CN1475272A - Sydroxy carthamin A and its preparation method and use - Google Patents
Sydroxy carthamin A and its preparation method and use Download PDFInfo
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- CN1475272A CN1475272A CNA021327815A CN02132781A CN1475272A CN 1475272 A CN1475272 A CN 1475272A CN A021327815 A CNA021327815 A CN A021327815A CN 02132781 A CN02132781 A CN 02132781A CN 1475272 A CN1475272 A CN 1475272A
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- hydroxysafflor yellow
- concentrated solution
- yellow
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- hydroxysafflor
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- 238000002360 preparation method Methods 0.000 title claims description 18
- WLYGSPLCNKYESI-RSUQVHIMSA-N Carthamin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1[C@@]1(O)C(O)=C(C(=O)\C=C\C=2C=CC(O)=CC=2)C(=O)C(\C=C\2C([C@](O)([C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(O)=C(C(=O)\C=C\C=3C=CC(O)=CC=3)C/2=O)=O)=C1O WLYGSPLCNKYESI-RSUQVHIMSA-N 0.000 title description 4
- DYQVDISPPLTLLR-HJQYTNQXSA-N Carthamin Natural products CC[C@H]1O[C@H]([C@H](O)[C@@H](O)[C@@H]1O)[C@]2(O)C(=C(C=C/3C(=O)C(=C(O)[C@](O)([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C3=O)C(=O)C=Cc5ccc(O)cc5)C(=O)C(=C2O)C(=O)C=Cc6ccc(O)cc6)O DYQVDISPPLTLLR-HJQYTNQXSA-N 0.000 title description 2
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- 239000008280 blood Substances 0.000 claims abstract description 7
- IAVUBSCVWHLRGE-UXEKTNMQSA-N (6e)-2,5-dihydroxy-6-[(e)-1-hydroxy-3-(4-hydroxyphenyl)prop-2-enylidene]-2,4-bis[(2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]cyclohex-4-ene-1,3-dione Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C(C(C(O)([C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)C1=O)=O)=C(O)\C1=C(/O)\C=C\C1=CC=C(O)C=C1 IAVUBSCVWHLRGE-UXEKTNMQSA-N 0.000 claims description 89
- ZZMASNSDVDSYKO-UHFFFAOYSA-N hydroxysafflor yellow A Natural products OCC1OC(C(O)C(O)C1O)C2=C(O)C(O)(C3OC(CO)C(O)C(O)C3O)C(=O)C(=C2O)C(=O)C=Cc4ccc(O)cc4 ZZMASNSDVDSYKO-UHFFFAOYSA-N 0.000 claims description 89
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- 238000004440 column chromatography Methods 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
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- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
A hydroxy carthamuranidin A is prpared from safflower through extracting and purifying by chromatography. Its advantages are low cost, no environmental pollution, and high output rate and purity. It can be used to prepare medicines for preventing and treating cerebral ischemia, cerebral infarction and cerebral thrombus, and reducing blood viscosity with high curative effect.
Description
Technical field
The S-A Hydroxysafflor yellow A that the present invention relates to from Chinese medicine safflower, prepare, and its production and application.
Background technology
Chinese medicine Flos Carthami (the feverfew Flos Carthami belongs to the dried floral of Flos Carthami Carthamus tinctorius L.) has significantly function such as blood circulation promoting and blood stasis dispelling, inducing menstruation to relieve menalgia.The extraction of effective ingredient in the Flos Carthami is more and more caused relevant person's concern, Recent study confirms that the effective ingredient of Flos Carthami mainly concentrates on water miscible flavochrome part, preliminary analysis shows that Carthamus yellow is the mixture of three kinds of water soluble ingredients: S-A Hydroxysafflor yellow A (Hydroxysaffloryellow-A), Safflomin B, Carthamus yellow C.A small amount of report about Carthamus yellow is only arranged at present, but do not find the report of S-A Hydroxysafflor yellow A and its production and application as yet.
Summary of the invention
S-A Hydroxysafflor yellow A (Hydroxysafflor yellow-A), molecular formula is C
27H
32O
16, being orange-yellow powder, flavor is slightly pained, and nothing is smelt.Very easily be dissolved in water, be soluble in methanol, slightly be dissolved in ethanol, the atomic acetone that is dissolved in, almost insoluble or insoluble in chloroform, ether, petroleum ether, benzene equal solvent.
