CN1631426A - Freeze dried powder injection for treating coronary disease and its preparation process - Google Patents
Freeze dried powder injection for treating coronary disease and its preparation process Download PDFInfo
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Abstract
The invention discloses a freeze dried powder injection for treating coronary disease and its preparation process, wherein the injection comprises the purified significant part extracted from Chinese medicinal radix salvia miltiorrhiza and Ligusticum wallichii, and medicinal auxiliary material, wherein the content of salviol in the freeze dried injection is not lower than 30mg/unit, the content of tanshinone is not lower than 6mg/unit, the content of ligustrazine is not lower than 18mg/unit. Pharmacological experiment results show that, the preparation provided by the invention has better pharmaceutical actions.
Description
Affiliated technical field
The invention belongs to field of traditional Chinese medicine pharmacy, be specifically related to a kind of freeze dried powder injection for treating coronary disease and preparation method thereof.
Technical background
Radix Salviae Miltiorrhizae, be labiate Radix Salviae Miltiorrhizae Salvia miltiorrhiza Bge. root and rhizome, cold nature, bitter in the mouth, has stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, the relieving restlessness effect that clears away heart-fire is used for diseases such as menoxenia, amenorrhea dysmenorrhea, lump in the abdomen, breast ventral spine pain, pyretic arthralgia pain, skin infection are swollen and ache, hepatosplenomegaly, angina pectoris; Radix Salviae Miltiorrhizae mainly contains water solublity and liposoluble constituent, and water soluble ingredient is based on Radix Salviae Miltiorrhizae total phenolic acids, and main effect has: (1) to myocardial ischemia have protective effect (Zheng Ruoyun etc., combination of Chinese and Western medicine magazine, 1990,10:609); (2) to effect (Wang Shuxian etc., Chinese herbal medicine, 1986,10 (10)) myocardium, the cerebral tissue energy metabolism; (3) have the myocardial infarct size of dwindling and alleviate course of disease effect (Yang Xueyi etc., Chinese patent medicine research, 1981,2:35,45); (4) have obvious coronary artery dilator effect (Dong Zhongtian, Jiang Wende, Acta Pharmaceutica Sinica, 1982,17 (3): 226) (5) discharge influence (Li Cheng strain etc., combination of Chinese and Western medicine magazine, 1983,3 (5): 297) of angiogenic substance to platelet; (6) influence thrombins (Zhu Liang etc., the Shanghai first medical college journal, 1985,12 (6) 461) such as platelet; Liposoluble constituent is based on total tanshinone, and main effect has: and (1) antibacterial action (Gu Kexian, dermatosis and sexually transmitted disease (STD), 1994 03 phases, 11-13); (2) to protective effect (Yang Tiande etc., Acta Pharmacologica Sinica, 1997 of myocardial ischaemia; 13 (1): 45-47); (3) offside props up the circulation effect; (4) influence thrombin such as platelet (Yang Yi, the Hubei Journal of Traditional Chinese Medicine, 1999 the 21st the 6th phases of volume, 284-286); The water solublity of Radix Salviae Miltiorrhizae and liposoluble constituent have pharmacological action widely to cardiovascular disease, therefore, be in the formulation preparation of crude drug with the Radix Salviae Miltiorrhizae, to keep water solublity and liposoluble constituent as far as possible, in the domestic Radix Salviae Miltiorrhizae solid preparation, kept two kinds of compositions as far as possible, but in injection, in order to solve the problem of dissolubility, extract with water extract-alcohol precipitation, this technology has only kept water soluble ingredient, liposoluble constituent is lost in a large number or is not had (the different extraction processes of Radix Salviae Miltiorrhizae relatively a, Liu Chongfang etc., Chinese patent medicine, 1999,21 (8), 385-388), if employing alcohol extraction process, because the chemical property of total tanshinone, under hot conditions, TANSHINONES (the Fructus Perillae core etc. that are degraded, 1997 19 11 phases of volume, 5-6) therefore, in the technology of extracting Radix Salviae Miltiorrhizae, also should not adopt alcohol extraction process.
Rhizoma Chuanxiong, this product is the dry rhizome of samphire Rhizoma Chuanxiong Ligusticum chuanxiong Hort., has blood-activating and qi-promoting, the effect of wind-expelling pain-stopping is used for menoxenia, the amenorrhea dysmenorrhea, the twinge of the breast side of body, headache, tumbling and swelling, diseases such as rheumatic arthralgia, Rhizoma Chuanxiong mainly contains volatile oil and ligustrazine, the effect of ligustrazine has: (1) is to atherosclerotic preventive and therapeutic effect (Mei Jiajun, Cai Dayong, Chen Zhenfa etc., Rhizoma Chuanxiong is prevented and treated the research of atherosclerosis effective site, microcirculation is learned magazine, 2000,10 (3): 51); (2) to anoxybiotic protective effect (Zhang Fuyu, Zhang Xiuhua, Liu Zongping, heavy dose of ligustrazine treatment nephrotic syndrome high sticky blood, Binzhou Medical College's journal, 2000,23 (4): 348); (3) to cardiovascular protective effect (Guo Chunyan etc., medical science summary the 7th the 7th phase of volume of calendar year 2001,436-437); Rhizoma Chuanxiong volatile oil has mainly acted on: (1) is overrun to sinus rate and is had therapeutical effect; (2) atrial fibrillation and angina pectoris there is therapeutical effect (Zhejiang Normal University's journal, the 26th the 2nd phase of volume, in May, 2003).
