CN1216896C - Echinocystic acid preparation, medicinal preparation and new use as medicine - Google Patents
Echinocystic acid preparation, medicinal preparation and new use as medicine Download PDFInfo
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- CN1216896C CN1216896C CN 03100676 CN03100676A CN1216896C CN 1216896 C CN1216896 C CN 1216896C CN 03100676 CN03100676 CN 03100676 CN 03100676 A CN03100676 A CN 03100676A CN 1216896 C CN1216896 C CN 1216896C
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Abstract
The present invention discloses a new method for extracting and preparing an echinocystic acid from fructus in an industrialized mode and the new application of the echinocystic acid. The reflux extraction of traditional Chinese medicine fructus is carried out through 70% to 95% of alcohol, and the traditional Chinese medicine fructus is purified for obtaining total saponin with methods, such as pH value regulation, D101 macroporous resin column chromatography, etc.; then, acids with certain concentration and certain volume are added, the hydrolysis and the purification of the total saponin and the acids are carried out, and an echinocystic acid pure product is obtained. The echinocystic acid purified through the present invention can be used as raw material medicine of traditional Chinese medicine preparations, has the function of coronary artery expansion, and can be used for preventing and curing diseases, such as coronary diseases, stenocardia, myocardial ischemia, etc.
Description
Technical field
The invention relates to the invention of extraction novel preparation method, pharmaceutical preparation and the new purposes thereof of Echinocystic acid (Echinocystic Acid), its new purposes is a coronary artery dilator, and prevention and treatment stenocardia, myocardial ischemia belong to the field of Chinese medicines.
Background technology
Chinese honey locust (Gleditsia Sinesis Lam.) has sensible, phlegm-dispelling functions, can be used for treatment of diseases such as apoplexy, belongs to the class Chinese medicine of having one's ideas straightened out.Contain abundant triterpenoid saponin in the Chinese honey locust, after acid hydrolysis, can obtain the triterpenic acid compounds, and have reducing blood-fat and suppress the cholesterol absorption effect.Echinocystic acid (Echinocystic Acid) has the free type of part to exist in Chinese honey locust, most of form with glycosides exists, before finishing, the present invention do not extract the preparation method about the Echinocystic acid industrialization, Echinocystic acid monomer also of no use is that raw material is made the pharmaceutical dosage form that allows on the pharmaceutics, and be used for the report of aspects such as prevention and treatment of diseases such as coronary heart disease and cerebral thrombosis, the launch relevant not more with the present invention.In Echinocystic acid separation and purification process in the past, be mostly with the research structure to be purpose, generally all use inflammable and explosive ether, Petroleum ether extraction, and then prepare the Echinocystic acid monomer with silica gel column chromatography separating purification.These methods only limit to research structure in the laboratory, and the production cycle is longer, and cost is also higher, and environment is also caused severe contamination.With Echinocystic acid is that raw material development dripping pill, tablet, capsule etc. are used for diseases such as coronary heart disease, stenocardia, cerebral thrombosis and did not appear in the newspapers before the present invention finishes.
The structure of Echinocystic acid (Echinocystic Acid):
Summary of the invention
One of purpose of the present invention has provided the pharmaceutical preparation of Echinocystic acid.
Two of purpose of the present invention has provided a kind of method for preparing Echinocystic acid.
Three of purpose of the present invention has provided Echinocystic acid and pharmaceutical preparation prevention thereof and has treated the new purposes of coronary heart disease, stenocardia, myocardial ischemia disease.
Pharmaceutical preparation of the present invention contains the Echinocystic acid of 1%-99% and the vehicle of 99%-1% (medicine that comprises other adapted); Preferably contain the Echinocystic acid of 30%-80% and the pharmaceutical excipient of 70%-20% (medicine that comprises other adapted); Preferably contain the Echinocystic acid of 60%-70% and the vehicle of 40%-30%.
Press practice of pharmacy, Echinocystic acid of the present invention can be prepared into the various clinical pharmaceutical dosage form, comprise the formulation of oral preparations or parenterai administration as preventing and treating coronary heart disease, stenocardia, myocardial ischemia disease.Said oral preparations is selected from any in tablet, capsule, pill, granule, suspensoid, dripping pill, the oral liquid; Said non-enteron aisle is selected from a kind of in the middle of injection, aerosol, suppository or the subcutaneous administration formulation to formulation.
