CN102512496B - White flower danshen total phenanthrenequinone extract for treating angiitis, medicinal composition and preparation method - Google Patents
White flower danshen total phenanthrenequinone extract for treating angiitis, medicinal composition and preparation method Download PDFInfo
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Abstract
The invention relates to a white flower danshen total phenanthrenequinone extract for treating angiitis, a medicinal composition and a preparation method. The white flower danshen total phenanthrenequinone extract is a mixture of tanshinone which is obtained by extracting white flower danshen roots through a solvent and performing column chromatography and purification. The white flower danshen total phenanthrenequinone extract mainly comprises tanshinone IIA, cryptotanshinone and tanshinone I, wherein the total content of the three components is not less than 70 percent; and the mass ratio between the cryptotanshinone and the tanshinone IIA is 0.45 to 0.80. The total phenanthrenequinone extract has a better treatment effect on thromboangitis obliterans, and can be processed into various formulations, such as tablets, capsules, soft capsules, dripping pills, medicinal granules and the like according to conventional production process in pharmaceutics.
Description
Technical field
The present invention relates to a kind of Chinese medicine extract, more specifically say that by Salvia miltiorrhiza f., extracting refining form a kind of treats vasculitic White flower danshen total phenanthrenequinone extract (TANSHINONES mixture), pharmaceutical composition and preparation method thereof and application.
Background technology
Thromboangiitis obliterans (Thromboangitis Obliterans, TAO) be a kind of chronic occlusion disease that segmental, non-atherosclerotic, aseptic inflammation and Endovascular thrombosis is feature of take, mainly involve distal limbs in, small artery and vein, be apt to occur in lower limb, course of disease length is more to be delayed into property and increases the weight of gradually, often cause limbs generation ischemia or blood stasis disease damage, very person's limbs fester and come off, and are a kind of chronic peripheral vascular diseases.All there is morbidity China various places, are more common in north cold area, and especially male adults is common, and serious harm people's is healthy.
Salvia miltiorrhiza f. (Salvia miltiorrhiza Bunge var alba) is the modification of labiate Radix Salviae Miltiorrhizae, main product in Zhangqiu in Shandong province, the knob such as Laiwu, Tai'an, its root is used as medicine, and within 2002, Salvia miltiorrhiza f. is incorporated into < < Shandong Province Chinese crude drug standard > >.In the Chinese herbal medicine compilation > > of the < < whole nation, record: Salvia miltiorrhiza f. likeness in form Radix Salviae Miltiorrhizae, floral white only, what have can be slightly purple dizzy, originate in Shandong, also with root, be used as medicine, local useful Salvia miltiorrhiza f. wine treatment thromboangiitis obliterans person (national Chinese herbal medicine compilation [first volume], People's Health Publisher, 1975).
Salvia miltiorrhiza f. root for vasculitis treatment, has been obtained gratifying curative effect clinically.Shandong Province Zhangqiu County hospital applied folk remedy Salvia miltiorrhiza f. treatment thromboangiitis obliterans since 1967, from in October, 1971 to 1975 year December application Salvia miltiorrhiza f. treatment vasculitis 147 examples, clinical cure rate 27.2%, remarkable improvement rate 45.6%, total effective rate 93.2%, through treatment, suffering limb blood circulation has improvement in various degree, and can ease the pain and promote ulcer healing, and clinical grouping comparison is observed, the curative effect of Salvia miltiorrhiza f. is higher than Radix Salviae Miltiorrhizae, referring to Journal of Traditional Chinese Medicine, 1976, (11): 23-24.
According to the journal > > of < < Shandong College of Traditional Chinese Medicine and < < treatment, record with healthy medicated wine > >: Salvia miltiorrhiza f. is soaked in to Salvia miltiorrhiza f. wine that the Chinese liquor of 55 degree makes as folk prescription or proved recipe, among the people in order to treat the vasculitis history of existing more than 80 year, and think that Salvia miltiorrhiza f. is better than Radix Salviae Miltiorrhizae to vasculitic curative effect, referring to Xu Qingfeng, treatment and healthy medicated wine, 1988, p117.