GUANXINNING ZHUSHEYE side is made up of Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong two flavor Chinese medicines, has blood circulation promoting and blood stasis dispelling, the effect of freeing vessels and nourishing heart, the clinical treatment that is mainly used in angina pectoris.Standard is the preparation method that WS3-B-3267-98 discloses GUANXINNING ZHUSHEYE, this method adopts the method for water extraction, twice ethanol precipitation to be prepared, this extraction process only keeps effective ingredient Radix Salviae Miltiorrhizae total phenolic acids and ligustrazine, and given up total tanshinone and the Rhizoma Chuanxiong volatile oil composition that cardiovascular disease is had good curative effect, on resource, caused waste, aspect drug effect, reduce the effect that two flavor Chinese medicines carry out compatibility treatment cardiovascular disease, the advantage of the two flavor drug matchings of failing to make full use of to greatest extent.
It is the injection of feedstock production that number of patent application " 03141365 " discloses with Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong, this patent adopts the method for organic solvent extraction, column chromatography purification to be prepared into injection respectively to Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong, and this method acquires a certain degree of difficulty in course of industrialization; Number of patent application " 9910202 " discloses the method that Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong prepare injection, and this technology adopts the ethanol heating extraction to Radix Salviae Miltiorrhizae, and this method makes total tanshinone that certain loss be arranged.
Summary of the invention
For these reasons, the present invention adopts CO to Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong
2Supercritical extraction obtains TANSHINONES, Rhizoma Chuanxiong volatile oil, carries out 2-HP-enclose again and obtains clathrate, and the control temperature is no more than 50 ℃ in the technology, keeps TANSHINONES as far as possible; To the residue that has extracted adopt again that water is carried, the method for precipitate with ethanol, overclocking concussion ultrafiltration obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong water extract; Clathrate and water extract are added freeze-dried excipient, be prepared into lyophilized injectable powder, control Radix Salviae Miltiorrhizae total phenolic acids (in catechu aldehyde) in the preparation and be not less than 30mg/ and prop up, it is that 6mg/ props up that control total tanshinone (in tanshinone) content is not less than, and the control ligustrazine is not less than 18mg/ and props up; The pharmacological results shows that lyophilized injectable powder of the present invention has better pharmacological action.
The object of the invention is to provide a kind of freeze dried powder injection for treating coronary disease;
The object of the invention also is to provide a kind of preparation method of freeze dried powder injection for treating coronary disease.
The present invention is achieved through the following technical solutions.
One. process recipes
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 3-5 weight portion, Rhizoma Chuanxiong 3-5 weight portion;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 15-35Mpa, and extraction temperature is 40 ℃-50 ℃, flow is 40-100L/h, the pressure of extraction-container 1 is 5-7Mpa, and resolution temperature is 30 ℃-35 ℃, and the pressure of extraction-container 2 is 3-5Mpa, resolution temperature is 20 ℃-25 ℃, extracted 4-6 hour, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 20-30 (M/M), the 2-hydroxypropyl is made saturated solution with distilled water, put into 30 ℃-40 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stir, slowly drip and dissolve the material of dissolve with ethanol completely, continue to stir 12-24 hour, placed 12-24 hour at refrigerator, 30 ℃ of-40 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second, three times each 1.5 hours, collecting decoction, filter, it is 1.15-1.20 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.05-1.10, shakes the ultrafilter membrane bag with the intercepting molecular weight for the 3000-8000 overclocking and carry out ultrafiltration, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 96-160 weight portion, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 72-108 weight portion, pharmaceutic adjuvant freeze-dried excipient 132-232 weight portion.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 5.5-6.5, and cillin bottle is injected in sterilization, and lyophilization obtains freeze dried powder injection for treating coronary disease.
Two. detection method
1. Radix Salviae Miltiorrhizae total phenolic acids check and analysis
According to high effective liquid chromatography for measuring.
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol: glacial acetic acid: water (25: 1: 224) is mobile phase; The detection wavelength is 280nm.Number of theoretical plate is pressed the protocatechualdehyde peak and is calculated, and should be not less than 1500.
The preparation precision of reference substance solution takes by weighing the protocatechualdehyde reference substance 10mg that is dried to constant weight at 105 ℃, puts in the 100ml measuring bottle, adds mobile phase to scale, shakes up.Precision is measured 2ml, puts in the 10ml measuring bottle, adds mobile phase to scale, shakes up, and promptly gets (containing protocatechualdehyde 0.02mg among every 1ml).
The algoscopy precision is measured this product 500mg, puts in the 100ml measuring bottle, adds mobile phase to scale, shakes up.Precision is measured 10 μ l and is injected chromatograph of liquid, the record chromatogram; Other gets reference substance solution, measures with method, presses external standard method with calculated by peak area, promptly.Measurement result sees Table 1:
2. total tanshinone check and analysis
According to high effective liquid chromatography for measuring.
Experimental apparatus day island proper Tianjin LC-10AT type HPLC chromatograph.
