CN1742792A - Danhong freez-fried powder injecta and preparing method - Google Patents
Danhong freez-fried powder injecta and preparing method Download PDFInfo
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- CN1742792A CN1742792A CN 200510094740 CN200510094740A CN1742792A CN 1742792 A CN1742792 A CN 1742792A CN 200510094740 CN200510094740 CN 200510094740 CN 200510094740 A CN200510094740 A CN 200510094740A CN 1742792 A CN1742792 A CN 1742792A
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Abstract
The present invention relates to a Danhong freeze-dried powder injection and its preparation method. Its composition includes 0.1-10 portions of effective components of salvia root and carthamus flower, 0.001-10 portions of excipient and 0.01-5 portions of water. Said invention also provides the concrete steps of its preparation method.
Description
Technical field
The present invention relates to a kind of preparation containing red sange root and safflower, be specifically related to a kind of injection freeze-dried powder that contains Radix Salviae Miltiorrhizae, safflower effective ingredients and preparation method thereof.
Background technology
Radix Salviae Miltiorrhizae has another name called that blood is taken root, Radix Salviae Miltiorrhizae, Herba Wedeliae Wallichii, Arisaema balansae Engl..Be labiate Radix Salviae Miltiorrhizae Salviamiltiorrhiza Bge. root and rhizome.Radix Salviae Miltiorrhizae is traditional conventional Chinese medicine material, and nearly 2000 applicating histories are arranged, and Ming Dynasty's Compendium of Material Medica is carried the effect of " Radix Salviae Miltiorrhizae is invigorated blood circulation, logical percardium ".The Radix Salviae Miltiorrhizae active ingredient mainly is made up of water-soluble components phenolic acid compound and fat-soluble composition tanshinone compound.Radix Salviae Miltiorrhizae has the expansion blood vessel, brings high blood pressure down, the effect of antithrombotic, microcirculation improvement, anti-inflammation, to treatment coronary heart disease, angina pectoris, the rhythm of the heart overrun, disease such as acne has significant curative effect.The clinical treatment of diseases such as cardiovascular system, nervous system, viral infection that are widely used in.Traditional application process of Radix Salviae Miltiorrhizae is a decocting liquid.
Flos Carthami has another name called Flos Carthami, FLOS CARTHAMI from Henan of China, Flos Carthami, Flos Carthami, stir-fry Flos Carthami.Dried floral for feverfew Flos Carthami Carthamus tinctorius L..The Flos Carthami acrid in the mouth, warm in nature.GUIXIN, Liver Channel.The pharmacological action of Flos Carthami is mainly blood circulation promoting and blood stasis dispelling, and blood vessel dilating increases coronary blood flow and antithrombotic and forms, and is mainly used in the control of cardiovascular system diseases clinically, as prevents and treats atherosclerosis, coronary heart disease, vasculitis, angina pectoris etc.The all right treatment of diabetic retinopathy change of Flos Carthami, diabetes kidney damage, the disease group of spinal cord central authorities, skin nodules erythema, medicamentous rhinitis etc.The Flos Carthami main component is a flavone compound, comprises multiple active ingredients such as Carthamus yellow, carthamin, saffloside, mostly is water-soluble substances.
DANHONG ZHUSHEYE is Radix Salviae Miltiorrhizae, Flos Carthami compound preparation, has the pharmacological action of Radix Salviae Miltiorrhizae and Flos Carthami concurrently, studies have shown that have blood circulation promoting and blood stasis dispelling, menstruction regulating and pain relieving, blood vessel dilating increases coronary blood flow, blood viscosity lowering is removed effects such as free radical.The clinical diseases such as treatment coronary heart disease, angina pectoris, myocardial infarction, cerebral thrombosis that are widely used in.Present Radix Salviae Miltiorrhizae, Flos Carthami compound preparation are injection, be to adopt the method for conventional water extract-alcohol precipitation to make, and not only bad for the storage and the transportation of product, and quality and unstable properties, be unfavorable for clinical practice.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of Danhong freez-fried powder injecta and preparation method thereof, to overcome the defective that prior art exists.