The purpose of this invention is to provide the S-A Hydroxysafflor yellow A that extracts from Flos Carthami, this S-A Hydroxysafflor yellow A can make with following method:
(1), extracts: get the Chinese crude drug Flos Carthami, add the water of the material weight 10-30 that offers medicine times of institute, under 25-100 ℃ of condition, 10 minutes to 24 hours after-filtration of stirring and leaching slowly, filtering residue repeats to extract after-filtration, merging filtrate 2-4 time by above-mentioned condition again, be cooled to room temperature, get extracting solution A;
(2), separate: get extracting solution A, be 100-130 by the ratio of making a basket medical material weight (gram) and packing volume (liter): 1 amount is carried out column chromatography, and the usefulness deionized water is with 0.1-10mL/cm
2.min flow velocity eluting merges the eluent of collecting, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution B:
(3), pure heavy: as to get concentrated solution B, adding medicinal ethanol or methanol or acetone under constantly stirring makes and contains the alcohol amount and reach 60-90%, separate out orange-yellow post precipitation, under 4-30 ℃ of condition, left standstill 1-48 hour, cross the orange-yellow precipitation of leaching, add the ultra-pure water dissolution filter again, filtrate is evaporated to proportion under 25-100 ℃ of condition be 1.03-1.8, gets concentrated solution C;
(4), purification: get concentrated solution C, be 1 by the ratio of concentrated solution volume and packing volume: the amount of 1-100 is carried out column chromatography, with ultra-pure water with 0.1-10mL/cm
2.min flow velocity eluting is collected orange-yellow colour band stream part, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution D;
(5), repurity: getting concentrated solution D by (4) described technology, is eluent purification 1-3 time repeatedly with water for injection, concentrated solution D
n(n is the number of times of repurity)
(6), degerming lyophilization: with concentrated solution D
nAfter carrying out heat sterilization with 0.45 μ ultrafilter membrane, lyophilization immediately, content be the S-A Hydroxysafflor yellow A dry powder of 90-99%.
Another object of the present invention provides the preparation method of S-A Hydroxysafflor yellow A, and this preparation method comprises the steps:
(1), extracts: get the Chinese crude drug Flos Carthami, add the water of the material weight 10-30 that offers medicine times of institute, under 25-100 ℃ of condition, 10 minutes to 24 hours after-filtration of stirring and leaching slowly, filtering residue repeats to extract after-filtration, merging filtrate 2-4 time by above-mentioned condition again, be cooled to room temperature, get extracting solution A;
(2), separate: get extracting solution A, be 100-130 by the ratio of making a basket medical material weight (gram) and packing volume (liter): 1 amount is carried out column chromatography, and the usefulness deionized water is with 0.1-10mL/cm
2.min flow velocity eluting merges the eluent of collecting, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution B;
(3), pure heavy: as to get concentrated solution B, adding medicinal ethanol or methanol or acetone under constantly stirring makes and contains the alcohol amount and reach 60-90%, separate out orange-yellow post precipitation, under 4-30 ℃ of condition, left standstill 1-48 hour, cross the orange-yellow precipitation of leaching, add the ultra-pure water dissolution filter again, filtrate is evaporated to proportion under 25-100 ℃ of condition be 1.03-1.8, gets concentrated solution C;
(4), purification: get concentrated solution C, be 1 by the ratio of concentrated solution volume and packing volume: the amount of 1-100 is carried out column chromatography, with ultra-pure water with 0.1-10mL/cm
2.min flow velocity eluting is collected orange-yellow colour band stream part, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution D;
(5), repurity: getting concentrated solution D by (4) described technology, is eluent purification 1-3 time repeatedly with water for injection, concentrated solution D
n(n is the number of times of repurity)
(6), degerming lyophilization: with concentrated solution D
nAfter carrying out heat sterilization with 0.45 μ ultrafilter membrane, lyophilization immediately, content be the S-A Hydroxysafflor yellow A dry powder of 90-99%.
Filler in column chromatography preparation technology of the present invention can be selected macroporous resin, polydextran gel, polyamide, silica gel etc. for use, can use one separately, also can reuse respectively.
The most preferably scheme of column chromatography filler is to use the macroporous resin filler in separating technology, uses the polydextran gel filler in purification, repurity technology.
Another purpose of the present invention provides S-A Hydroxysafflor yellow A and prevents and the treatment ischemic cerebrovascular in preparation: cerebral ischemia, cerebral infarction, cerebral thrombosis etc., and the application in the medicine of blood viscosity lowering.