Pharmacological experiment study is treated vasculitis for application Salvia miltiorrhiza f. reliable theoretical foundation is provided.By research Salvia miltiorrhiza f., on mouse platelets adhesion function and hemorheological impact, find that Salvia miltiorrhiza f. has obvious antiplatelet and adheres to agglutination, and there is the function that reduces blood viscosity, referring to Han Jiju etc., Chinese crude drug, 2007,30 (6): 699-701.Salvia miltiorrhiza f. is to H
2o
2damage descendant umbilical cord blood endothelial progenitor cells has remarkable protective effect; referring to Jiao Peng etc.; CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2011,36 (13): 1830-1832; can effectively promote people's umbilical cord blood endothelial progenitor cells increment, stick and discharge NO ability; significantly improve the function of people's umbilical cord blood endothelial progenitor cells, referring to Jiao Peng etc., Chinese Chinese medicine magazine; 2011,26 (11): 2687-2689.
CN1899371A (CN200610045270.X) provides the application of a kind of Salvia miltiorrhiza f. in pharmaceutical field and the preparation method of white flower red sage medicine.The content of Danshensu of Salvia miltiorrhiza f. is the twice of pale reddish brown Radix Salviae Miltiorrhizae, and this material is used for the treatment of cardiovascular and cerebrovascular disease and other relevant diseases, has the effect of the silt pain relieving of dispelling, promoting blood circulation to restore menstrual flow, the relieving restlessness that clears away heart-fire.The preparation method of described white flower red sage medicine is: a. gets Salvia miltiorrhiza f. and inserts in extraction pot, adds the water of 4～10 times of weight portions to carry out water extraction, filters to obtain water extraction liquid; Or will after Salvia miltiorrhiza f. micronizing, carry out supersound extraction, filter to obtain ultra micro extract powder; B. get the ultra micro extract powder of a operation or be 1.0～1.4 water extraction liquid through being concentrated into relative density, add 50%～90% ethanol to carry out alcohol precipitation, after filtering with 20%～40% highly basic, solution is adjusted pH=6.5～8.5, coldly put rear filtration, repeat alcohol precipitation, obtain filtrate; C. the filtrate of b operation being concentrated into relative density is 1.0～1.4, adds 0.5%～2% active carbon, and heated and boiled is filtered, and sterilizing, obtains liquid agent.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of treat vasculitic White flower danshen total phenanthrenequinone extract and preparation method thereof and application are provided.
The present invention also provides the pharmaceutical composition of White flower danshen total phenanthrenequinone extract.
Term explanation:
Total phenanthrenequione, refers to the total tanshinone in Salvia miltiorrhiza f., and in Natural Medicine Chemistry teaching material, TANSHINONES is called Radix Salviae Miltiorrhizae quinone, and this compounds belongs to phenanthrenequione class formation from structure parent nucleus.
White flower danshen total phenanthrenequinone extract, refers to the mixture of the various TANSHINONES of extracting from Salvia miltiorrhiza f..
Technical solution of the present invention is as follows:
Treat a vasculitic White flower danshen total phenanthrenequinone extract, the root of Salvia miltiorrhiza f. of take is raw material, by solvent extraction, solvent extraction, chromatography and purification, forms; Mainly contain tanshinone ⅡA, cryptotanshinone, Tanshinone I, secondly also contain a small amount of 1,2-dihydrotanshinone I, miltirone, 15,16-dihydrotanshinone I, 1-carbonyl miltirone and rubiquinone B, wherein tanshinone ⅡA, cryptotanshinone and Tanshinone I three's total content is not less than 70wt%, and the mass ratio of tanshinone ⅡA and cryptotanshinone is 0.45～0.80.
The present invention treats vasculitic White flower danshen total phenanthrenequinone extract, prepares by the following method:
The root of Salvia miltiorrhiza f. of take is raw material, after pulverizing, with methanol, 95% ethanol or ethyl acetate are for extracting solvent, heating extraction, supersound extraction, the weight ratio of described quantity of solvent and raw material is 6～15: 1, repeat to extract 1～3 time, remove medicinal residues, it is 1.20～1.35 (60 ℃ of mensuration) paste that merging filtrate is concentrated into proportion under normal pressure or reduced pressure, gained paste is with aqueous suspension, with organic solvent extraction 2～3 times, combining extraction liquid, again with water washing extract 2～3 times, organic solvent extraction liquid is concentrated, carry out silica gel column chromatography separation, silicagel column eluting solvent is petroleum ether-ethyl acetate, collect the eluting part of 5: 3 volume ratios of petroleum ether-ethyl acetate, boil off solvent, merge, carry out crystallization and recrystallization, obtain White flower danshen total phenanthrenequinone extract.
Preferably, described extraction organic solvent is ethyl acetate, chloroform or dichloromethane.