Component and parts by weight before the Danhong freez-fried powder injecta lyophilizing of the present invention comprise:
0.1～10 part of the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami
0.001～10 part of excipient
0.01～5 part in water
The pH that makes the preceding solution of lyophilizing is 5.0～6.0 pH regulator agent;
Said excipient is an acceptable lyophilizing excipient arbitrarily commonly used on the galenic pharmacy, and preferred excipient is one or more the mixture in mannitol, lactose, sucrose, glucose or the dextran;
Said pH regulator agent is selected from a kind of or its mixture in sodium hydroxide, sodium bicarbonate, sodium carbonate or hydrochloric acid, phosphoric acid, nitric acid, the sulphuric acid.
The effective ingredient of said Radix Salviae Miltiorrhizae and Flos Carthami is to adopt the crude drug of following parts by weight to prepare:
1～5 part of Radix Salviae Miltiorrhizae, 1～5 part on Flos Carthami;
The preparation method of the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami is a decoction and alcohol sedimentation technique, specifically comprises the steps:
(1) gets Radix Salviae Miltiorrhizae and Flos Carthami two flavor medical materials, add the water of 5～15 times of amounts respectively, decocted 1～3 hour, filter;
(2) be concentrated into the clear paste that relative density is 1.10-1.20 (about 1.16), add weight concentration and be 80～95% ethanol, make to contain the alcohol amount and reach 75%, cold preservation 15～30 hours;
(3) filter, the clear paste that ethanol to relative density is 1.00-1.10 (about 1.06) is flung in evaporation, adds weight concentration and be 80～95% ethanol, makes to contain the alcohol amount and reach 80%, cold preservation 15～30 hours;
(4) filter, the clear paste that ethanol to relative density is 1.00-1.10 (about 1.06) is flung in evaporation, with weight concentration is that 10～50% sodium hydroxide is regulated pH to 8.5～9.5, boiled 0.5～2 hour, 1M hydrochloric acid is regulated pH to 5.5～6.5, filters, and the adding weight concentration is 80～95% ethanol, make and contain alcohol amount and reach 85%, cold preservation 15～30 hours;
(5) filter, the clear paste that ethanol to relative density is 1.10-1.20 (about 1.14) is flung in evaporation, adds the water of gross weight 75%, promptly obtains the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami.
The preparation method of Danhong freez-fried powder injecta of the present invention comprises the steps:
With weight concentration is the pH to 5.0-6.0 that the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami is regulated in 20～50% pH regulator agent, adds excipient, dissolving, and moisturizing is to full dose, cross doughnut microporous filter membrane (molecular cut off 1000～10000), degerming, fill, lyophilizing, gland promptly obtains product;
The using method of freeze-drying powder injection containing red-rooted salvia safflower of the present invention, identical with other lyophilized injectable powder, before the injection, dissolve with sterilized water for injection, being mixed with to weight concentration is 2～80% injection, put on the patient who needs treatment by the intravenous drip approach, dosage is generally 200～800mg/ kg body weight.
A kind of freeze-drying powder injection containing red-rooted salvia safflower preparation technology of the present invention, be water soluble ingredient according to danshensu sodium in the Radix Salviae Miltiorrhizae and protocatechualdehyde, the character that flavones ingredient in the Flos Carthami is also soluble in water, adopt direct water extraction, the deimpurity extracting method of precipitate with ethanol has effectively kept the flavonoids effective constituent in the phenolic acids and Flos Carthami in the Radix Salviae Miltiorrhizae then.Be better than in country of National Drug Administration standard for traditional Chinese medicines compilation (internal medicine is felt concerned about fascicle) " DANHONG ZHUSHEYE ", Radix Salviae Miltiorrhizae Diluted Alcohol warm macerating twice merges the Flos Carthami water temperature and soaks twice extraction process.A kind of Danshen freeze-drying preparation that application the inventive method makes is loose porous, solubility good, and active component is not destroyed, and stability is improved, and is convenient to guarantee the quality of product, also is beneficial to simultaneously to store and transportation.
The specific embodiment
Embodiment 1
Directly water extraction and first alcohol leaching again water propose the comparative experiments of Radix Salviae Miltiorrhizae total phenolic acids
Radix Salviae Miltiorrhizae can coronary blood flow increasing, blood fat reducing, inhibition thrombosis or antithrombotic, microcirculation improvement effect.Its main effective ingredient is water-soluble phenolic acid: danshensu sodium and protocatechualdehyde.Fat-soluble diterpene quinones: tanshinone.This experiment is an index with danshensu sodium and protocatechualdehyde, relatively the quality of red sage root water soluble ingredient extracting method.