Prevention of the present invention and treatment ischemic cerebrovascular: cerebral ischemia, cerebral infarction, cerebral thrombosis etc., and the medicine of blood viscosity lowering can be multiple dosage forms such as tablet, capsule, injection.
The most preferably scheme of the injection that the present invention uses is the S-A Hydroxysafflor yellow A lyophilized injectable powder.
The S-A Hydroxysafflor yellow A lyophilized injectable powder is made up of following component: (consumption is a weight portion)
25 parts of S-A Hydroxysafflor yellow As
Mannitol 25-75 part
Water for injection 400-1200 part
Its preparation process is: take by weighing S-A Hydroxysafflor yellow A dried powder, mannitol respectively, add the injection water and make dissolving and add and add to the full amount of water for injection, stir evenly, aseptic filtration, filtrate are sub-packed in the cillin bottle, vacuum lyophilization, tamponade, the envelope aluminium lid gets product.
The capsule that the present invention uses is the S-A Hydroxysafflor yellow A capsule.
The S-A Hydroxysafflor yellow A capsule is made up of following component: (consumption is a weight portion)
50 parts of S-A Hydroxysafflor yellow As
Dried starch 100-200 part
Its preparation process is: take by weighing S-A Hydroxysafflor yellow A dried powder and dried starch respectively, behind the mix homogeneously, divide in the hard capsule of packing into, promptly get the S-A Hydroxysafflor yellow A oral capsule.
The tablet that the present invention uses is the S-A Hydroxysafflor yellow A tablet.
The S-A Hydroxysafflor yellow A tablet is made up of following component: (consumption is a weight portion)
50 parts of S-A Hydroxysafflor yellow As
Magnesium stearate 5-20 part
Starch 50-200 part
Its preparation process is: take by weighing S-A Hydroxysafflor yellow A dried powder, magnesium stearate and starch respectively, behind the mix homogeneously, pharmaceutical methods promptly gets the S-A Hydroxysafflor yellow A tablet through technologies such as tabletting, coating, packing, packings routinely.
Technology of the present invention is simple, and cost is low, and the S-A Hydroxysafflor yellow A content that makes reaches more than 90%, and yield reaches more than 1%, can be applicable to extensive, high efficiency, industrialization is extracted in the class new Chinese medicine.
Description of drawings
The specific embodiment
In the various embodiments of the present invention, the Chinese crude drug Flos Carthami is all available from Tacheng (May to June flower is plucked when red by xanthochromia, dry in the shade or drying in the sun is first-class or second-class Flos Carthami).
Embodiment 1: the polyamide purifying legal system is equipped with S-A Hydroxysafflor yellow A
(1), extract: take by weighing Chinese crude drug Flos Carthami 20kg, add 600kg water, under 100 ℃ of conditions, 24 hours after-filtration of stirring and leaching slowly, filtering residue repeats to extract after-filtration 2 times by above-mentioned condition again, merging filtrate is cooled to room temperature, extracting solution A.
(2), separate: get extracting solution A, last bed volume is the macroporous resin column of 200L, uses deionized water with 10mL/cm
2.min flow velocity eluting merges the eluent of collecting, and being evaporated to proportion under 100 ℃ of conditions is 1.8, gets concentrated solution B.
(3), pure heavy: as to get concentrated solution B, adding methanol under constantly stirring makes and contains the alcohol amount and reach 90%, separate out orange-yellow precipitation this moment, under 30 ℃ of conditions, left standstill 48 hours, filter, get orange-yellow precipitation, add the ultra-pure water dissolving, filter, filtrate is evaporated to proportion under 100 ℃ of conditions be 1.8, gets concentrated solution C.
(4), purification: get concentrated solution C, last bed volume is the polyamide column of 200L, uses ultra-pure water with 10mL/cm
2.min flow velocity eluting is collected orange-yellow colour band stream part, and being evaporated to proportion under 100 ℃ of conditions is 1.8, gets concentrated solution D.
(5), repurity: get concentrated solution D, go up polyamide column again by (4) described condition, use the water for injection eluting, purification is 3 times repeatedly, gets concentrated solution D at last
3
(6), degerming lyophilization: with concentrated solution D
3Behind 0.45 μ filter membrane heat sterilization, lyophilization immediately, must contain is 95.6% S-A Hydroxysafflor yellow A dry powder 202g, yield 1.01%.