The present invention treats vasculitic White flower danshen total phenanthrenequinone extract preparation method, and detailed step is as follows:
(1) solvent extraction
The root of raw material Salvia miltiorrhiza f. is after pulverizing, take methanol, 95% ethanol, ethyl acetate as extracting solvent, heating extraction or supersound extraction, the weight ratio of solvent for use amount and raw material is 6～15: 1, repeat to extract 1～3 time, remove medicinal residues, merging filtrate, it is 1.20～1.35 (60 ℃ of mensuration) paste that gained filtrate is concentrated into proportion under normal pressure or reduced pressure.
Preferably, described heating extraction is to be that solvent carries out reflux, extract, with 95% ethanol, 10 times of weight that solvent is raw material.
(2) extraction
The paste that step (1) is obtained suspends with the distilled water of 6～12 times of weight, with with the isopyknic organic solvent extraction of water, repeat combining extraction liquid, concentrating under reduced pressure 2～3 times, use again and the isopyknic water extracting and washing of concentrate, repeat to wash 2～3 times, discard water layer, then separate the organic solvent layer on upper strata, pressure reducing and steaming solvent, obtains solids.
(3) column chromatography
The solids that step (2) extraction is obtained carries out silica gel column chromatography separating purification, first with petroleum ether-ethyl acetate 100: 3,4～6 retention volumes of volume ratio eluting, then with 8～12 retention volumes of 5: 3 volume ratio eluting of petroleum ether-ethyl acetate, collect the petroleum ether-ethyl acetate eluting part of 5: 3, pressure reducing and steaming solvent, obtains red extract.
(4) purification
By red extract obtained above, with 95% dissolve with ethanol, crystallize, leaches crystallization, then with 95% ethyl alcohol recrystallization, obtains White flower danshen total phenanthrenequinone extract.
Preferred according to the present invention, the extraction organic solvent described in step (2) is ethyl acetate, chloroform or dichloromethane, and most preferably dichloromethane is as extraction organic solvent.
Preferred according to the present invention, extraction and the concentrating under reduced pressure described in step (2) when extraction is evaporated to 0.5 times of extraction liquids accumulated amount 2 times time, is evaporated to 0.35 times of extraction liquids accumulated amount when extraction 3 times.
In the White flower danshen total phenanthrenequinone of the inventive method gained, tanshinone ⅡA, cryptotanshinone and Tanshinone I three's total amount is not less than 70%, and the mass ratio 0.45～0.80 of topmost two composition cryptotanshinones and tanshinone ⅡA wherein.
The pharmaceutical preparation that different dosage form is made in the vasculitic White flower danshen total phenanthrenequinone extract for the treatment of of the present invention and pharmaceutic adjuvant combination.
Treat a pharmaceutical composition for vasculitic White flower danshen total phenanthrenequinone extract, White flower danshen total phenanthrenequinone extract of the present invention and one or more pharmaceutically acceptable carriers or excipient.
Preferably, described pharmaceutical composition is tablet, capsule, drop pill and soft capsule.Can prepare according to pharmaceutics conventional production process.
The pharmaceutical preparation of described pharmaceutical composition different dosage form is described in detail as follows:
1, the making of tablet or capsule, all by the percentage by weight of White flower danshen total phenanthrenequinone extract total amount:
Get described White flower danshen total phenanthrenequinone extract, add the diluent I of 2～5 times of weight, the wetting agent of 5～10wt%, the disintegrating agent of 4～15wt%, wet granulation routinely, dry after granulate, then add the lubricant of 0.5～3wt%, tabletting or incapsulate shell.
Above-mentioned diluent I is selected from starch, Icing Sugar, dextrin or microcrystalline cellulose;
Above-mentioned wetting agent is selected from water or ethanol;
Above-mentioned disintegrating agent is carboxymethyl starch sodium;
Above-mentioned lubricant is magnesium stearate or Pulvis Talci.
2, the making of soft capsule
Get described White flower danshen total phenanthrenequinone extract, add diluent II, mix, then add antioxidant, suspending agent, stir, room temperature is standing, obtains the medicinal liquid of White flower danshen total phenanthrenequinone extract soft capsule content; By mould, it is pressed into soft capsule together with the prior soft capsule shell material of preparing with gelatin, glycerol, antiseptic.
Above-mentioned diluent II is selected from vegetable oil;
Above-mentioned antioxidant is selected from sodium ascorbate, citric acid or sodium pyrosulfite;
Above-mentioned suspending agent is selected from Cera Flava, chitin methylcellulose or agar.