The auxiliary material that the present invention is used for preventing and treat coronary heart disease, stenocardia, myocardial ischemia disease medicine is meant conventional vehicle, as solvent, disintegrating agent, correctives, sanitas, tinting material, tackiness agent etc.The present invention is used for preventing and treat the medicine that other compatibility of coronary heart disease, stenocardia, myocardial ischemia disease medicine is used, and the Echinocystic acid that refers to effective dose is certain medicine material, again compatibility other allowed the Chinese medicine or the pharmaceutical chemicals that share.
The preparation method of Echinocystic acid can be selected from a kind of in the following method:
1, gets dry Chinese honey locust (fruit) medicinal material, be cut into pieces, use twice of 60-90% alcohol reflux.Filter, merge extracted twice liquid, transferring pH value with calcium oxide or calcium hydroxide breast is 8-10, and abundant the stirring filtered, and it is 6-7 that filtrate is transferred PH with sulfuric acid, adds medicinal activated carbon purification again, filters decompression filtrate recycling ethanol, the dry Chinese honey locust total saponins that gets of concentrated solution.Get the Chinese honey locust total saponins, with ethanol liquid hydrolysis in 100 ℃ of water-baths of hydrochloric acid.Filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, gets the Echinocystic acid crude product; Use dissolve with ethanol again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred PH with dilute hydrochloric acid, placed 3-4 hour, and filtered, it is 3-4 that filtrate is transferred PH, placed 24 hours, filter, filter cake is washed till neutrality with deionized water, drying, use 95% ethyl alcohol recrystallization, get the Echinocystic acid white, needle-shaped crystals.
2, get dry Chinese honey locust (fruit) medicinal material, be cut into pieces, use twice of 60-90% alcohol reflux, filter, merge extracted twice liquid, add that medicinal gac fully stirs, filtration, concentrating under reduced pressure reclaim ethanol, concentrated solution is purifying on the D101 macroporous adsorbent resin of anticipating, wash with water to effluent liquid colourless earlier, use ethanol elution again, collect elutriant, decompression recycling ethanol, the dry Chinese honey locust total saponins that gets of concentrated solution.Get the Chinese honey locust total saponins, with ethanol liquid hydrolysis in 100 ℃ of water-baths of hydrochloric acid, filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, gets the Echinocystic acid crude product; Use ethanol (in the Echinocystic acid crude product) dissolving again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred PH with dilute hydrochloric acid, placed 3-4 hour, and filtered, it is 3-4 that filtrate is transferred PH, placed 24 hours, filter, filter cake is washed till neutrality with deionized water, drying, use 95% ethyl alcohol recrystallization, get the Echinocystic acid white, needle-shaped crystals.
Production technique of the present invention is with short production cycle, safety, and cost is low, the yield height, purity can reach more than 95%.Be particularly suitable for the industrialization mass production.The effect of the coronary artery dilator that has in view of Echinocystic acid, technology of the present invention industrialization from Chinese honey locust prepares Echinocystic acid in a large number and will hold out broad prospects.
The Echinocystic acid crystallinity monomer that aforesaid method of the present invention extracts, by high performance liquid chromatography and LC-MS stratographic analysis and in conjunction with the data analyses such as nucleus magnetic resonance that Chinese Academy of Sciences's Changchun applied chemistry research generation surveys, verify that the crystallinity monomer of method preparation of the present invention is exactly an Echinocystic acid.
Echinocystic acid that the present invention makes and pharmaceutical preparation thereof have coronary artery dilator, prevention and diseases such as treatment stenocardia, myocardial ischemia.These pharmacological actions can be confirmed by the pharmacodynamics test example.
Experimental example 1The checking of Echinocystic acid crystallinity monomer
1, high performance liquid phase (HPLC) is analyzed
Instrument: U.S. Agillent1100 type high performance liquid chromatograph (joining quaternary pump, diode array detector, automatic sampler, column oven, software is the multiple several automated processing systems of Agillent1100 type).