1 instrument and reagent
Liquid phase pump: LC-10ATvp, day island proper Tianjin instrument company;
Detector: SPD-10vp, day island proper Tianjin instrument company;
Column oven: CTO-10Asvp, day island proper Tianjin instrument company;
Chromatographic column: C
18200mm * 4.6mm, 10 μ m, Dalian Yilite Analytical Instrument Co., Ltd;
Chromatographic work station: the intelligent information institute N2000 of Zhejiang University dual pathways chromatographic work station;
Methanol: high performance liquid chromatogram special use, Huaiyin, Jiangsu plastic factory fine chemistry industry institute;
Glacial acetic acid: analytical pure, Shantou Xilong Chemical Factory, Guangdong.
2, method and result
(1) chromatographic condition
Chromatographic column:: C
18200mm * 4.6mm, 10 μ m, Dalian Yilite Analytical Instrument Co., Ltd;
Mobile phase: methanol: 1% glacial acetic acid=13: 87;
Flow velocity: 1.0ml/min;
Detect wavelength: 280nm;
Column temperature: 25 ℃;
Quantitative approach: external standard method;
Danshensu sodium reference substance retention time is: 5.5min; Protocatechualdehyde reference substance retention time is: 9min.
(2) content assaying method
The preparation precision of reference substance solution takes by weighing danshensu sodium, the protocatechualdehyde reference substance is an amount of, adds water respectively and makes the solution that every 1ml contains 50 μ g, promptly.
The preparation of need testing solution
Test sample A: get Radix Salviae Miltiorrhizae dry root 150 grams, add Diluted Alcohol 900ml respectively, 80 ℃ of water-baths,
Warm macerating twice, each 1 hour, filter, filtering residue adds water 900ml respectively, 80 ℃ of water-baths, warm macerating twice, each 1 hour, filter, merge each filtrate, reclaim solution to 100ml, promptly.
Test sample B: get Radix Salviae Miltiorrhizae dry root 150 grams, add water 1500ml respectively, decoct twice, each 1 hour, filter, merging filtrate is recycled to 100ml, promptly.
(3) preparation of standard curve
Danshensu sodium its corresponding absworption peak area in the concentration range of 0.01～0.10mg/mL is good linear relationship, equation of linear regression: A=7.0 * 10
6C
Correlation coefficient: r=0.9995.
Protocatechualdehyde its corresponding absworption peak area in the concentration range of 0.01～0.10mg/mL is good linear relationship, equation of linear regression: A=5 * 10
7C
Correlation coefficient: r=0.9997.
(4) precision test
Precision is measured need testing solution 10 μ l, and continuous sample introduction six times, the RSD of danshensu sodium are 0.30%; The RSD of protocatechualdehyde is 0.10%.
(5) average recovery test
Measure three Concentraton gradient, three test samples of each prepared at concentrations.The average recovery rate of danshensu sodium is: 101.58, and RSD is: 0.30%; The average recovery rate of protocatechualdehyde is: 99.50, and RSD is 0.40%.
(6) sample determination is drawn need testing solution 10 μ l, and sample introduction calculates content according to external standard method, and the result is as follows:
| Sample | Measure lot number | ||||||
| 1 | 2 | 3 | 4 | 5 | X | ||
| Test sample A | Danshensu sodium (mg/ bottle) | 4.32 | 4.11 | 3.75 | 3.62 | 4.28 | 4.02 |
| Protocatechualdehyde (mg/ bottle) | 0.36 | 0.41 | 0.29 | 0.24 | 0.39 | 0.34 | |
| Test sample B | Danshensu sodium (mg/ bottle) | 7.95 | 8.51 | 8.32 | 8.69 | 8.74 | 8.44 |
| Protocatechualdehyde (mg/ bottle) | 1.42 | 1.56 | 1.54 | 1.61 | 1.59 | 1.54 | |
Embodiment 2
Specification (1000 bottles)
(1) the material Radix Salviae Miltiorrhizae 7500g and Flos Carthami 2500g that gets it filled adds the water of 10 times of amounts, decocts twice, each 1 hour, filters merging filtrate.