Embodiment 11: the S-A Hydroxysafflor yellow A lyophilized injectable powder.
S-A Hydroxysafflor yellow A 25g
Mannitol 25g
Water for injection 400g
Take by weighing S-A Hydroxysafflor yellow A dried powder, mannitol respectively, adding the injection water makes dissolving and adds and add to the full amount of water for injection, stir evenly, aseptic filtration, filtrate are sub-packed in the cillin bottle, every bottle of 0.4mL, vacuum lyophilization, tamponade, the envelope aluminium lid makes 955 bottles of S-A Hydroxysafflor yellow A lyophilized injectable powders.
Embodiment 12: the S-A Hydroxysafflor yellow A lyophilized injectable powder.
S-A Hydroxysafflor yellow A 25g
Mannitol 50g
Water for injection 800g
Take by weighing S-A Hydroxysafflor yellow A dried powder, mannitol respectively, adding the injection water makes dissolving and adds and add to the full amount of water for injection, stir evenly, aseptic filtration, filtrate are sub-packed in the cillin bottle, every bottle of 0.8mL, vacuum lyophilization, tamponade, the envelope aluminium lid makes 977 bottles of S-A Hydroxysafflor yellow A lyophilized injectable powders.
Embodiment 13: the S-A Hydroxysafflor yellow A lyophilized injectable powder.
S-A Hydroxysafflor yellow A 25g
Mannitol 75g
Water for injection 1200g
Take by weighing S-A Hydroxysafflor yellow A dried powder, mannitol respectively, adding the injection water makes dissolving and adds and add to the full amount of water for injection, stir evenly, aseptic filtration, filtrate are sub-packed in the cillin bottle, every bottle of 1.2mL, vacuum lyophilization, tamponade, the envelope aluminium lid makes 961 bottles of S-A Hydroxysafflor yellow A lyophilized injectable powders.
Embodiment 14: the S-A Hydroxysafflor yellow A capsule.
S-A Hydroxysafflor yellow A 50g
Dried starch 150g
Take by weighing S-A Hydroxysafflor yellow A dried powder and dried starch respectively, behind the mix homogeneously, divide in 1000 hard capsules of packing into, get the S-A Hydroxysafflor yellow A oral capsule.
Embodiment 15: the S-A Hydroxysafflor yellow A tablet.
S-A Hydroxysafflor yellow A 50g
Magnesium stearate 10g
Starch 100g
Take by weighing S-A Hydroxysafflor yellow A dried powder, magnesium stearate and starch respectively, behind the mix homogeneously, pharmaceutical methods gets 1000 tablets of S-A Hydroxysafflor yellow A tablets through technologies such as tabletting, coating, packing, packings routinely.
The present patent application people presses embodiment 9 methods three batches of S-A Hydroxysafflor yellow As of preparation continuously, and is as follows through verification test result:
One, character test:
The gained S-A Hydroxysafflor yellow A is orange-yellow powder after testing.FeCl
3Test is blackish green deeply, and the Mg-HCl test is negative response.Very easily be dissolved in water, be soluble in methanol, slightly be dissolved in ethanol, the atomic acetone that is dissolved in, at chloroform, ether, petroleum ether, almost insoluble or insoluble in the benzene equal solvent.
Two, structure is identified:
1, ultra-violet absorption spectrum (UV) is identified
Sample thief adds methanol in right amount and makes the solution that contains 10 μ g S-A Hydroxysafflor yellow As among every 1mL, by " Chinese pharmacopoeia current edition spectrophotography is drawn absorption curve in the 200-500nm wave-length coverage, there is absorption maximum at the place at 401 ± nm wavelength.Test result is seen Fig. 1.
2, infrared absorption spectroscopy (IR) is identified
IR υ
Max KBrCm
-1Present 3415 (OH peaks), 2927 (association hydroxyls), 1624 (association hydroxyl or quinone ketone C=O), 1604,1514,1440 (phenyl ring peaks), 1604,926 (phenyl ring conjugation trans double bond-CH=CH-), 1235,1078,1008 (glycosyl C-D).Test result is seen Fig. 2.
3, mass spectrum is identified
FAB-MS[M+1]
+Be 613, the molecular weight that shows sample is 612.Test result is seen Fig. 3.