Condition: chromatographic column is Zorbax C
18(4.6cm * 150cm), sample size is 5ul to the reverse phase silica gel post, and moving phase is methyl alcohol: water (PH=3.7)=85: 15, flow velocity are 1.0ml/min, and the detection wavelength is 215nm.
Analytical results: the Echinocystic acid retention time is 4.385min.
2, liquid-matter coupling (LC/MSD) is analyzed
Instrument: U.S. Agillent liquid-matter combined instrument (joining quaternary pump, compensating unit pump, diode array detector, automatic sampler, column oven, software is Agillent1100 type several data treatment system).
Condition: chromatographic column is ZOBAX EXTEND C
18Post, moving phase are acetonitrile: water (PH is 3.5)=80: 20.Flow velocity is 0.9ml/min, and the post post-compensation is urged ionization reagent ammonia soln (0.1ml/min), and the mass spectrum condition is negative ion mode (NEG) electron spray(ES) (API-ESI) scanning.
Experimental example 2,Echinocystic acid is to the influence of anesthetized dog hat blood flow volume
Materials and methods
The adult assorted dog of animal health, female, male dual-purpose, body weight 12～18kg.
The medicine Echinocystic acid, Tianyao Science and Technology Co Ltd, Jilin Chemistry for Chinese Traditional Medicine chamber provides, white, needle-shaped crystals, lot number is 20020903; FUFANG DANSHEN DIWAN, specification: the 25mg/ grain, lot number: 20020414, Tianjin Tasly Pharmaceutical Co., Ltd's product; Vetanarcol, specification: the 25g/ bottle, lot number: 950427, Tong County, Beijing Fine Chemical Works product of cultivating people of ability.
Instrument CBI-8000 doppler blood flow instrument (U.S. BIOPAC company product); Powerlab/8s type eight derivatives are registering instrument and related accessories (Australian Ai De company product) according to one's analysis; SC-3 type breathing apparatus, Shanghai Medical Equipment Factory's product; HL-2 type constant flow pump, Shanghai City Hu Xi instrument plant product.
The method laboratory animal is divided into control group at random, and positive controls (nifedipine, 1.5mg/kg), totally 4 groups of Echinocystic acid high dosage (150mg/kg) and Echinocystic acid low dosages (50mg/kg).Laboratory animal intravenous injection 3% vetanarcol (30mg/kg) anesthesia.Operation on neck, trachea cannula connects the breathing apparatus, separates left carotid, and intubate writes down arteriotony through pressure transducer; Separate femoral vein for liquid make-up or anaesthetic; Duodenal intubation is done in abdominal operation, for duodenal administration; Open chest, vertically cut off pericardium, do the fixing heart that holds up of pocket, separate LCA, place the probe that is fit to bore, be used to measure coronary flow.Operation finishes, stablize 30min, earlier coronary artery blood flow contrasts before as administration under one section normal circumstances of record, begin administration then, positive control drug FUFANG DANSHEN DIWAN (Compound Danshen Dripping Pills, CDDP) and Echinocystic acid through duodenal administration, control animals gives equal-volume distilled water through duodenum, writes down 30min, 45min after the administration, 60min, 90min, 120min, 150min and 180min coronary artery blood flow (CAF) respectively.Different time has or not considerable change after more every observation index administration.Experimental data is added and subtracted standard deviation (x ± s) expression, t-check between statistical procedures method employing group with mean.
The result
After duodenum gave Echinocystic acid 150min, coronary artery blood flow obviously increased (P＜0.05) before than administration to experimental dog with 150mg/kg; To administration during 180min, the effect of its coronary blood flow increasing is obviously (P＜0.05) still, shows that Echinocystic acid has the effect of coronary blood flow increasing, sees Table 1.