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are the chromatographic column filler, and methanol-water (75: 25) is a mobile phase, and the detection wavelength is 270nm.
The preparation reference substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute) of reference substance solution, reference substance solution is made 40 μ g/ml solution with methanol.
The preparation of reference substance solution is got 0.6g with lyophilized injectable powder of the present invention, and accurate the title decides, and puts in the tool plug conical flask, the accurate methanol 50ml that adds, close plug claims to decide weight, remove plug, change condensing tube, reflux 1h, put coldly, close plug claims to decide weight again, supply the weight that subtracts mistake with methanol, shake up, filter, get subsequent filtrate, as need testing solution.Accurate respectively reference substance solution and each the 5 μ l of need testing solution of drawing of algoscopy, injecting chromatograph is measured content.The results are shown in Table 1:
3. ligustrazine check and analysis
The content of rp-hplc determination ligustrazine
Experimental apparatus Hitachi655A pump, variable-wavelenght detector, ShiridoC-R4A chromatography system.
Experimental drug ligustrazine reference substance is available from Chinese biological goods calibrating institute, and methanol is chromatographically pure, and water is double distilled water, and other reagent is analytical pure.
Chromatographic condition and system suitability test ZorbaxC18 analytical column (4.6mm * 250mm); Mobile phase: methanol: water (1% acetic acid)=35: 65, flow velocity 0.8ml/min; Detect wavelength: 300nm.
The preparation precision of reference substance solution takes by weighing the about 4mg of reference substance, puts in the 10ml measuring bottle, and the adding distil water dissolving also is diluted to scale, shakes up, as storing solution; Accurate respectively absorption 0.1,0.2,0.4,0.6,0.8,1.0ml put in the 10ml volumetric flask, and adding distil water is diluted to scale, shakes up, in contrast product solution.
The preparation of reference substance solution is got 0.6g with lyophilized injectable powder of the present invention, and accurate the title decides, and puts in the tool plug conical flask, the accurate methanol 50ml that adds, close plug claims to decide weight, remove plug, change condensing tube, reflux 1h, put coldly, close plug claims to decide weight again, supply the weight that subtracts mistake with methanol, shake up, filter, get subsequent filtrate, as need testing solution.
Accurate respectively reference substance solution and each the 8 μ l of need testing solution of drawing of algoscopy, injecting chromatograph is measured content.The results are shown in Table 1:
According to above-mentioned detection method to commercially available GUANXINNING ZHUSHEYE (Huida Pharmaceutical Co., Ltd., Datong City's production) carry out check and analysis, experimental result sees Table 1:
Table 1 'Guanxinning ' active constituent content relatively
Radix Salviae Miltiorrhizae total phenolic acids (in catechu aldehyde) total tanshinone (in tanshinone) ligustrazine
Group
Mg/ props up mg/ and props up mg/ and prop up
Commercially available GUANXINNING ZHUSHEYE 35.3---17.4
Freeze dried powder injection for treating coronary disease 39.7 8.7 24.1 of the present invention
---expression does not detect
Result: show that by above check and analysis experiment technology of the present invention has practical significance.
Three. pharmacology embodiment
Embodiment 1
To the effect of rat myocardial ischemia and reperfusion injury protection
Laboratory animal and model: male wistar rat, body weight 200-250g.
Experiment medicine: GUANXINNING ZHUSHEYE (Huida Pharmaceutical Co., Ltd., Datong City)
Freeze dried powder injection for treating coronary disease of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong)
Experimental apparatus and reagent: MDA test kit, SOD test kit, GSHPX test kit and ATP enzyme reagent kit, other reagent are homemade analytical pure or biochemical reagents.High speed tabletop centrifuge (Shanghai Biochemical Research institute of the Chinese Academy of Sciences), XHF-1 type high speed dispersion device (going up Haixing County China Electronic Instruments Plant), High speed refrigerated centrifuge (Hungary's product), UV-754 type spectrophotometer (Shanghai the 3rd analytical tool factory).
Experimental technique:
Ischemia filling group again: with pentobarbital (50mk/kg) intraperitoneal injection of anesthesia, it is fixing to lie on the back.Open breast, behind the ligation left anterior descending coronary artery 30min, cut off ligature again perfusion 20min cause the ischemical reperfusion injury model.
Myocardial ischemia group: only ligation left anterior descending coronary artery 30min.
The medicament protection group: (the 0.8g crude drug/kg), surplus operation is with ischemia filling group again for commercially available GUANXINNING ZHUSHEYE of 60min lumbar injection and lyophilized injectable powder of the present invention before the ligation coronary artery.
Matched group: not ligation of a threading coronary artery, the same ischemia-reperfusion group of surplus operation.
Myocardial cell membrane separates with mitochondrial: the separation of myocardial cell membrane is pressed the wollf[woman's bow and is given birth to, Zhao Xiaoman, the protection Chinese Pharmacological circular of the strict taurine on rat treating myocardial ischemia damage of thunder, 1996; 12 (1): 42] method is carried out, and mitochondrial preparation is undertaken by literature method.Protein quantification adopts the Lowrry method, is standard substance with the bovine serum albumin.
ATP enzyme, SOD and GSHPX vigor are analyzed myocardial cell membrane Ca
2+-ATP enzyme, K
+SOD and the analysis of GSHPX vigor are all strict in-ATP enzyme, SOD and GSHPX vigor and the mitochondrion is undertaken by the test kit explanation.