4, nuclear magnetic resoance spectrum is identified
1HNMR is at δ 2.49 (1H, d, j=9.6H
2, I '-H) and 4.75 (1H, d, j=9.6H
2, " existence of two Fructus Vitis viniferae sugar charcoal glycosides of signal indicating anomeric proton of H) locating is two hydrogen protons on the para-orientation phenyl ring at δ 6.77 and 7.28 to I.At δ 7.34,7.37 is the chemical potential shape of trans conjugation alkene hydrogen.The proton signal δ 9.73 (C that also have two hydroxyl proton signals in addition
4-OH) at δ 9.73 places a phenolic hydroxyl group proton signal (4-OH) is arranged with δ 18.64.Other has an associating enol proton signal of hydroxyl at low δ 18.64 places.Test result is seen Fig. 4.
1327 of C-NMR demonstrations are unimodal, and prompting contains chalcone derivative and hexose molecule, and its ratio is 1: 2, shows that its molecular formula is C
27H
32O
16Test result is seen Fig. 5.
Three, stability test:
Get three batches of S-A Hydroxysafflor yellow A samples of continuous preparation, under the room temperature natural conditions, airtight, drying was deposited three months, detected respectively at 0 month, 1 month, 2 months, 3 months, and the test result no change proves its steady quality.
Four, assay:
Adopting the content of high effective liquid chromatography for measuring S-A Hydroxysafflor yellow A, is filler with octadecylsilane chemically bonded silica, and methanol: acetonitrile: 0.45% phosphoric acid water (32.5: 2.5: 65) is a mobile phase, and detecting wavelength is UV 401 ± nm.Theoretical cam curve is pressed the S-A Hydroxysafflor yellow A peak and is calculated, and should be not less than 2000.
Sample thief during mensuration adds water and makes the solution that every 1mL contains the 0.13mg S-A Hydroxysafflor yellow A, shakes up filtration, discards filtrate just, draws subsequent filtrate 10 μ L, injects hplc determination, presses normalization method with calculated by peak area.Three batches of S-A Hydroxysafflor yellow A main peak content are respectively 98.93%, 99.06%, 99.08%.Test result is seen Fig. 6,7,8.
Five, pharmacological toxicology test:
1, pharmacodynamic study
This experimental study S-A Hydroxysafflor yellow A to the prevention of animal ischemic brain infarction and therapeutical effect and to the influence of thrombosis and hemorheology etc.Experimental result shows, S-A Hydroxysafflor yellow A 2～4mg/kg intravenous injection, re-perfusion model behind the experimental full brain of animal and focal cerebral ischemia and the ischemia there are tangible prevention and therapeutical effect, increase effect to cerebral blood flow is more obvious than peripheral blood vessel, can prevent thrombosis, blood viscosity lowering and do not influence plasma viscosity and plasma fibrin and plasmin activity.
2, general pharmacology is learned research
This experimental study S-A Hydroxysafflor yellow A the general pharmacology of anesthesia Cor Canitis electricity, blood pressure, breathing is learned influence and to the influence of conscious mouse nervous system and general behavior.Experimental result shows, S-A Hydroxysafflor yellow A intravenous injection 2-4mg/kg, and to the not obviously influence of electrocardio, blood pressure and breathing of anesthetized animal, the 10mg/kg intravenous injection can reduce heart rate and blood pressure.The mouse mainline S-A Hydroxysafflor yellow A is not seen obvious influence to the general behavior of conscious mouse yet.
3, toxicologic study
(1), acute toxicity test: result of the test shows that the acute toxicity of mice oral administration and intravenous injection S-A Hydroxysafflor yellow A is all greater than 2000mg/kg; The acute toxicity of rat oral administration and intravenous injection S-A Hydroxysafflor yellow A is all greater than 1000mg/kg.
(2), long term toxicity test: result of the test shows rats by intraperitoneal injection, monkey intravenous injection S-A Hydroxysafflor yellow A 4,18,80mg, continuous three months long term toxicity tests, the overt toxicity reflection is found to have in the end, and its nontoxic dose is 80mg/kg/d, is equivalent to 40 times of clinical dosage.
(3), mutagenesis and tertogenicity test: result of the test shows that S-A Hydroxysafflor yellow A does not have mutagenesis and teratogenesis, and embryo and tire son are not had toxicity.
4, pharmacokinetics test
This test comprises that haemoconcentration changes test, tissue distribution detects, drains test.