Table 1. Echinocystic acid is to the influence of anesthetized dog coronary artery blood flow (x ± s)
| Group | Dosage mg/kg | Example number (only) | Before the administration | Different time coronary flow (ml/min) after the administration | ||||||
| 30min | 45min | 60min | 90min | 120min | 150min | 180min | ||||
| Contrast CDDP CDDP Echinocystic acid Echinocystic acid | - 300 150 150 50 | 5 5 5 5 5 | 32.7±2.8 28.8±9.9 30.8±5.6 26.9±4.5 28.7±4.5 | 33.2±3.3 29.5±10.4 31.4±11.1 27.8±4.4 28.6±5.1 | 34.5±3.7 31.3±12.1 30.8±10.5 28.2±14.2 29.2±6.1 | 33.0±1.2 33.1±13.2 31.9±10.8 29.1±5.1 30.2±6.6 | 35.5±7.1 30.8±7.1 29.9±10.7 30.7±4.2 30.21±7.2 | 34.0±6.6 29.3±9.6 28.6±11.6 32.5±4.8 33.1±10.8 | 31.4±2.8 28.9±7.8 30.4±9.7 35.9±6.4* 32.9±10.6 | 30.4±2.5 27.5±7.3 30.1±9.6 34.9±3.9* 31.3±8.7 |
Annotate: with before the administration relatively: * P＜0.05, all the other are P＞0.05
Experimental example 3,Echinocystic acid is to the influence of anesthetized dog myocardial ischemia effect
The animal health mongrel dogs, the male and female dual-purpose, body weight is 12.5-17.5kg.
The medicine Echinocystic acid, Tianyao Science and Technology Co Ltd, Jilin Chemistry for Chinese Traditional Medicine chamber provides, white, needle-shaped crystals, lot number is 20020903; FUFANG DANSHEN DIWAN, specification: the 25mg/ grain, lot number: 20020414, Tianjin Tasly Pharmaceutical Co., Ltd's product; Vetanarcol, specification: the 25g/ bottle, lot number: 950427, Tong County, Beijing Fine Chemical Works product of cultivating people of ability.
Method experiment divides four groups, each 5 of every group of domesticated dogs, and first group is physiology saline control group, second group of positive medicine FUFANG DANSHEN DIWAN (20mg/kg) group, third and fourth group is for being subjected to little, heavy dose of organize (10mg/kg, the 20mg/kg) of reagent.With domesticated dog with 3% vetanarcol (30mg/kg) intravenous anesthesia, separate tracheae, intubate connects breathing apparatus's (WH-2 type, Tianjin Medical Appliance Factory produces), the 4th intercostal is opened chest in the left side, expose heart, cut off pericardium, do the pericardium art and separate left anterior descending coronary artery, the stage casing threading is in order to ligation.Press infarct, marginarium, 24 epicardial leads of normal district's placement.Stablize 10min after operation is finished, measure normal epicardial electrogram then.Femoral venous catheter is got blood to measure AST, CK, LDH, does operation on duodenum and tests medicine and physiological saline, after administration 5,10,30,45,60,90,120,150,180,210,240,300,360min.The record epicardial electrogram, raising greater than 2mv with the S-T section is judging criterion, (S-T section total mv that raises is a ∑-ST), raises greater than the shared ratio of 2mv with the S-T section and calculates myocardial ischemia scope (N-ST) with this calculating myocardium degree of ischemia.Write down after 360 minutes, get blood for the second time, with AST, CK, LDH behind the mensuration medicine from femoral vein.Experiment is taken off heart after finishing, behind the normal saline flushing heart, the heavy whole-heartedly and left ventricular mass of weighing, be cut into 6 with left chamber is cross-section equably, place in nitro tetrazole orchid (N-BT) dye liquor, normal temperature dyeing 15min, measure the infarct (N-BT dye district) of every myocardium bilateral and non-infarct (N-BT dye district) outward with weighting method, every cardiac muscle is weighed, and calculates the weight of every cardiac muscle and the gross weight of infarct, calculates infarct and accounts for the left ventricle and the per-cent of dirty weight whole-heartedly.Get near fritter cardiac muscle (the coronary ligation line) and do pathological section, further observe the effect of medicine myocardial ischemia.The experimental result statistics is judged its significance with measured value t check.
The result
2.1 to the degree of myocardial ischemia (influence of ∑-ST)
The physiological saline control group does not have obvious effect to ∑-ST after administration.Positive drug control group had obvious statistical significance (P＜0.01) in 60-240 minute after administration.Small dose group had obvious statistical significance (P＜0.05) in 60-120 minute after administration.Heavy dose of group after administration 45-240 minute has obvious statistical significance (P＜0.01).The results are shown in Table 2.