MDA and cardiac muscular tissue's calcium content are measured the MDA assay and are undertaken by the explanation of purchasing test kit.The mensuration of calcium adopts atomic absorption spectrophotometry.
Experimental result:
The ATPase activities in cell membrane variation sees Table 2
The variation of reflection OFR index sees Table 3 in the cardiac muscle
Cardiac muscular tissue's calcium content and MDA changes of contents see Table 4
Table 2 ATPase activities in cell membrane changes
Group Ca
2+-ATP enzyme K
+-ATP enzyme Mg
2+-ATP enzyme
Matched group 37.8 ± 4.4 36.5 ± 4.1 34.9 ± 4.0
Ischemia group 28.6 ± 5.1
*26.5 ± 4.0
*29.8 ± 4.7
Ischemia filling group again 17.9 ± 3.8
*17.1 ± 3.8
*25.6 ± 4.0
*
GUANXINNING ZHUSHEYE protection group 31.0 ± 3.7## 30.9 ± 3.4## 29.1 ± 4.2
Freeze dried powder injection for treating coronary disease protection group 35.1 ± 3.4## 34.9 ± 3.7## 31.6 ± 4.5 of the present invention
Annotate: compare ##P＜0.01 with ischemia filling group again; Compare with matched group
*P＜0.05,
*P＜0.01
The comparison of reflection OFR index in table 3 cardiac muscle
SOD/u(g
*pro)
-1SOD/u(g
*pro)
-1GSH
*PX/u(mg
*pro)
-1 GSH
*PX/u(mg
*pro)
-1
Group
Cell membrane mitochondrion cell membrane mitochondrion
Matched group 316.8 ± 38.1 507.8 ± 22.4 17.9 ± 4.0 36.7 ± 6.6
Ischemia group 306.5 ± 28.4 480.9 ± 26.9 16.8 ± 2.9 34.1 ± 5.4
Ischemia filling group again 244.5 ± 46.1
*386.4 ± 24.6
*12.4 ± 2.6
*27.9 ± 7.4
*
GUANXINNING ZHUSHEYE protection group 311.4 ± 38.9# 478.9 ± 27.9# 18.7 ± 3.4# 34.7 ± 6.9#
Freeze dried perhexiline powder for injection of the present invention
316.2±40.5## 499.4±26.4## 19.5±3.3# 35.0±7.8##
Agent protection group
Annotate: compare ##P＜0.01, #P＜0.05 with ischemia filling group again; Compare with matched group
*P＜0.05,
*P＜0.01
Table 4 cardiac muscular tissue calcium content and MDA content are relatively
Group MDA/u (mg*pro)
-1MDA/u (mg*pro)
-1Calcium content
Cell membrane mitochondrion/umol
*(g
*Dw)
-1
Matched group 3.8 ± 1.0 4.8 ± 0.5 3.4 ± 0.8
Ischemia group 4.7 ± 1.3
*5.9 ± 0.7
*5.5 ± 1.2
*
Ischemia filling group again 8.1 ± 1.1
*7.7 ± 0.9
*13.2 ± 1.5
*
GUANXINNING ZHUSHEYE protection group 4.5 ± 0.9# 5.6 ± 0.4# 7.1 ± 1.3##
Freeze dried powder injection for treating coronary disease protection group 4.0 ± 0.8## 5.1 ± 0.3## 5.9 ± 1.1## of the present invention
Annotate: compare ##P＜0.01, #P＜0.05 with ischemia filling group again; Compare with matched group
*P＜0.05,
*P＜0.01
Embodiment 2
To the protective effect of Cor Canitis myocardial ischemia
Laboratory animal: Beagle Canis familiaris L., body weight 7.5-10kg.
Experiment medicine: GUANXINNING ZHUSHEYE (Huida Pharmaceutical Co., Ltd., Datong City)
Freeze dried powder injection for treating coronary disease of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong)
Get experimental dogs, be divided into the normal saline group, the GUANXINNING ZHUSHEYE group, lyophilized injectable powder group of the present invention, the administration group is respectively in the subcutaneous cephalic vein administration of Canis familiaris L. forelimb, the each 0.3g crude drug/kg of dosage, normal saline groups etc. are held inequality, administration every day 1 time, successive administration 3 days, pentobarbital sodium 25mg/kg intravenous anesthesia is used in administration after the 3rd day, tracheal intubation connects artificial respirator positive pressure respiration in addition, and the 5th rib is opened breast from the left side, cut off pericardium, expose heart, the pericardial incision edge is sewn in thoracic wall, divide the second stage of ligation at ramus descendens anterior arteriae coronariae sinistrae, and slow iv lignocaine 8mg/kg is in case the ventricular fibrillation that may cause before the ligation is sewed up pericardium and thoracic wall subsequently.24h behind the heart infarction, Canis familiaris L. is put to death after pentobarbital sodium anesthesia, take out heart rapidly, excision trunk and fatty tissue, check the position of anterior descending branch ligation point, claim heavy whole-heartedly, excise right ventricle and left atrium then, stay interventricular septum and left atrium, claim to such an extent that left ventricle is heavy, from the apex of the heart and beginning and anterior descending branch vertical direction left ventricle is cut into the thick flesh sheet of 2-3mm, be dipped in dyeing 30min in the nitro tetrazolium blue solution (NBT), cut ischemic region cardiac muscular tissue and weigh, the calculating myocardium infarction size, that is: heart infarction scope=ischemic region weight/left ventricle is heavy by * 100%, the results are shown in Table 5.