The result shows, the curve during medicine of quiet notes 2,6 of rat and 18mg/kg, through process of fitting treatment, the feature that meets linear two-compartment model, the half-life t1/2 (α) that calculates by two-compartment model was respectively 0.0122,0.0371 and 0.0194 hour, t1/2 (β) was respectively 0.386,0.482 and 0.272 hour, apparent volume of distribution is 0.0669,0.0997 and 0.0829L/kg, and clearance rate is 0.3400,0.3508 and 0.4439L/kg/min.S-A Hydroxysafflor yellow A area under the drug-time curve AUC proportional increase when dosage increases to 18mg/kg by 2mg/kg is linear kinetics and eliminates (r=0.9968).After the intravenous injection 5 minutes, distribution is promptly arranged in each internal organs, its center, liver, lung, kidney, thymus, pancreas, stomach, thyroid, lymph node, intestinal and ovary content are higher.Behind the rat intravenous injection S-A Hydroxysafflor yellow A 18mg/kg dosage, mainly drain from urine with the original shape medicine in vivo, less through the excretory amount of excrement, the urinary excretion in 48 hours reaches 76.1% of dosage, 48 hours excretion is 5.34% in the feces, and bile excretion is 4.77%.
Six, clinical observation on the therapeutic effect result:
For showing S-A Hydroxysafflor yellow A lyophilized injectable powder (every bottle of hydroxyl carthamin yellow A-containing 25mg) that the present invention makes therapeutic effect to ischemic cerebrovascular such as cerebral ischemia, cerebral infarction, cerebral thrombosiss, the present invention has carried out the clinical observation of 105 routine systems, selects medical history, the state of an illness, age, sex and matched group.
Consumption: everyone every day 2 times, each 1 bottle.
Usage: intravenous drip, 4 weeks of the course of treatment.Test statistics shows: with lyophilized injectable powder prevention of the present invention and treatment ischemic cerebrovascular, that obtains significant curative effect accounts for 51%, substantially effectively accounts for 44%, and invalid accounts for 5%, and total effective rate reaches 95%.
Subordinate list
| Embodiment number | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 | ??9 | ??10 | |
| Extract | Drop into the water yield (kg) | ??600 | ??560 | ??500 | ??440 | ??400 | ??360 | ??320 | ??2800 | ??240 | ??200 |
| The extraction temperature (℃) | ??100 | ??90 | ??25 | ??30 | ??40 | ??50 | ??60 | ??70 | ??80 | ??90 | |
| Extraction time (h) | ??24 | ??18 | ??12 | ??12 | ??6 | ??8 | ??4 | ??2 | ??1 | ??10 | |
| Number of times | ??2 | ??2 | ??3 | ??3 | ??3 | ??3 | ??3 | ??3 | ??3 | ??4 | |
| Separate | Column packing | ??A | ??A | ??A | ??A | ??A | ??A | ??A | ??A | ??A | ??A |
| Column packing volume (L) | ??200 | ??200 | ??150 | ??190 | ??180 | ??190 | ??180 | ??170 | ??160 | ??150 | |
| Eluent flow rate | ??10 | ??9 | ??7 | ??5 | ??4 | ??3 | ??2 | ??1 | ??0.5 | ??0.1 | |
| The concentrating under reduced pressure temperature | ??100 | ??90 | ??25 | ??30 | ??40 | ??50 | ??60 | ??70 | ??80 | ??90 | |
| Concentrated solution proportion | ??1.8 | ??1.6 | ??1.4 | ??1.7 | ??1.5 | ??1.5 | ??1.3 | ??1.23 | ??1.15 | ??1.03 | |
| Pure heavy | Add alcohol | First | First | Second | Second | Third | Third | In | Second | Second | First |
| Reach pure content (%) | ??90 | ??85 | ??75 | ??65 | ??60 | ??70 | ??90 | ??85 | ??80 | ??75 | |
| Dwell temperature (℃) | ??30 | ??20 | ??10 | ??25 | ??10 | ??25 | ??15 | ??10 | ??5 | ??4 | |