2.2 influence to myocardial ischemia scope (N-ST)
The physiological saline group does not have obvious effect to N-ST after administration, positive drug control group after administration 60-240 minute has tangible statistical significance (P＜0.05).Small dose group after administration 60-210 minute has statistical significance (P＜0.05).Heavy dose of group after administration 60-240 minute has tangible statistical significance (P＜0.01).See Table 3.
Table 2 Echinocystic acid is to (the influence (x ± SD n=5) of ∑-ST) of dog acute myocardial ischemia degree
Value 5 10 30 45 60 behind the value medicine before the group dosage medicine
Salt solution group (-) 5.75 ± 0.835 139.35 ± 29.185 146.74 ± 16.935 155.15 ± 18.012 147.75 ± 12.658 139.38 ± 21.275
Positive group 20mg/kg 5.76 ± 2.587 109.74 ± 19.647 128.16 ± 20.152 143.15 ± 20.470 128.75 ± 18.276 110.38 ± 12.753
*
Administration group 10mg/kg 5.74 ± 1.094 123.93 ± 22.567 134.76 ± 18.76 146.14 ± 20.189 130.55 ± 17.538 111.54 ± 10.555
*
Administration group 20mg/kg 4.57 ± 1.139 126.93 ± 16.700 138.03 ± 13.429 148.04 ± 5.288 132.15 ± 4.917
*116.05 ± 4.634
*
90 120 150 180 210 240 300 360min
142.38±15.318 137.18±24.313 142.62±20.143 142.03±20.337 125.18±15.119 117.49±14.989 104.37±13.313 99.42±15.437
101.37±9.859
** 95.38±8.206
** 91.43±6.538
*** 92.00±4.628
*** 90.78±3.954
** 96.05±6.010
* 98.25±2.773 100.83±4.147
102.25±12.599
** 91.76±13.533
** 102.43±5.417
** 109.80±14.700
* 103.17±15.044
* 102.38±14.361 101.81±16.083 102.41±18.889
104.07±8.487
** 86.75±3.113
** 88.02±4.893
*** 83.60±4.975
*** 93.05±4.581
** 94.84±9.312
** 101.80±9.497 105.23±7.950
Compare with the salt solution group: * P＜0.05, * * P＜0.01, * * * P＜0.001
Table 3 Echinocystic acid is to the influence (x ± SD n=5) of dog acute myocardial ischemia scope (N-ST)
Value 5 10 30 45 60 behind the value medicine before the group dosage medicine
Salt solution group (-) 4.38 ± 1.816 18.01 ± 1.871 19.00 ± 1.000 18.00 ± 1.871 17.80 ± 2.864 18.03 ± 2.540
Positive group 20mg/kg 4.62 ± 1.674 15.43 ± 1.949 17.20 ± 16.43 17.20 ± 2.588 15.40 ± 1.817 13.22 ± 1.633
*
Administration group 10mg/kg 3.41 ± 1.512 15.08 ± 2.236 18.40 ± 0.894 19.20 ± 1.304 16.60 ± 0.894 14.45 ± 1.170
*
Administration group 20mg/kg 3.82 ± 1.303 17.05 ± 2.000 18.60 ± 0.894 17.80 ± 1.483 16.00 ± 1.225 13.62 ± 0.538
*
90 120 150 180 210 240 300 360min
17.67±3.347 18.22±3.565 18.86±3.273 17.83±3.563 17.05±3.206 16.24±2.683 15.01±2.735 14.06±3.086
11.20±1.654
** 12.64±0.546
** 11.45±1.676
** 10.82±1.644 11.46±2.194
* 11.83±1.643
* 12.05±1.583 11.42±1.145
12.20±1.095
** 11.43±1.516
** 12.43±1.815
** 12.43±1.515
* 12.63±1.142
* 13.82±0.833 12.62±1.141 13.05±1.873
12.40±5.548
** 12.02±1.224
** 12.02±1.416
** 11.05±0.703
** 11.44±0.544
** 11.22±0.81
** 12.24±0.835 11.87±0.832
Compare with the salt solution group: * P＜0.05, * * P＜0.01, * * * P＜0.001
Embodiment
Embodiment 1
Get dry Chinese honey locust (fruit) medicinal material 1kg, be cut into pieces (about 1cm is long), alcohol reflux twice, the twice ethanol consumption with 80% is respectively 7 times of amounts and 5 times of amounts of medicinal material weight, and the time is 3 hours.Filter, merge extracted twice liquid, transferring pH value with calcium oxide or calcium hydroxide breast is 9, fully stirs 2 hours, filter, it is 6 that filtrate is transferred pH with sulfuric acid, adds medicinal gac 30g purifying again, filters, decompression filtrate recycling ethanol ethanol, the dry about 150g of Chinese honey locust total saponins that gets of concentrated