(2) being concentrated into relative density is 1.18 clear paste, adds 90% ethanol, make to contain the alcohol amount and reach 75%, and cold preservation 24 hours.
(3) filter, reclaim ethanol to relative density and be 1.04 clear paste, add 95% ethanol, make to contain the alcohol amount and reach 80%, cold preservation 24 hours.
(4) filter, reclaim ethanol to relative density and be 1.07 clear paste, 40% sodium hydroxide is regulated pH to 9.0, heated and boiled 1 hour, and 1M hydrochloric acid is regulated pH to 6.0, filters, and adds 95% ethanol, makes to contain the alcohol amount and reach 85%, cold preservation 24 hours.
(5) filter, recovery ethanol to relative density is 1.12 clear paste, adds the water of gross weight 75%.
(6) filter, regulate pH to 5.81 with weight concentration for 1M hydrochloric acid, add injection mannitol 1500g, dissolving, moisturizing are to 5000ml, and mixing is crossed doughnut microporous filter membrane (molecular cut off 5000), degerming, and fill, lyophilizing, gland is promptly.
Embodiment 3
Specification (1000 bottles)
(1) the material Radix Salviae Miltiorrhizae 7500g and Flos Carthami 1500g that gets it filled adds the water of 10 times of amounts, decocts twice, each 1 hour, filters merging filtrate.
(2) being concentrated into relative density is 1.15 clear paste, adds 90% ethanol, make to contain the alcohol amount and reach 75%, and cold preservation 24 hours.
(3) filter, reclaim ethanol to relative density and be 1.06 clear paste, add 95% ethanol, make to contain the alcohol amount and reach 80%, cold preservation 24 hours.
(4) filter, reclaim ethanol to relative density and be 1.08 clear paste, 40% sodium hydroxide is regulated pH to 9.0, heated and boiled 1 hour, and 1M hydrochloric acid is regulated pH to 6.0, filters, and adds 95% ethanol, makes to contain the alcohol amount and reach 85%, cold preservation 24 hours.
(5) filter, recovery ethanol to relative density is 1.17 clear paste, adds the water of gross weight 75%.
(6) filter, weight concentration is 4% sodium hydroxide adjusting pH to 5.65, adds dextran 1 200g, injection lactose 1000g, dissolving, moisturizing is to 5000ml, and mixing is crossed doughnut microporous filter membrane (molecular cut off 5000), degerming, fill, lyophilizing, gland is promptly.
Embodiment 4
Specification (1000 bottles)
(1) the material Radix Salviae Miltiorrhizae 7500g and Flos Carthami 1500g that gets it filled adds the water of 10 times of amounts, decocts twice, each 1 hour, filters merging filtrate;
(2) being concentrated into relative density is 1.13 clear paste, adds 90% ethanol, makes to contain the alcohol amount and reach 75%, cold preservation 24 hours;
(3) filter, reclaim ethanol to relative density and be 1.04 clear paste, add 95% ethanol, make to contain the alcohol amount and reach 80%, cold preservation 24 hours;
(4) filter, reclaim ethanol to relative density and be 1.05 clear paste, 40% sodium hydroxide is regulated pH to 9.0, heated and boiled 1 hour, and 1M hydrochloric acid is regulated pH to 6.0, filters, and adds 95% ethanol, makes to contain the alcohol amount and reach 85%, cold preservation 24 hours;
(5) filter, recovery ethanol to relative density is 1.14 clear paste, adds the water of gross weight 75%;
(6) filter, weight concentration is 30% sodium hydroxide adjusting pH to 5.83, adds Dextran 150 0g, injection sucrose 1200g, dissolving, moisturizing is to 5000ml, and mixing is crossed doughnut microporous filter membrane (molecular cut off 5000), degerming, fill, lyophilizing, gland is promptly.
Embodiment 5
The stability test result
1, Danhong for injection embodiment 1 stability test the results are shown in Table 1.
