, Hesperidin hydrate is 2:1～1:20 with the weight ratio of diosmin or its solvated compounds or its pharmaceutical salts, wherein, the weight of Hesperidin hydrate and diosmin or its solvated compounds or its pharmaceutical salts both can calculate according to its crystalline hydrate weight, also can calculate according to the weight of its anhydride.
The pharmaceutical composition of flavone compound entity the most according to claim 7, it is characterized in that: in the pharmaceutical composition containing this chemical entities, Hesperidin hydrate is 1:1～1:10 with the weight ratio of diosmin or its solvated compounds or its pharmaceutical salts, wherein, the weight of Hesperidin hydrate and diosmin or its solvated compounds or its pharmaceutical salts both can calculate according to its crystalline hydrate weight, it is possible to calculates according to the weight of its anhydride.
Pharmaceutical composition any one of 11. claim 7-9, it comprises the compound any one of claim 1-5, and the weight of described compound is 5-500mg.
12. according to the purposes of the flavone compound entity described in claim 1-5, it is characterized in that preparation reduces the fragility of capillary tube, protection blood capillary, prevent microvascular hemorrhage, chronic venous insufficiency, hemorrhoid, vitamin C deficiency, hydrarthrosis, venous leg ulcers, premenstrual tension syndrome, the microangiopathies of diabetics and Secondary cases upper limb lymphedema, cardiovascular disease, blood pressure and blood lipoid regulates, blood pressure regulating, anti-inflammation, antiviral, anticancer, regulation immunity, radioprotective, the liver protecting, resisting rheumatoid arthritis or arthritis, antiulcer, eliminate the phlegm, relieving asthma, black speck, passeris montani saturati speckle, free radical resisting, application in antioxidative treatment or the food of prevention or health food or medicine.
13. flavone compound entities according to claim 1, its preparation method, it is characterised in that: its preparation method is selected from:
Method A., in reaction vessel, adds the dry Pericarpium Citri junoris powder of the pulverizing of constant weight, adds the water of 3-60 times amount, C1-C6Low mass molecule alcohol, one or more in acetone are soaked and by ultrasonic extraction or microwave extraction 0.1-2 hour, wherein, w/v=gram: milliliter；Then one or more in saturated limewater, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor are added, stirring, control pH and be about 9-13, extract or microwave extraction 0.1-3 hour in so soaking and with ultrasonic assistant, filter separating solid substances, obtain filtrate and the Part I filtering residue of Part I；The filtrate diluted mineral acid of gained Part I or organic acid soln regulation pH to 4～7, place, make precipitation fully separate out, filter, the precipitate of Part I filtrate；Gained Part I filtering residue is again with the water of 2-30 times amount, C1-C6Low mass molecule alcohol, one or more in acetone soak ultrasonic extraction or microwave extraction 0.1-2 hour, then one or more in saturated limewater, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor are added, stirring, control pH and be about 9-13, so soak and by ultrasonic extraction or microwave extraction 0.1-2 hour, filter, the filtrate mineral acid of gained Part II or organic acid soln regulation pH to 4～7, place, make precipitation fully separate out；Filter, obtain the precipitate of Part II filtrate；Collect Part I filtrate and the precipitate of Part II filtrate, be washed to weakly acidic pH, obtain wet solids；
One or more in gained solids saturated limewater solution, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor are dissolved, adds the 20 of 2-40 times amount～the C of 60%1-C6Low mass molecule alcohol, acetone or water, stirring, place, filter, gained filtrate diluted mineral acid or organic acid soln regulation pH to 4～7,25 DEG C are arranged below, make precipitation fully separate out, and wash gained precipitate to weakly acidic pH with water, then use C1-C6Low mass molecule alcohol, C2-C8Low molecule ether, C3-C8Low molecule ketone, C2-C8Low molecule ester, C4-C10Low molecule alkane or cycloalkane, petroleum ether in one or more abundant rinses 1～6 times, filter, gained solid is added appropriate organic solvent Methanamide, N, in dinethylformamide one or more, after being stirred to dissolve, add proper amount of active carbon, stir about 15-60 minute, cross and filter to remove activated carbon, by gained filtrate water, C1-C6Low mass molecule alcohol, C2-C6Rudimentary nitrile, C3-C8Low molecule ketone in one or more carry out crystallization operation, 20～about-25 DEG C placements, make precipitation