solution, with ethanol liquid (alcohol concn the is 45%) hydrolysis in water-bath (100 ℃) of 2000ml 2mol/L hydrochloric acid, hydrolysis time is 3 hours.Filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, and drying gets the about 42g of Echinocystic acid crude product; Use the 600ml dissolve with ethanol again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred pH with dilute hydrochloric acid, placed 3 hours, and filtered, it is 3-4 that filtrate is transferred pH, placed 24 hours, and filtered, filter cake is washed till neutrality with deionized water, dry, use 95% ethyl alcohol recrystallization, get the about 18g of Echinocystic acid white, needle-shaped crystals, yield is 1.8%.
Embodiment 2
Get dry Chinese honey locust (fruit) medicinal material 1kg, be cut into pieces (about 1cm is long), alcohol reflux twice, the twice ethanol consumption with 85% is 7 times of amounts of medicinal material weight, and the time is 3 hours.Filter, merge extracted twice liquid, add that medicinal gac 50g fully stirs, filtration, concentrating under reduced pressure reclaim ethanol to there not being the alcohol flavor, concentrated solution is purifying on the D101 macroporous adsorbent resin of anticipating, and washes with water to effluent liquid colourless earlier, use 85% ethanol elution again, collect elutriant, decompression recycling ethanol, the dry about 140g of Chinese honey locust total saponins that gets of concentrated solution, with ethanol liquid (alcohol concn the is 45%) hydrolysis in water-bath (100 ℃) of 1800ml 2mol/L hydrochloric acid, hydrolysis time is 3 hours.Filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, gets the about 40g of Echinocystic acid crude product; Use the 600ml dissolve with ethanol again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred pH with dilute hydrochloric acid, placed 3-4 hour, and filtered, it is 3-4 that filtrate is transferred pH, placed 24 hours, and filtered, filter cake is washed till neutrality with deionized water, dry, use 95% ethyl alcohol recrystallization, get Echinocystic acid white, needle-shaped crystals 19g, yield is 1.9%.
Embodiment 3(capsule)
Echinocystic acid raw material 1000g, medical starch 1000g mixes, the capsule of packing into No. 1, every 0.2g, each oral 2-3 grain, twice of every day.
Embodiment 4(tablet)
Echinocystic acid raw material 1000g, medical starch 400g, dextrin 100g mixes, and uses an amount of alcohol granulation, through the whole grain of pelletizing machine, compressing tablet, every 0.25g, oral, each 2, twice of every day.
Embodiment 5(injection)
Echinocystic acid raw material 10g, propylene glycol 20ml, polyoxyethylene glycol-400 50ml, water for injection 300ml mixes heating in water bath 30 minutes, add phenylcarbinol 50ml, add to 1000ml with water for injection again, in ultrasonic wave, handled 10 minutes, heated 30 minutes in the water-bath again, adjust pH 5.5-6.5, filter clear and bright, embedding, the sterilization promptly.Every 2ml, intramuscular injection, a 2ml, 1-2 time on the one.
Embodiment 6(pill)
Take by weighing the 300g Macrogol 4000, in water-bath, melt, add Echinocystic acid raw material 100g, stir, in the impouring insulating pipe, regulate thermostat, make soup under 80-90 ℃, splash in the whiteruss that cooled off (temperature ± 4 ℃), after dripping off, to blot paraffin oil on the pill impouring filter paper, add a small amount of talcum powder again, mixing gets 1000 of Echinocystic acid dripping pills.Oral, a 2-3 grain, three times on the one, one after each meal.