The influence of table 5 pair Cor Canitis chamber infarction size
Heavy whole-heartedly left chamber is heavy
Group
Heavy (g) heart infarction scope (%) of ischemic region
(g) (g)
Normal saline group 66.37 ± 8.79 42.31 ± 5.01 10.47 ± 0.85 24.74 ± 1.38
GUANXINNING ZHUSHEYE 67.94 ± 8.26 43.26 ± 4.75 4.14 ± 0.66 9.57 ± 0.45
*
Freeze-dried powder of the present invention
67.71±7.68 43.09±4.26 2.11±0.24 4.89±0.17
**
The agent group
Annotate: compare * P＜0.05, * * P＜0.01 with the normal saline group
Embodiment 3
The experimentation that resists myocardial ischemia
(1) pit is caused the influence of Acute Myocardial Ischemia in Rats
With body weight 150g-200gWistar rat, male and female half and half are divided into normal saline group, GUANXINNING ZHUSHEYE group, lyophilized injectable powder group of the present invention.Each group is 30min lumbar injection before experiment all, dosage 0.8g crude drug/kg.Experimental technique press the Xu Shi method [Xu Lina is etc. No. 2 sides of blood circulation promoting and blood stasis dispelling coronary disease and form medicine to resisting myocardial ischemia and strengthening the experimentation [J] of anoxia ability. Acta Pharmaceutica Sinica, 1979,14 (8): 461.].Measurement result sees Table 6
Table 6 couple pit causes the influence of Acute Myocardial Ischemia in Rats
Group myocardial ischemia negative rate (Mus number)
Normal saline group 6.6% (15)
GUANXINNING ZHUSHEYE group 46.6% (15)
*
Lyophilized injectable powder group 53.3% (15) of the present invention
*
Annotate: compare with the normal saline group
*P＜0.01
(2) to the influence of isolated rat heart coronary flow
The female rat of body weight 250g-300g is divided into 3 groups at random, 6 every group.Get rat heart, with the oxygen enrichment (95%O of 7.4,36 ℃ of pH value
2And 5%CO
2) the krebs-henseteit nutritional solution, under constant temperature, constant-pressure conditions, do the isolated heart perfusion by the leagendonff method.After perfusion 1h treats the coronary flow substantially constant, measure 3 times (ml/min) with a small amount of tube continuously, get its meansigma methods for the preceding flow of experiment, then by the side pipe dosing, normal saline group, GUANXINNING ZHUSHEYE group, lyophilized injectable powder group of the present invention, dosage 0.8g crude drug/kg.The coronary flow result of variations sees 7 after the observed and recorded medication:
The influence of table 7 pair isolated rat heart coronary flow
P value behind the group medicine prodrug
Normal saline group 7.34 ± 0.4 7.37 ± 0.28＞0.05
GUANXINNING ZHUSHEYE group 7.27 ± 0.3 7.5 ± 0.28＜0.05
Lyophilized injectable powder group 7.10 of the present invention ± 0.3 8.22 ± 0.14
*＜0.01
Annotate: the P value is for comparing before and after the administration in the table: compare with positive controls
*P＜0.05
(3) to the influence of mouse cardiac muscle following time-to-live of anaerobic condition
Body weight 21g-30g closed colony Kunming kind is a male white mouse, be divided into normal saline group, GUANXINNING ZHUSHEYE group, lyophilized injectable powder group of the present invention at random, dosage 1.2g crude drug/kg, respectively organize all 30min intraperitoneal injection of drugs before experiment, 15min distinguishes lumbar injection isoproterenol 20mg/kg body weight again before the experiment.Mice is put into the wide mouthed bottle that 500ml is placed with the 10g sodica calx, 1 every bottle, seal a bottle with vaseline then, record mice time-to-live measurement result sees Table 8:
The influence of table 8 pair mouse cardiac muscle following time-to-live of anaerobic condition
Mice prolonged survival period rate
Group
(minute) (%)
Normal saline group 45.31 ± 6.87---
GUANXINNING ZHUSHEYE group 53.67 ± 10.84 18.45
Lyophilized injectable powder group 64.11 of the present invention ± 11.26 41.49
*
Annotate: compare with positive controls
*P＜0.05
(4) isotope
86The influence of Rb mapping mice trophism myocardial flow
86Rbcl is provided by Chinese atomic energy science institute Beijing Isotope Research.Be made into the solution of 6000 pulses/0.1/min before the experiment with normal saline.With 30 body weight 21g-23g closed colony Kunming kinds is that male white mouse is divided into 3 groups at random.Normal saline group, GUANXINNING ZHUSHEYE group, lyophilized injectable powder group of the present invention, dosage 1.2g crude drug/kg.Experimental technique press the Zhu Shi method [Zhu Xiuai etc. use
86Rb measures the method [J] of mice trophism myocardial flow. Chinese Medical Journal, 1975,8:559.] carry out.The results are shown in Table 9:
The influence of table 9 pair mice trophism myocardial flow
The cardiac muscle picked-up
86Rb percentage rate rate of increase
Group
(％) (％)
Normal saline group 9.97 ± 0.51---
GUANXINNING ZHUSHEYE group 13.21 ± 1.42 32.5
Lyophilized injectable powder group 14.19 of the present invention ± 2.18 42.3
*
Annotate: compare with positive controls
*P＜0.05
Conclusion: show that by above-mentioned pharmacological evaluation freeze dried powder injection for treating coronary disease of the present invention has better pharmacological action.