fully separate out, filter, with water, C1-C6Low mass molecule alcohol washing solid 1-8 time, sucking filtration, by gained solid appropriate Methanamide, N, in dinethylformamide, DMSO, one or more, after being stirred to dissolve, add proper amount of active carbon, stir about 15-60 minute, crosses and filters to remove activated carbon, by gained filtrate water, C1-C6Low mass molecule alcohol, C2-C6Rudimentary nitrile, C3-C8Low molecule ketone in one or more carry out recrystallization operation, one or many recrystallization operation, 20～about-25 DEG C placements can be carried out the most in accordance with the law further, make solid fully separate out, filter, with water, C1-C6Low mass molecule alcohol, C3-C8Low molecule ketone washing solid 1-8 time, filtration, gained solids is dried, obtains hesperidin crystal hydrate；Wherein, frequency during supersound extraction is between 10kHz-2000kHz, and the power of microwave extraction is between 100W-1000W；
Or method B. is in reaction vessel, add the dry Pericarpium Citri junoris powder of the pulverizing of constant weight, add the water of 3-60 times amount, C1-C6Low mass molecule alcohol soak extraction 0.5-4 hour, wherein, w/v=gram: milliliter；Then one or more in saturated limewater, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor are added, stirring, control pH=10-13, so soak extraction 1-4 hour, filter separating solid substances, the filtrate diluted mineral acid of gained Part I or organic acid soln regulation pH to 4～7, place, make precipitation fully separate out；Gained Part I filtering residue extracts with the water soaking of 2-30 times amount again, then one or more in saturated limewater, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor are added, stirring, control pH=10-13, such soak extraction 1-4 hour, filter, the filtrate of gained Part II is with mineral acid or organic acid solns such as dilute hydrochloric acid, sulphuric acid, phosphoric acid, regulation pH to 4～7, places, makes precipitation fully separate out；Filter, collect Part I filtrate and the precipitate of Part II filtrate, be washed to weakly acidic pH, obtain wet solids；
One or more in gained solids use, saturated limewater solution, sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor are dissolved, adds the 20 of 2-60 times amount～the C of 60%1-C6Low mass molecule alcohol, acetone or water, stirring, places, and filters, gained filtrate adds up the activated carbon (envelope-bulk to weight ratio=milliliter: gram) of the about 0.01-3% of amount of liquid, stir about 10-60 minute, sucking filtration, gained filtrate diluted mineral acid or organic acid soln regulation pH to 4～7,25 DEG C arranged below, make precipitation fully separate out, gained precipitate is washed with water to weakly acidic pH, then uses C1-C6Low mass molecule alcohol, C2-C8Low molecule ether, C3-C8Low molecule ketone, C2-C8Low molecule ester, C4-C10Low molecule alkane or cycloalkane, petroleum ether in one or more abundant rinses 1～6 times, filter, gained solid is added one or more in appropriate organic solvent dimethyl sulfoxide, Methanamide, DMF, after being stirred to dissolve, add the activated carbon of the about 0.01-3% of total amount of liquid, wherein, the weight of activated carbon and liquor capacity than=gram: milliliter, stir about 15-60 minute, cross and filter to remove activated carbon, by gained filtrate water, C1-C6Low mass molecule alcohol, C2-C6Rudimentary nitrile, C3-C8Low molecule ketone in one or more carry out crystallization operation, 20～about-25 DEG C placements, make precipitation fully separate out, filter, with water, C1-C6Low mass molecule alcohol washing solid 1-8 time, filter, by gained solid with in appropriate DMSO, Methanamide, DMF (DMF) one or more, after being stirred to dissolve, add the activated carbon of the about 0.01-3% of total amount of liquid, wherein, envelope-bulk to weight ratio=milliliter: gram, stir about 15-60 minute, cross and filter to remove activated carbon, by gained filtrate water, C1-C6Low mass molecule alcohol, C2-C6Rudimentary nitrile, C3-C8Low molecule ketone in one or more carry out recrystallization operation, one or many recrystallization operation can be carried out the most in accordance with the law further, in 20～about-25 DEG C placements, be preferable over 10～about-10 DEG C placements, make solid fully separate out, filter, with water, C1-C6Low mass molecule alcohol, C3-C8Low molecule ketone in one or more washing solids 1-10 time, filtration, gained solids is dried, obtains hesperidin crystal hydrate.
CN201510024470.6A 2015-01-16 2015-01-16 Flavonoid new chemical entity, composition and use Pending CN105837646A (en)

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