3, the making of drop pill
Get described White flower danshen total phenanthrenequinone extract, add appropriate dehydrated alcohol, then add in Macrogol 4000 or polyethylene glycol 6000 fused solution, 60 ℃ of constant temperature water baths stir, until ethanol is waved to the greatest extent; Then this fused solution is proceeded in the surge drum of pill dripping machine, under the condition of 80～85 ℃ of insulations, splash in condensed fluid, collect drop pill.
Preferably, the weight ratio of described White flower danshen total phenanthrenequinone extract and Macrogol 4000 is 1: 6.
Of the present inventionly be used for the treatment of vasculitic White flower danshen total phenanthrenequinone extract and drug combination preparation is used for the treatment of thromboangiitis obliterans, improve the caused chronic ulcer of limb ischemia, pain, feel cold and intermittent limping.
The pharmacodynamic study of the vasculitic White flower danshen total phenanthrenequinone extract for the treatment of of the present invention.
Animal: 60 of Wistar male white rats, body weight 280～300g ，You Shandong University Experimental Animal Center provides.
Medicine: will prepare White flower danshen total phenanthrenequinone extract porphyrize according to embodiment 1 method, and cross 80 mesh sieves, and be mixed with the suspension of 0.1g/ml, 0.05g/ml and 0.025g/ml with 0.5% sodium carboxymethyl cellulose solution.To treat clinically at present the positive contrast of conventional oral medicine TONGSAIMAI PIAN (Jiangsu Nanxing Pharmaceutical Co., Ltd's product) of thromboangiitis obliterans, by its porphyrize, cross 80 mesh sieves, with 0.5% sodium carboxymethyl cellulose solution, be mixed with the suspension of 0.11g/ml.
Modeling and grouping: adopt general Femoral Artery Injection Laurel acid system both at home and abroad, reference literature method: Miao Zhiru etc., Chinese crude drug, 2008,31 (6): 880-882, prepares Thromboangitis Obliterans Model in Rat.By 60 rats, be sham operated rats, model group, TONGSAIMAI PIAN matched group, White flower danshen total phenanthrenequinone extract high dose group, middle dosage group and low dose group at random.
Administration: adopt administration by gavage administration.High, medium and low three kinds of variable concentrations White flower danshen total phenanthrenequinone extract suspensions that White flower danshen total phenanthrenequinone extract high dose group, middle dosage group and low dose group give to have prepared according to the dosage of 0.6g/kg, 0.3g/kg and 0.15g/kg respectively.The TONGSAIMAI PIAN suspension solution that positive controls gives to have prepared according to the dosage of 0.66g/kg.Each group is gastric infusion after operation all, administration every day 1 time, continuous 1 week.
Experimental result:
Rat sign Index is observed: gross examination of skeletal muscle rat suffering limb skin color, temperature, suffering limb have or not swelling, have or not degree, the limping situation of gangrene and gangrene.With reference to Wang Jun etc., Chinese combination of Chinese and Western medicine magazine, 1996,16 (7): 421-423.The grade scale classification adopting, I level: pathological changes is confined to toenail portion; II level: pathological changes is confined to toe; III level: pathological changes is confined to sufficient claw; IV level: pathological changes is confined to below knee joint; V level: pathological development is to more than knee joint.Experimental result is as shown in table 1, and the pathological changes of model group is the most serious, and the pathological changes of the middle and high dosage group of TONGSAIMAI PIAN group and White flower danshen total phenanthrenequinone is the lightest, relatively has significant difference with model group.
The impact that table 1 White flower danshen total phenanthrenequinone changes the local sign of TAO rat
Note: with model group comparison
*p < 0.05
Pathological observation: get the arteries of experimental rat suffering limb, paraffin embedding, section, observes, and sees Fig. 2.Compare with TAO model, the thrombosis scope of TONGSAIMAI PIAN group and middle and high dosed administration group all reduces, and tube chamber is more regular, the infiltration of blood vessel and a small amount of inflammatory cell of surrounding tissue, and inflammatory reaction alleviates.Show that White flower danshen total phenanthrenequinone has therapeutical effect to Thromboangitis Obliterans Model in Rat.
Biochemical Indices In Serum is measured: the content of determination experiment rat blood serum TXB2,6-K-PGF1 α, ET, result is as shown in table 2.Modeling rat after White flower danshen total phenanthrenequinone treatment, middle and high dosed administration group and model group comparison, 6-K-PGF in serum
1 αcontent obviously raises, TXB
2, ET content reduces, and shows that White flower danshen total phenanthrenequinone can improve the anti-thrombus function of modeling rat aorta, vascular endothelial cell is had to protective effect.