Four. preparation embodiment
Embodiment 1
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 3000 grams, Rhizoma Chuanxiong 3000 grams;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 15Mpa, and extraction temperature is 40 ℃, flow is 40L/h, the pressure of extraction-container 1 is 5Mpa, and resolution temperature is 30 ℃, and the pressure of extraction-container 2 is 3Mpa, resolution temperature is 20 ℃, extracted 4 hours, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 20, the 2-hydroxypropyl is made saturated solution with distilled water, put into 30 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stirs, and slowly drips and dissolves the material of dissolve with ethanol completely, continue to stir 12 hours, placed 12 hours at refrigerator, 30 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second and third time each 1.5 hours, collecting decoction, filter, it is 1.15 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.05, is that 3000 overclockings are shaken the ultrafilter membrane bag and carried out ultrafiltration with the intercepting molecular weight, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 96 grams, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 72 grams, pharmaceutic adjuvant freeze-dried excipient lactose 232 grams.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 5.5, and cillin bottle is injected in sterilization, and lyophilization obtains 1000 of freeze dried powder injection for treating coronary disease.[carry out check and analysis, Radix Salviae Miltiorrhizae total phenolic acids in the preparation (in catechu aldehyde) content is that 30mg/ props up, total tanshinone (in tanshinone) content is that 6mg/ props up, and ligustrazine content is that 18mg/ props up.]
Embodiment 2
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 5000 grams, Rhizoma Chuanxiong 5000 grams;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 35Mpa, and extraction temperature is 50 ℃, flow is 100L/h, the pressure of extraction-container 1 is 7Mpa, and resolution temperature is 35 ℃, and the pressure of extraction-container 2 is 5Mpa, resolution temperature is 25 ℃, extracted 6 hours, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 30, the 2-hydroxypropyl is made saturated solution with distilled water, put into 40 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stirs, and slowly drips and dissolves the material of dissolve with ethanol completely, continue to stir 24 hours, placed 24 hours at refrigerator, 40 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second and third time each 1.5 hours, collecting decoction, filter, it is 1.15-1.20 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.10, is that 8000 overclockings are shaken the ultrafilter membrane bag and carried out ultrafiltration with the intercepting molecular weight, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 160 grams, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 108 grams, pharmaceutic adjuvant freeze-dried excipient sucrose 132 grams.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 6.5, and cillin bottle is injected in sterilization, and lyophilization obtains 1000 of freeze dried powder injection for treating coronary disease.[carry out check and analysis, Radix Salviae Miltiorrhizae total phenolic acids in the preparation (in catechu aldehyde) content is that 50mg/ props up, total tanshinone (in tanshinone) content is that 10mg/ props up, and ligustrazine content is that 30mg/ props up.]
Embodiment 3
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 4000 grams, Rhizoma Chuanxiong 4000 grams;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 20Mpa, and extraction temperature is 45 ℃, flow is 80L/h, the pressure of extraction-container 1 is 6Mpa, and resolution temperature is 33 ℃, and the pressure of extraction-container 2 is 4Mpa, resolution temperature is 22 ℃, extracted 5 hours, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 25, the 2-hydroxypropyl is made saturated solution with distilled water, put into 35 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stirs, and slowly drips and dissolves the material of dissolve with ethanol completely, continue to stir 18 hours, placed 18 hours at refrigerator, 35 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second and third time each 1.5 hours, collecting decoction, filter, it is 1.18 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.08, is that 5000 overclockings are shaken the ultrafilter membrane bag and carried out ultrafiltration with the intercepting molecular weight, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 130 grams, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 91 grams, pharmaceutic adjuvant freeze-dried excipient mannitol 179 grams.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 6.0, and cillin bottle is injected in sterilization, and lyophilization obtains 1000 of freeze dried powder injection for treating coronary disease.[carry out check and analysis, Radix Salviae Miltiorrhizae total phenolic acids in the preparation (in catechu aldehyde) content is that 39.8mg/ props up, total tanshinone (in tanshinone) content is that 8.7mg/ props up, and ligustrazine content is that 24.1mg/ props up.]