Claims (10)
1, a kind of pharmaceutical preparation is characterized in that containing Echinocystic acid and one or more pharmaceutically acceptable vehicle for the treatment of significant quantity.
2, pharmaceutical preparation according to claim 1 is characterized in that containing the Echinocystic acid of 1%-99% and the vehicle of 99%-1%.
3, pharmaceutical preparation according to claim 2 is characterized in that containing the Echinocystic acid of 60%-70% and the vehicle of 40%-30%.
4, pharmaceutical preparation according to claim 1 is characterized in that the activeconstituents that also can be used for other coronary artery dilators, prevention and treatment stenocardia and myocardial ischemia disease makes up.
5, a kind of method for preparing Echinocystic acid is characterized in that this method is selected from a kind of in following two kinds of methods:
A, get dry Chinese honey locust (fruit) medicinal material, be cut into pieces, with twice of 60-90% alcohol reflux; Filtering, merge extracted twice liquid, is 8-10 with calcium oxide or calcium hydroxide breast adjust pH, and abundant the stirring filtered, and it is 6-7 that filtrate is transferred pH with sulfuric acid, adds medicinal activated carbon purification again, filters decompression filtrate recycling ethanol, the dry Chinese honey locust total saponins that gets of concentrated solution; Get the Chinese honey locust total saponins, with ethanol liquid hydrolysis in 100 ℃ of water-baths of hydrochloric acid; Filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, gets the Echinocystic acid crude product; Use dissolve with ethanol again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred pH with dilute hydrochloric acid, placed 3-4 hour, and filtered, it is 3-4 that filtrate is transferred pH, placed 24 hours, filter, filter cake is washed till neutrality with deionized water, drying, use 95% ethyl alcohol recrystallization, get the Echinocystic acid white, needle-shaped crystals;
B, get dry Chinese honey locust (fruit) medicinal material, be cut into pieces,, filter with 60-90% alcohol reflux twice, merge extracted twice liquid, add that medicinal gac fully stirs, filtration, concentrating under reduced pressure reclaim ethanol, concentrated solution is purifying on the D101 macroporous adsorbent resin of anticipating, and washes with water to effluent liquid colourless earlier, use ethanol elution again, collect elutriant, decompression recycling ethanol, the dry Chinese honey locust total saponins that gets of concentrated solution; Get the Chinese honey locust total saponins, with ethanol liquid hydrolysis in 100 ℃ of water-baths of hydrochloric acid, filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, gets the Echinocystic acid crude product; Use dissolve with ethanol again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred pH with dilute hydrochloric acid, placed 3-4 hour, and filtered, it is 3-4 that filtrate is transferred pH, placed 24 hours, filter, filter cake is washed till neutrality with deionized water, drying, use 95% ethyl alcohol recrystallization, get the Echinocystic acid white, needle-shaped crystals.