The impact of table 2 White flower danshen total phenanthrenequinone on TAO rat blood serum TXB2,6-K-PGF1 α, ET
Note: with model group comparison
*p < 0.05.
Above-mentioned experimental result shows, the vasculitic White flower danshen total phenanthrenequinone extract for the treatment of of the present invention has antithrombotic and forms, improves suffering limb blood circulation, alleviates the effect of suffering limb inflammatory reaction, can be used for treating thromboangiitis obliterans, and the suffering limb chronic ulcer, the pain that by it, are caused, feel cold and intermittent limping, there is good effect, feature easy to use.
Compare with the TONGSAIMAI PIAN that is used for the treatment of clinically at present thromboangiitis obliterans, wherein dosage group is better than TONGSAIMAI PIAN matched group, illustrates that White flower danshen total phenanthrenequinone extract can be applicable to the treatment to thromboangiitis obliterans clinically.This total phenanthrenequinone extract can be processed into various dosage forms according to pharmaceutics conventional production process, as tablet, capsule, soft capsule, drop pill and electuary.
Accompanying drawing explanation
Fig. 1 is embodiment 1 White flower danshen total phenanthrenequinone LC-MS chromatogram, A: uv absorption chromatogram; B: total ions chromatogram.Peak 1.15,16-dihydrotanshinone I; Peak 2.1-carbonyl miltirone; Peak 3. rubiquinone B; Peak 5. cryptotanshinones; Peak 6. Tanshinone Is; Peak 7.1,2-dihydrotanshinone I; Peak 8. tanshinone ⅡAs; Peak 9. miltirones.
Fig. 2 be each pharmacological evaluation group thromboangiitis obliterans rat suffering limb arteries histopathology slice map (HE dyeing, 200x), A. sham operated rats, B. model group, C. TONGSAIMAI PIAN group, D. high dose group, dosage group in E., F. low dose group.A～F grouping is by aforementioned pharmacodynamic study part.
The specific embodiment
Below in conjunction with embodiment, the present invention will be further described, but be not limited to this.
Embodiment 1:
Salvia miltiorrhiza f. root after crushed, add 10 times of amount 95% ethanol, reflux, extract, 1.5 hours for the first time, 1 hour for the second time, extract altogether 2 times, extracting solution is evaporated to without alcohol taste, be incorporated as the water of 6 times of amounts of medical material weight, stirring suspension, add again and the isopyknic dichloromethane of water, re-extract 3 times, combined dichloromethane extract, be concentrated into 0.35 times of original volume, and then with isopyknic water extracting and washing, repeat to wash 2 times, discard water lotion, separate the dichloromethane extraction liquid of lower floor, concentrated, gained solids is with the acetone solution of its 12 times of weight, add the silica gel for column chromatography (granularity is 200～300 orders) of gained solids 6 times of weight to mix thoroughly, volatilize, porphyrize, for mixing sample silica gel, in chromatographic column, first pack into and take the silica gel that petroleum ether suspends (40 times that silica gel consumption is sample size), to mix again sample silica gel and pack chromatographic column into, first with petroleum ether-ethyl acetate (100: 3, volume ratio) 5 retention volumes of eluting, then with petroleum ether-ethyl acetate (5: 3, volume ratio) 10 retention volumes of eluting, collect the eluting part of petroleum ether-ethyl acetate (5: 3), pressure reducing and steaming solvent, gained solids, again with 95% dissolve with ethanol, is placed, crystallize, leach crystallization, then with 95% ethyl alcohol recrystallization, obtain White flower danshen total phenanthrenequinone extract.
In White flower danshen total phenanthrenequinone extract, tanshinone ⅡA, cryptotanshinone and Tanshinone I three's total amount is not less than 72%, and wherein the mass ratio of cryptotanshinone and tanshinone ⅡA is 0.64.