| Time of repose (h) | ??48 | ??24 | ??12 | ??12 | ??8 | ??24 | ??18 | ??12 | ??8 | ??4 | |
| The concentrating under reduced pressure temperature | ??100 | ??90 | ??25 | ??30 | ??40 | ??50 | ??60 | ??70 | ??80 | ??90 | |
| Concentrated solution proportion | ??1.8 | ??1.6 | ??1.4 | ??1.7 | ??1.5 | ??1.5 | ??1.3 | ??1.23 | ??1.15 | ??1.03 | |
| Purification | Column packing | ??B | ??B | ??A | ??C | ??C | ??D | ??D | ??D | ??D | ??D |
| Column packing volume (L) | ??200 | ??100 | ??150 | ??150 | ??100 | ??50 | ??30 | ??20 | ??10 | ??2 | |
| Eluent flow rate | ??10 | ??9 | ??7 | ??5 | ??4 | ??3 | ??2 | ??1 | ??0.5 | ??0.1 | |
| The concentrating under reduced pressure temperature | ??100 | ??90 | ??25 | ??30 | ??40 | ??50 | ??60 | ??70 | ??80 | ??90 | |
| Concentrated solution proportion | ??1.8 | ??1.6 | ??1.4 | ??1.7 | ??1.5 | ??1.5 | ??1.3 | ??1.23 | ??1.15 | ??1.03 | |
| The repurity number of times | ??3 | ??2 | ??3 | ??3 | ??2 | ??1 | ??2 | ??3 | ??3 | ??3 | |
| Get dry powder amount (g) | ??202 | ??206 | ??204 | ??202 | ??204 | ??206 | ??210 | ??218 | ??214 | ??212 | |
| Dry powder content (%) | ??95.6 | ??96.2 | ??95.5 | ??97.3 | ??96.8 | ??98.7 | ??99.1 | ??98.9 | ??99.0 | ??99.2 | |
| Yield (%) | ??1.01 | ??1.03 | ??1.02 | ??1.01 | ??1.02 | ??1.03 | ??1.05 | ??1.09 | ??1.07 | ??1.06 | |
Claims (9)
1, a kind of S-A Hydroxysafflor yellow A, this S-A Hydroxysafflor yellow A can make with following method:
(1), extracts: get the Chinese crude drug Flos Carthami, add the water of the material weight 10-30 that offers medicine times of institute, under 25-100 ℃ of condition, 10 minutes to 24 hours after-filtration of stirring and leaching slowly, filtering residue repeats to extract after-filtration, merging filtrate 2-4 time by above-mentioned condition again, be cooled to room temperature, get extracting solution A;
(2), separate: get extracting solution A, be 100-130 by the ratio of making a basket medical material weight (gram) and packing volume (liter): 1 amount is carried out column chromatography, and the usefulness deionized water is with 0.1-10mL/cm
2.min flow velocity eluting merges the eluent of collecting, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution B;
(3), pure heavy: as to get concentrated solution B, adding medicinal ethanol or methanol or acetone under constantly stirring makes and contains the alcohol amount and reach 60-90%, separate out orange-yellow post precipitation, under 4-30 ℃ of condition, left standstill 1-48 hour, cross the orange-yellow precipitation of leaching, add the ultra-pure water dissolution filter again, filtrate is evaporated to proportion under 25-100 ℃ of condition be 1.03-1.8, gets concentrated solution C;
(4), purification: get concentrated solution C, be 1 by the ratio of concentrated solution volume and packing volume: the amount of 1-100 is carried out column chromatography, with ultra-pure water with 0.1-10mL/cm
2.min flow velocity eluting is collected orange-yellow colour band stream part, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution D;
(5), repurity: getting concentrated solution D by (4) described technology, is eluent purification 1-3 time repeatedly with water for injection, concentrated solution D
n
(6), degerming lyophilization: with concentrated solution D
nAfter carrying out heat sterilization with 0.45 μ ultrafilter membrane, lyophilization immediately, content be the S-A Hydroxysafflor yellow A dry powder of 90-99%.