6, the preparation method of Echinocystic acid as claimed in claim 5 is characterized in that this method is selected from a kind of in following two kinds of methods:
A. get dry Chinese honey locust (fruit) medicinal material 1 weight part, cut into the long section of 1cm, alcohol reflux twice, the twice ethanol consumption with 80% is respectively 7 times of amounts and 5 times of amounts of medicinal material weight, and the time is 3 hours; Filtering, merge extracted twice liquid, is 9 with calcium oxide or calcium hydroxide breast adjust pH, fully stirs 2 hours, filter, it is 6 that filtrate is transferred pH with sulfuric acid, adds medicinal gac 0.03 weight part purifying again, filter decompression filtrate recycling ethanol, the dry Chinese honey locust total saponins that gets of concentrated solution; With the concentration of 2 parts by volume 2mol/L hydrochloric acid is ethanol liquid hydrolysis in 100 ℃ of water-baths of 45%, and hydrolysis time is 3 hours; Filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, and drying gets the Echinocystic acid crude product; Use 0.6 parts by volume dissolve with ethanol again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred pH with dilute hydrochloric acid, placed 3 hours, and filtered, it is 3-4 that filtrate is transferred pH, placed 24 hours, filter, filter cake is washed till neutrality with deionized water, drying, use 95% ethyl alcohol recrystallization, get the Echinocystic acid white, needle-shaped crystals;
B. get dry Chinese honey locust (fruit) medicinal material 1 weight part, cut into the long section of 1cm, alcohol reflux twice, the twice ethanol consumption with 85% is 7 times of amounts of medicinal material weight, and the time is 3 hours; Filter, merge extracted twice liquid, add that medicinal gac 0.05 weight part fully stirs, filtration, concentrating under reduced pressure reclaim ethanol to there not being the alcohol flavor, concentrated solution is purifying on the D101 macroporous adsorbent resin of anticipating, and washes with water to effluent liquid colourless earlier, use 85% ethanol elution again, collect elutriant, decompression recycling ethanol, the dry Chinese honey locust total saponins that gets of concentrated solution, with the concentration of 1.8 parts by volume 2mol/L hydrochloric acid is ethanol liquid hydrolysis in 100 ℃ of water-baths of 45%, and hydrolysis time is 3 hours; Filter, discard hydrolyzed solution, filter cake is washed till neutrality with deionized water, gets the Echinocystic acid crude product; Use 0.6 parts by volume dissolve with ethanol again, it is an amount of to add medicinal gac, and heating in water bath refluxes, filtered while hot, filtrate decompression concentrates, and it is 5-6 that concentrated solution is transferred pH with dilute hydrochloric acid, placed 3-4 hour, and filtered, it is 3-4 that filtrate is transferred pH, placed 24 hours, filter, filter cake is washed till neutrality with deionized water, drying, use 95% ethyl alcohol recrystallization, get the Echinocystic acid white, needle-shaped crystals.
7,, it is characterized in that said medicine is oral preparations or parenterai administration agent type according to claim 1,2,3 or 4 described pharmaceutical preparations.
8, pharmaceutical preparation according to claim 7 is characterized in that said oral preparations is selected from a kind of in the middle of the tablet, pill, capsule, granule, suspensoid, dripping pill, oral liquid.
9, pharmaceutical preparation according to claim 7 is characterized in that said parenterai administration formulation is selected from a kind of in the middle of the injection, aerosol, suppository form of administration.
10, the application of Echinocystic acid in the medicine of preparation coronary artery dilator, prevention and treatment coronary heart disease, stenocardia, myocardial ischemia.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03100676 CN1216896C (en) | 2003-01-21 | 2003-01-21 | Echinocystic acid preparation, medicinal preparation and new use as medicine |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03100676 CN1216896C (en) | 2003-01-21 | 2003-01-21 | Echinocystic acid preparation, medicinal preparation and new use as medicine |
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| CN1216896C true CN1216896C (en) | 2005-08-31 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5671524B2 (en) * | 2009-05-15 | 2015-02-18 | 成都康弘制薬有限公司 | Pharmaceutical composition for the treatment of cardiovascular disorders and use thereof |
| CN101919901B (en) * | 2009-06-10 | 2012-01-11 | 赵全成 | Application of total aglycone of Gleditsia sinensis Lam in preparation of alpha-glucosidase inhibitor drugs |
| CN102240293B (en) * | 2010-05-11 | 2013-04-24 | 成都康弘制药有限公司 | Application of echinocystic acid in preparing medicament preventing and treating cardiovascular diseases |
| CN102464698A (en) * | 2010-11-19 | 2012-05-23 | 苏州宝泽堂医药科技有限公司 | Method for preparing high-content echinocystic acid |
| CN103768078B (en) * | 2012-10-22 | 2019-02-05 | 北京大学 | Tetraterpene derivatives and its anti influenza purposes |
| CN103145790B (en) * | 2013-03-18 | 2015-02-11 | 山东省中医药研究院 | Method for simultaneously preparing oleanolic acid and echinocystic acid from fructus gleditsiae |
| CN106550942A (en) * | 2016-10-17 | 2017-04-05 | 徐州得铸生物科技有限公司 | A kind of bactericidal composition containing 1,8 cineoles |
| CN110563792A (en) * | 2019-09-09 | 2019-12-13 | 南开大学 | G protein coupled bile acid receptor agonist and application thereof |
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