Embodiment 4
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 3500 grams, Rhizoma Chuanxiong 3500 grams;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 18Mpa, and extraction temperature is 42 ℃, flow is 45L/h, the pressure of extraction-container 1 is 5.5Mpa, and resolution temperature is 32 ℃, and the pressure of extraction-container 2 is 3.5Mpa, resolution temperature is 22 ℃, extracted 4.5 hours, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 22, the 2-hydroxypropyl is made saturated solution with distilled water, put into 32 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stirs, and slowly drips and dissolves the material of dissolve with ethanol completely, continue to stir 16 hours, placed 16 hours at refrigerator, 32 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second and third time each 1.5 hours, collecting decoction, filter, it is 1.16 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.06, is that 3000 overclockings are shaken the ultrafilter membrane bag and carried out ultrafiltration with the intercepting molecular weight, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 108 grams, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 84 grams, pharmaceutic adjuvant freeze-dried excipient mannitol, sucrose 208 grams.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 5.8, and cillin bottle is injected in sterilization, and lyophilization obtains 1000 of freeze dried powder injection for treating coronary disease.[carry out check and analysis, Radix Salviae Miltiorrhizae total phenolic acids in the preparation (in catechu aldehyde) content is that 36.4mg/ props up, total tanshinone (in tanshinone) content is that 7.1mg/ props up, and ligustrazine content is that 19.6mg/ props up.]
Embodiment 5
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 4500 grams, Rhizoma Chuanxiong 4500 grams;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 30Mpa, and extraction temperature is 48 ℃, flow is 90L/h, the pressure of extraction-container 1 is 6.5Mpa, and resolution temperature is 34 ℃, and the pressure of extraction-container 2 is 4.5Mpa, resolution temperature is 24 ℃, extracted 5.5 hours, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 28, the 2-hydroxypropyl is made saturated solution with distilled water, put into 38 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stirs, and slowly drips and dissolves the material of dissolve with ethanol completely, continue to stir 22 hours, placed 22 hours at refrigerator, 38 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second and third time each 1.5 hours, collecting decoction, filter, it is 1.19 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.09, is that 8000 overclockings are shaken the ultrafilter membrane bag and carried out ultrafiltration with the intercepting molecular weight, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 146 grams, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 101.3 grams, pharmaceutic adjuvant freeze-dried excipient sucrose, lactose 152.7 grams.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 5.5-6.5, and cillin bottle is injected in sterilization, and lyophilization obtains 1000 of freeze dried powder injection for treating coronary disease.[carry out check and analysis, Radix Salviae Miltiorrhizae total phenolic acids in the preparation (in catechu aldehyde) content is that 45.1mg/ props up, total tanshinone (in tanshinone) content is that 9.2mg/ props up, and ligustrazine content is that 26.7mg/ props up.]
Embodiment 6
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 3000 grams, Rhizoma Chuanxiong 5000 grams;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 25Mpa, and extraction temperature is 46 ℃, flow is 60L/h, the pressure of extraction-container 1 is 6.5Mpa, and resolution temperature is 35 ℃, and the pressure of extraction-container 2 is 3Mpa, resolution temperature is 20 ℃, extracted 4 hours, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 30, the 2-hydroxypropyl is made saturated solution with distilled water, put into 40 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stirs, and slowly drips and dissolves the material of dissolve with ethanol completely, continue to stir 12 hours, placed 24 hours at refrigerator, 40 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second and third time each 1.5 hours, collecting decoction, filter, it is 1.20 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.05, is that 3000 overclockings are shaken the ultrafilter membrane bag and carried out ultrafiltration with the intercepting molecular weight, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 121.9 grams, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 86.3 grams, pharmaceutic adjuvant freeze-dried excipient mannitol, lactose 191.8 grams.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 6.2, and cillin bottle is injected in sterilization, and lyophilization obtains 1000 of freeze dried powder injection for treating coronary disease.[carry out check and analysis, Radix Salviae Miltiorrhizae total phenolic acids in the preparation (in catechu aldehyde) content is that 32.3mg/ props up, total tanshinone (in tanshinone) content is that 6.2mg/ props up, and ligustrazine content is that 28.9mg/ props up.]
Embodiment 7
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 5000 grams, Rhizoma Chuanxiong 3000 grams;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 28Mpa, and extraction temperature is 50 ℃, flow is 95L/h, the pressure of extraction-container 1 is 5Mpa, and resolution temperature is 30 ℃, and the pressure of extraction-container 2 is 3Mpa, resolution temperature is 20 ℃, extracted 4 hours, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 20, the 2-hydroxypropyl is made saturated solution with distilled water, put into 30 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stirs, and slowly drips and dissolves the material of dissolve with ethanol completely, continue to stir 12 hours, placed 12 hours at refrigerator, 30 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second and third time each 1.5 hours, collecting decoction, filter, it is 1.15 that filtrate is concentrated into 50 ℃ of relative densities, handle secondary with ethanol precipitation and make for the first time and contain the alcohol amount and reach 75%, and be 85% for the second time, equal cold preservation is placed after adding ethanol at every turn, filter, merging filtrate reclaims ethanol to most, adding water, to make 20 ℃ of relative densities of solution be 1.05, with the intercepting molecular weight is that 38000 overclockings concussion ultrafilter membrane bag carries out ultrafiltration, keeps permeate, concentrates, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) preparation prescription is:
Radix Salviae Miltiorrhizae water extract weight portion, Rhizoma Chuanxiong water extract 116.5 grams, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 90.3 grams, pharmaceutic adjuvant freeze-dried excipient mannitol, sucrose, lactose 193.2 grams.
(6) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 6.0, and cillin bottle is injected in sterilization, and lyophilization obtains 1000 of freeze dried powder injection for treating coronary disease.[carry out check and analysis, Radix Salviae Miltiorrhizae total phenolic acids in the preparation (in catechu aldehyde) content is that 48.2mg/ props up, total tanshinone (in tanshinone) content is that 9.4mg/ props up, and ligustrazine content is that 18.2mg/ props up.]