Table 1 Danhong for injection embodiment 1 stability test result
| The examination project | 0 month | January | February | March | June | JIUYUE | |
| Proterties is differentiated clarity pH Zhi moisture (%) | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.27 2.6 cultivate the clarification of parent tube clarification cultivation parent tube cultivates the parent tube clarification | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.29 2.9 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.24 2.5 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.28 3.0 cultivate the clarification of parent tube clarification cultivation parent tube cultivates the parent tube clarification | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.30 2.7 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.26 2.9 | |
| Aseptic | Aerobe anaerobe fungus | ||||||
| Anaphylaxis hemolytic excitant pyrogen Related Component (%) | Animal subject do not had sensitization does not have haemolysis and agglutination does not have obvious stimulation Zuo Yong up to specification 18.14 9.56 108.91 to the rabbit auricular vein | 18.30 9.53 107.49 | 18.76 9.51 107.23 | Animal subject do not had sensitization does not have haemolysis and agglutination does not have obvious stimulation Zuo Yong up to specification 19.09 9.50 106.02 to the rabbit auricular vein | 19.68 9.44 105.41 | 18.26 9.39 103.41 | |
| Content | Radix Salviae Miltiorrhizae (mg/ props up) total flavones (mg/ props up) | ||||||
2, Danhong for injection embodiment 2 stability tests the results are shown in Table 2.
Table 2 Danhong for injection embodiment 2 stability test results
| The examination project | 0 month | January | February | March | June | JIUYUE | |
| Proterties is differentiated clarity pH Zhi moisture (%) | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.24 2.7 cultivate the clarification of parent tube clarification cultivation parent tube cultivates the parent tube clarification | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.22 2.8 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.21 2.7 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.24 2.6 cultivate the clarification of parent tube clarification cultivation parent tube cultivates the parent tube clarification | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.26 2.9 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.21 2.8 | |
| Aseptic | Aerobe anaerobe fungus | ||||||
| Anaphylaxis hemolytic excitant pyrogen Related Component (%) | Animal subject do not had sensitization does not have haemolysis and agglutination does not have obvious stimulation Zuo Yong up to specification 18.23 9.67 109.77 to the rabbit auricular vein | 18.96 9.64 108.86 | 19.45 9.64 107.58 | Animal subject do not had sensitization does not have haemolysis and agglutination does not have obvious stimulation Zuo Yong up to specification 19.98 9.59 106.32 to the rabbit auricular vein | 18.25 9.52 105.14 | 19.28 9.42 104.20 | |
| Content | Radix Salviae Miltiorrhizae (mg/ props up) total flavones (mg/ props up) | ||||||
3, Danhong for injection embodiment 3 stability tests the results are shown in Table 3.
Table 3 Danhong for injection embodiment 3 stability test results
| The examination project | 0 month | January | February | March | June | JIUYUE | |
| Proterties is differentiated clarity pH Zhi moisture (%) | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.29 2.9 cultivate the clarification of parent tube clarification cultivation parent tube cultivates the parent tube clarification | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.28 2.7 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.26 2.8 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.31 2.5 cultivate the clarification of parent tube clarification cultivation parent tube cultivates the parent tube clarification | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.30 3.0 | The yellow freeze-drying block of Zong or powder are Yu the fluorescence spot of the aobvious same color of control medicinal material is clear and bright; Trace white point, foreign, qualified 5.31 2.9 | |
| Aseptic | Aerobe anaerobe fungus | ||||||
| Anaphylaxis hemolytic excitant pyrogen Related Component (%) | Animal subject do not had sensitization does not have haemolysis and agglutination does not have obvious stimulation Zuo Yong up to specification 18.16 9.35 107.89 to the rabbit auricular vein | 18.38 9.33 108.11 | 19.79 9.31 106.86 | Animal subject do not had sensitization does not have haemolysis and agglutination does not have obvious stimulation Zuo Yong up to specification 18.88 9.28 105.94 to the rabbit auricular vein | 18.22 9.21 104.35 | 19.37 9.10 102.85 | |
| Content | Radix Salviae Miltiorrhizae (mg/ props up) total flavones (mg/ props up) | ||||||
The stability test conclusion
Preliminarily stabilised test to test agent among 3 three crowdes of Danhong for injection embodiment 1, embodiment 2, the embodiment.The character, discriminating, clarity, pH value, moisture of examination Danhong for injection, aseptic, anaphylaxis, hemolytic, zest, relevant composition, content, through nine months investigation, the result showed that all items index has no significant change, meet clinical with Danhong for injection quality standard draft
Embodiment 6
Pharmacological toxicology research data summary
One, main pharmacodynamics research
Dog coronary ligation myocardial ischemia experimental result shows that Danhong for injection 8g crude drug/kg, 4g crude drug/kg, 2g crude drug/kg all do not have obviously influence (P＞0.05) to each time point ligation dog systolic pressure (SAP), diastolic pressure (DAP), mean pressure (MAP), heart rate (HR), serum creatine kinase (CK).This medicine 8g crude drug/Kg can extremely significantly reduce ligation dog infarcted myocardium weight (P＜0.01), extremely significantly reduces infarct/ventricle percentage rate (P＜0.01); Danhong for injection 4g crude drug/Kg, 2g crude drug/Kg can significantly reduce ligation dog infarcted myocardium weight, infarct/ventricle percentage rate (P＜0.05).