Embodiment 2:
Salvia miltiorrhiza f. root after crushed, add 10 times of amount methanol, reflux, extract, 1.5 hours for the first time, 1 hour for the second time, extract altogether 2 times, extracting solution is evaporated to without methanol, be incorporated as the water of 6 times of amounts of medical material weight, stirring suspension, add again and the isopyknic dichloromethane of water, re-extract 3 times, combined dichloromethane extract, be concentrated into 0.35 times of original volume, and then with isopyknic water extracting and washing, repeat to wash 2 times, discard water lotion, separate the dichloromethane extraction liquid of lower floor, concentrated, gained solids is with the acetone solution of its 12 times of weight, add the silica gel for column chromatography (granularity is 200～300 orders) of its 6 times of weight to mix thoroughly, volatilize, porphyrize, for mixing sample silica gel, in chromatographic column, first pack into and take the silica gel that petroleum ether suspends (40 times that silica gel consumption is sample size), to mix again sample silica gel and pack chromatographic column into, first with petroleum ether-ethyl acetate (100: 3, volume ratio) 5 retention volumes of eluting, then with petroleum ether-ethyl acetate (5: 3, volume ratio) 10 retention volumes of eluting, collect the eluting part of petroleum ether-ethyl acetate (5: 3), pressure reducing and steaming solvent, gained solids, again with 95% dissolve with ethanol, is placed, crystallize, leach crystallization, then with 95% ethyl alcohol recrystallization, obtain White flower danshen total phenanthrenequinone extract.
In White flower danshen total phenanthrenequinone extract, tanshinone ⅡA, cryptotanshinone and Tanshinone I three's total amount is not less than 73%, and wherein the mass ratio of cryptotanshinone and tanshinone ⅡA is 0.63.
Embodiment 3:
Salvia miltiorrhiza f. root after crushed, adds 10 times of amount ethyl acetate, reflux, extract,, 2 hours for the first time, latter twice each 1.5 hours, extract altogether 3 times, merge extractive liquid,, evaporated under reduced pressure solvent, obtains solids, then with the acetone solution of its 12 times of weight, add the silica gel for column chromatography (granularity is 200～300 orders) of gained solids 6 times of weight to mix thoroughly, volatilize, porphyrize, for mixing sample silica gel; In chromatographic column, first pack into and take the silica gel that petroleum ether suspends (40 times that silica gel consumption is sample size), to mix again sample silica gel and pack chromatographic column into, first with petroleum ether-ethyl acetate (100: 3, volume ratio) 5 retention volumes of eluting, then with petroleum ether-ethyl acetate (5: 3, volume ratio) 10 retention volumes of eluting, collect the eluting part of petroleum ether-ethyl acetate (5: 3), pressure reducing and steaming solvent, gained solids, again with 95% dissolve with ethanol, is placed, crystallize, leach crystallization, then with 95% ethyl alcohol recrystallization, obtain White flower danshen total phenanthrenequinone extract.
In White flower danshen total phenanthrenequinone extract, tanshinone ⅡA, cryptotanshinone and Tanshinone I three's total amount is not less than 76%, and wherein the mass ratio of cryptotanshinone and tanshinone ⅡA is 0.66.
Embodiment 4:
Salvia miltiorrhiza f. root after crushed, add 6 times of amount 95% methanol, under 50 ℃ of conditions, supersound extraction is 30 minutes, repeat to extract 5 times, merge extractive liquid, be evaporated to without alcohol taste, be incorporated as the water of 6 times of amounts of medical material weight, stirring suspension, add again and the isopyknic dichloromethane of water liquid, re-extract 3 times, combined dichloromethane extract, be concentrated into 0.35 times of original volume, and then with isopyknic water extracting and washing, repeat to wash 2 times, discard water lotion, separate the dichloromethane extraction liquid of lower floor, concentrated, gained solids is with the acetone solution of its 12 times of weight, add the silica gel for column chromatography (granularity is 200～300 orders) of gained solids 6 times of weight to mix thoroughly, volatilize, porphyrize, for mixing sample silica gel, in chromatographic column, first pack into and take the silica gel that petroleum ether suspends (40 times that silica gel consumption is sample size), to mix again sample silica gel and pack chromatographic column into, first with petroleum ether-ethyl acetate (100: 3, volume ratio) 5 retention volumes of eluting, then with petroleum ether-ethyl acetate (5: 3, volume ratio) 10 retention volumes of eluting, collect the eluting part of petroleum ether-ethyl acetate (5: 3), pressure reducing and steaming solvent, gained solids, again with 95% dissolve with ethanol, is placed, crystallize, leach crystallization, then with 95% ethyl alcohol recrystallization, obtain White flower danshen total phenanthrenequinone extract.
In White flower danshen total phenanthrenequinone extract, tanshinone ⅡA, cryptotanshinone and Tanshinone I three's total amount is not less than 73%, and wherein the mass ratio of cryptotanshinone and tanshinone ⅡA is 0.64.