Claims (3)
1. freeze dried powder injection for treating coronary disease, it is characterized in that it is by Radix Salviae Miltiorrhizae water extract, Rhizoma Chuanxiong water extract 96-160 weight portion, red sage and chuanxiong rhizome 2-hydroxypropyl-beta-cyclodextrin inclusion 72-108 weight portion, pharmaceutic adjuvant 132-232 weight portion is formed, wherein controlling Radix Salviae Miltiorrhizae total phenolic acids (in catechu aldehyde) is not less than 30mg/ and props up, it is that 6mg/ props up that control total tanshinone (in tanshinone) content is not less than, and the control ligustrazine is not less than 18mg/ and props up.
2. freeze dried powder injection for treating coronary disease according to claim 1 is characterized in that this injectable powder is that Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong are adopted CO
2Supercritical extraction obtains that liposoluble substance carries out that 2-HP-enclose obtains clathrate, Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong carried out water is carried again again, the method for precipitate with ethanol, ultrafiltration purification, obtains extract, mixes with pharmaceutic adjuvant, is prepared into.
3. according to the preparation method of the described a kind of freeze dried powder injection for treating coronary disease of claim 1, its feature may further comprise the steps:
(1) crude drug proportioning weight is:
Radix Salviae Miltiorrhizae 3-5 weight portion, Rhizoma Chuanxiong 3-5 weight portion;
(2) get Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong decoction pieces, pulverize, put into CO
2In the supercritical extraction equipment extraction kettle, adjusting extraction kettle pressure is 15-35Mpa, and extraction temperature is 40 ℃-50 ℃, flow is 40-100L/h, the pressure of extraction-container 1 is 5-7Mpa, and resolution temperature is 30 ℃-35 ℃, and the pressure of extraction-container 2 is 3-5Mpa, resolution temperature is 20 ℃-25 ℃, extracted 4-6 hour, and merged the material of extraction-container 1,2, standby, the extraction kettle material takes out, and is standby;
(3) adding of the material in above-mentioned extraction-container dissolve with ethanol is complete, simultaneously according to material: the ratio of 2-hydroxypropyl=1: 20-30 (M/M), the 2-hydroxypropyl is made saturated solution with distilled water, put into 30 ℃-40 ℃ water-bath, temperature is controlled in strictness well, by the time 2-hydroxypropyl saturated aqueous solution reaches bath temperature, stir, slowly drip and dissolve the material of dissolve with ethanol completely, continue to stir 12-24 hour, placed 12-24 hour at refrigerator, 30 ℃ of-40 ℃ of dryings obtain clathrate;
(4) with residue in the above-mentioned extraction kettle, decoct with water 3 times, 2 hours for the first time, second, three times each 1.5 hours, collecting decoction, filter, it is 1.15-1.20 that filtrate is concentrated into 50 ℃ of relative densities, handles secondary with ethanol precipitation, make for the first time and contain the alcohol amount and reach 75%, be 85% for the second time, add behind the ethanol all cold preservation at every turn and place, filter, merging filtrate, reclaim ethanol to the greatest extent, adding water, to make 20 ℃ of relative densities of solution be 1.05-1.10, shakes the ultrafilter membrane bag with the intercepting molecular weight for the 3000-8000 overclocking and carry out ultrafiltration, keep permeate, concentrate, drying obtains Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong extract;
(5) above-mentioned clathrate, red sage and chuanxiong rhizome extract are added the dissolving of injection water fully, add freeze-dried excipient, transferring pH value with meglumine is 5.5-6.5, and cillin bottle is injected in sterilization, and lyophilization obtains freeze dried powder injection for treating coronary disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410101281 CN1631426A (en) | 2004-12-20 | 2004-12-20 | Freeze dried powder injection for treating coronary disease and its preparation process |
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| Application Number | Priority Date | Filing Date | Title |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101040906B (en) * | 2006-03-21 | 2011-12-07 | 北京因科瑞斯生物制品研究所 | Injection for treating cardiovascular or cerebrovascular disease and the preparing method and the quality control method |
| CN102302549A (en) * | 2011-09-05 | 2012-01-04 | 贵州拜特制药有限公司 | Drug composition for treating cardiovascular and cerebrovascular diseases, preparation method and application thereof |
| CN111419900A (en) * | 2020-05-20 | 2020-07-17 | 西南大学 | Improved nano suspension freeze-dried preparation based on perhexiline and preparation method thereof |
-
2004
- 2004-12-20 CN CN 200410101281 patent/CN1631426A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101040906B (en) * | 2006-03-21 | 2011-12-07 | 北京因科瑞斯生物制品研究所 | Injection for treating cardiovascular or cerebrovascular disease and the preparing method and the quality control method |
| CN102302549A (en) * | 2011-09-05 | 2012-01-04 | 贵州拜特制药有限公司 | Drug composition for treating cardiovascular and cerebrovascular diseases, preparation method and application thereof |
| CN111419900A (en) * | 2020-05-20 | 2020-07-17 | 西南大学 | Improved nano suspension freeze-dried preparation based on perhexiline and preparation method thereof |
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