2, a kind of preparation method of S-A Hydroxysafflor yellow A, this preparation method comprises the steps:
(1), extracts: get the Chinese crude drug Flos Carthami, add the water of the material weight 10-30 that offers medicine times of institute, under 25-100 ℃ of condition, 10 minutes to 24 hours after-filtration of stirring and leaching slowly, filtering residue repeats to extract after-filtration, merging filtrate 2-4 time by above-mentioned condition again, be cooled to room temperature, get extracting solution A;
(2), separate: get extracting solution A, be 100-130 by the ratio of making a basket medical material weight (gram) and packing volume (liter): 1 amount is carried out column chromatography, and the usefulness deionized water is with 0.1-10mL/cm
2.min flow velocity eluting merges the eluent of collecting, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution B;
(3), pure heavy: as to get concentrated solution B, adding medicinal ethanol or methanol or acetone under constantly stirring makes and contains the alcohol amount and reach 60-90%, separate out orange-yellow post precipitation, under 4-30 ℃ of condition, left standstill 1-48 hour, cross the orange-yellow precipitation of leaching, add the ultra-pure water dissolution filter again, filtrate is evaporated to proportion under 25-100 ℃ of condition be 1.03-1.8, gets concentrated solution C;
(4), purification: get concentrated solution C, be 1 by the ratio of concentrated solution volume and packing volume: the amount of 1-100 is carried out column chromatography, with ultra-pure water with 0.1-10mL/cm
2.min flow velocity eluting is collected orange-yellow colour band stream part, and being evaporated to proportion under 25-100 ℃ of condition is 1.03-1.8, gets concentrated solution D;
(5), repurity: getting concentrated solution D by (4) described technology, is eluent purification 1-3 time repeatedly with water for injection, concentrated solution D
n
(6), degerming lyophilization: with concentrated solution D
nAfter carrying out heat sterilization with 0.45 μ ultrafilter membrane, lyophilization immediately, content be the S-A Hydroxysafflor yellow A dry powder of 90-99%.
3, according to the preparation method of the S-A Hydroxysafflor yellow A of claim 2, it is characterized in that the filler among the column chromatography preparation technology, can select macroporous resin, polydextran gel, polyamide, silica gel etc. for use, can use one separately, also can reuse respectively.
4, according to the preparation method of the S-A Hydroxysafflor yellow A of claim 3, the most preferably scheme that it is characterized in that the column chromatography filler is to use the macroporous resin filler in separating technology, uses the polydextran gel filler in purification, repurity technology.
5, the application of S-A Hydroxysafflor yellow A in the medicine for preparing prevention and treatment ischemic cerebrovascular, blood viscosity lowering.
6, according to the medicine of the prevention of claim 5 and treatment ischemic cerebrovascular, blood viscosity lowering, it is characterized in that these medicines can be made into tablet, capsule, injection.
7, according to the medicine of claim 6, the most preferably scheme that it is characterized in that described injection is an injection S-A Hydroxysafflor yellow A lyophilized injectable powder, and the S-A Hydroxysafflor yellow A lyophilized injectable powder is made up of following component: (consumption is a weight portion)
25 parts of S-A Hydroxysafflor yellow As
Mannitol 25-75 part
Water for injection 400-1200 part
Its preparation process is: take by weighing S-A Hydroxysafflor yellow A dried powder, mannitol respectively, add the injection water and make dissolving and add and add to the full amount of water for injection, stir evenly, aseptic filtration, filtrate are sub-packed in the cillin bottle, vacuum lyophilization, tamponade, the envelope aluminium lid gets product.
8, according to the medicine of claim 6, it is characterized in that capsule is the S-A Hydroxysafflor yellow A capsule, the S-A Hydroxysafflor yellow A capsule is made up of following component: (consumption is a weight portion)
50 parts of S-A Hydroxysafflor yellow As
Dried starch 100-200 part
Its preparation process is: take by weighing S-A Hydroxysafflor yellow A dried powder and dried starch respectively, behind the mix homogeneously, divide in the hard capsule of packing into, promptly get the S-A Hydroxysafflor yellow A oral capsule.
9, according to the medicine of claim 6, it is characterized in that tablet is the S-A Hydroxysafflor yellow A tablet, the S-A Hydroxysafflor yellow A tablet is made up of following component: (consumption is a weight portion)
50 parts of S-A Hydroxysafflor yellow As
Magnesium stearate 5-20 part
Starch 50-200 part
Its preparation process is: take by weighing S-A Hydroxysafflor yellow A dried powder, magnesium stearate and starch respectively, behind the mix homogeneously, pharmaceutical methods promptly gets the S-A Hydroxysafflor yellow A tablet through technologies such as tabletting, coating, packing, packings routinely.
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| CN106189352A (en) * | 2016-07-19 | 2016-12-07 | 广州中大南沙科技创新产业园有限公司 | A kind of extracting method of Carthamus yellow |
| CN106189352B (en) * | 2016-07-19 | 2018-06-26 | 广州中大南沙科技创新产业园有限公司 | A kind of extracting method of carthamin yellow |
| CN106616241A (en) * | 2016-12-28 | 2017-05-10 | 广州市聚吉科绿色化学共性技术研究院有限公司 | Preparation method of carthamin yellow zinc salt |
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