Embodiment 5:
Salvia miltiorrhiza f. root is after being ground into fine powder, put into container with lid, 95% second that adds again medical material amount 60%～70% volume, after the even moistening of alcohol, airtight, place 2 hours, medical material is fully expanded, then pack in diafiltration cylinder, from 95% methanol that adds suitable for reading of diafiltration cylinder, open the end opening of diafiltration cylinder, until ethanol, when flowing out, end opening closes end opening, place, soak, open diafiltration cylinder end opening after 24 hours again, percolate flows out from its end opening, and mouth constantly supplements 95% ethanol from it, keeps the ethanol in diafiltration cylinder can soak medical material all the time.With the ethanol of 30 times of amounts of medical material volume, carry out at ambient temperature diafiltration, the rate of outflow of controlling percolate is 5～10ml/ minute, collects percolate, is evaporated to without alcohol taste.Extractum is incorporated as to the water of 6 times of amounts of medical material weight, stirring suspension, add again and the isopyknic dichloromethane extraction of water, coextraction 3 times, combined dichloromethane extract, is concentrated into 0.35 times of original volume, and then with isopyknic water extracting and washing, the dichloromethane solution that washs altogether 2 Ci，Zai Jiang lower floors separates, concentrated.The solids obtaining, with the acetone solution of its 12 times of weight, adds the silica gel for column chromatography (granularity is 200～300 orders) of gained solids 6 times of weight to mix thoroughly, volatilizes, and porphyrize, for mixing sample silica gel; In chromatographic column, first pack into and take the silica gel that petroleum ether suspends (40 times that silica gel consumption is sample size), to mix again sample silica gel and pack chromatographic column into, first with petroleum ether-ethyl acetate (100: 3, volume ratio) 5 retention volumes of eluting, then with petroleum ether-ethyl acetate (5: 3, volume ratio) 10 retention volumes of eluting, collect the eluting part of petroleum ether-ethyl acetate (5: 3), pressure reducing and steaming solvent, gained solids, again with 95% dissolve with ethanol, is placed, crystallize, leach crystallization, then with 95% ethyl alcohol recrystallization, obtain White flower danshen total phenanthrenequinone extract.
In White flower danshen total phenanthrenequinone extract, tanshinone ⅡA, cryptotanshinone and Tanshinone I three's total amount is not less than 74%, and wherein the mass ratio of cryptotanshinone and tanshinone ⅡA is 0.65.
Embodiment 6: White flower danshen total phenanthrenequinone extract medicinal composition tablets
The White flower danshen total phenanthrenequinone extract 200g of embodiment 1 gained, adds starch 100g, dextrin 45g, cane sugar powder 5g, carboxymethyl starch sodium 17.5g, mix, granulation, dry at 60 ℃, granulate, adds Pulvis Talci 1.5g, carboxymethyl starch sodium 17.5g, mixes, and is pressed into 1000, obtains.
Embodiment 7: the agent of White flower danshen total phenanthrenequinone extract medicament composition capsule
The White flower danshen total phenanthrenequinone extract 200g of embodiment 2 gained, adds starch 100g, dextrin 45g, and microcrystalline Cellulose 3.5g, mixes, granulation, dry at 60 ℃, granulate, adds magnesium stearate 1.5g, mixes, and incapsulates 1000, shell, obtains.
Embodiment 8: White flower danshen total phenanthrenequinone extract medicament composition dropping pills
The White flower danshen total phenanthrenequinone extract 15g of gained in embodiment 4, add 30～50ml dehydrated alcohol, after slight fever is dissolved, filter, filtrate is added in the Macrogol 4000 fused solution of 85g, 60 ℃ of constant temperature water baths stir, until ethanol is waved to the greatest extent, eliminate bubble, then this fused solution is proceeded in the surge drum of pill dripping machine, be incubated dripping under 85 ℃ of conditions, drip apart from 3cm, take dimethicone as condensed fluid, control 20 ℃ to 0 ℃ gradients of condensate temperature cooling, treat that condensation is complete, condensed fluid inclines, collect drop pill, drop is clean and remove the condensed fluid on ball with filter paper, place in silica gel drier (or natural drying), obtain approximately 1000 of drop pill.
Embodiment 9: the agent of White flower danshen total phenanthrenequinone extract medicinal composition soft capsule
The White flower danshen total phenanthrenequinone extract 100g of gained in the preparation of soft capsule content: embodiment 5, porphyrize, cross 100 mesh sieves, add in 10g PEG-4000, heated and stirred, then add Oleum Arachidis hypogaeae semen 330g dilution, then add ascorbic acid 1.0g, p-Hydroxybenzoate 1.0g, cera alba 8g, be heated to 38 ℃ of left and right, stir simultaneously, obtain its soft capsule content; The preparation of soft capsule shell material: in parts by weight, by gelatin: glycerol: water: sorbic acid was according to mass ratio 1.0: 0.3: 0.85: 0.15 ratio is carried out proportioning, first will in a certain amount of glycerol, putting into of water glue tank, be heated to 65 ℃, and then by pharmagel, sorbitol inputization glue tank, stir, be heated to 65 ℃, pharmagel is dissolved completely, obtain capsule casing material; Soft capsule preparation: use encapsulating machine, the capsule casing material making is placed in the gelatin heat-preserving container of 70 ℃, the rubber of soft capsule processed, then injects the soft capsule content having made, and rolls mold pressing and makes 1000 soft capsules, dry, washes ball, then is dried, and obtains.
Claims (1)
1. the vasculitic White flower danshen total phenanthrenequinone extract for the treatment of, the root of Salvia miltiorrhiza f. of take is raw material, by solvent extraction, solvent extraction, column chromatography and purification; Mainly contain TANSHINONES
a, cryptotanshinone, TANSHINONES
, 1,2-dihydrotanshinone
, miltirone, 15,16-dihydrotanshinone
, 1-carbonyl miltirone and rubiquinone B, wherein contained TANSHINONES
a, cryptotanshinone and TANSHINONES
three's total content is not less than 70wt%, TANSHINONES
the mass ratio of A and cryptotanshinone is 0.45 ~ 0.80;
Preparation process is as follows:
(1) solvent extraction
The root of raw material Salvia miltiorrhiza f. is after pulverizing, take methanol, 95% ethanol, ethyl acetate as extracting solvent, heating extraction or supersound extraction, the weight ratio of solvent for use amount and raw material is 6 ~ 15:1, repeat to extract 1 ~ 3 time, remove medicinal residues, merging filtrate, it is 1.20 ~ 1.35 pastes that gained filtrate is concentrated into proportion under normal pressure or reduced pressure, 60 ℃ of mensuration;
(2) extraction
The paste that step (1) is obtained, with the aqueous suspension of 10 ~ 12 times of weight, is used and the isopyknic organic solvent extraction of water, and described extraction organic solvent is dichloromethane; Repeat 2 ~ 3 times, combining extraction liquid, concentrating under reduced pressure, then use and the isopyknic water extracting and washing of concentrate, repeat to wash 2 ~ 3 times, discard water layer, then separate the organic solvent layer on upper strata, pressure reducing and steaming solvent, obtains solids;
When extraction is evaporated to 0.5 times of extraction liquids accumulated amount 2 times time, when extraction 3 times, be evaporated to 0.35 times of extraction liquids accumulated amount;
(3) column chromatography
The solids that step (2) extraction is obtained carries out silica gel column chromatography separating purification, first with 4 ~ 6 retention volumes of eluant petroleum ether-ethyl acetate 100:3 volume ratio eluting, then with 8 ~ 12 retention volumes of petroleum ether-ethyl acetate 5:3 volume ratio eluting, collect the eluting part of petroleum ether-ethyl acetate 5:3, pressure reducing and steaming solvent, obtains red extract;
(4) purification
Red extract obtained above, with 95% dissolve with ethanol, is placed, and crystallize, leaches crystallization, then with 95% ethyl alcohol recrystallization, obtains White flower danshen total phenanthrenequinone extract.
2. White flower danshen total phenanthrenequinone extract as claimed in claim 1, the heating extraction that it is characterized in that step (1) is to be that solvent carries out reflux, extract, with 95% ethanol, 10 times of weight that solvent is raw material.
3. White flower danshen total phenanthrenequinone extract as claimed in claim 1, it is characterized in that in step (3), first with 5 retention volumes of petroleum ether-ethyl acetate 100:3 volume ratio eluting, then with 10 retention volumes of petroleum ether-ethyl acetate 5:3 volume ratio eluting, collect the eluting part of petroleum ether-ethyl acetate 5:3.
4. treat a pharmaceutical composition for vasculitic White flower danshen total phenanthrenequinone extract, comprise White flower danshen total phenanthrenequinone extract and one or more pharmaceutically acceptable carriers or excipient described in claim 1～3.
5. the pharmaceutical composition of White flower danshen total phenanthrenequinone extract as claimed in claim 4, is characterized in that described pharmaceutical composition is tablet, capsule, drop pill or electuary.
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