Danhong for injection 8g crude drug/Kg can extremely significantly reduce ligation dog 0 minute, 5 minutes, 20 minutes, 30 minutes, 120 minutes Δ N-ST numbers (P＜0.01), 10 minutes, the 60 minutes Δ N-ST numbers (P＜0.05) that obviously reduce the ligation dog; Danhong for injection 4g crude drug/Kg can extremely significantly reduce ligation dog 0 minute, 20 minutes, 30 minutes Δ N-ST numbers (P＜0.01), 5 minutes, 10 minutes, 60 minutes, the 120 minutes Δ N-ST numbers (P＜0.05) that significantly reduce the ligation dog; Danhong for injection 2g crude drug/Kg can extremely significantly reduce ligation dog 0 minute, 20 minutes Δ N-ST numbers (P＜0.01), 5 minutes, 10 minutes, 30 minutes, 60 minutes, the 120 minutes Δ N-ST numbers (P＜0.05) that significantly reduce the ligation dog.
Danhong for injection 8g crude drug/kg can extremely significantly reduce ligation dog 5 minutes, 30 minutes Δ ∑-ST (P＜0.01), 10 minutes, 20 minutes, 60 minutes, the 120 minutes Δ ∑-ST (P＜0.05) that significantly reduce the ligation dog; Danhong for injection 4g crude drug/kg can extremely significantly reduce 30 minutes Δ ∑-ST (P＜0.01) of ligation dog, 0 minute, 5 minutes, 10 minutes, 20 minutes, the 60 minutes 120 minutes Δ ∑-ST (P＜0.05) that significantly reduce the ligation dog; Danhong for injection 2g crude drug/kg can significantly reduce ligation dog 0 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes 120 minutes Δ ∑-ST (P＜0.05).
Danhong for injection 8g crude drug/kg, 4g crude drug/kg can extremely significantly increase by 60 minutes, 120 minutes ligation dog serum superoxide dismutase (SOD) (P＜0.01); Danhong for injection 2g crude drug/kg can extremely significantly increase by 60 minutes ligation dog serum SOD (P＜0.01), can obviously increase by 120 minutes dog serum SOD (P＜0.05).
Danhong for injection 8g crude drug/kg, 4g crude drug/kg can extremely obviously reduce by 60 minutes, 120 minutes ligation dog serum serum glutamic oxalacetic transaminases (AST) (P＜0.01).
Danhong for injection 8g crude drug/kg can extremely significantly reduce by 60 minutes ligation dog serum malonaldehyde (MDA) (P＜0.01), can significantly reduce by 120 minutes ligation dog serum MDA (P＜0.05); Danhong for injection 4g crude drug/Kg can extremely significantly reduce by 60 minutes ligation dog serum MDA (P＜0.01), obviously reduces by 120 minutes ligation dog serum MDA (P＜0.05).
Danhong for injection 8g crude drug/kg can extremely significantly reduce by 60 minutes ligation dog serum lactic acid dehydrogenases (LDH) (P＜0.01), can significantly reduce by 120 minutes ligation dog serum LDH (P＜0.05); Danhong for injection 4g crude drug/kg can extremely significantly reduce by 60 minutes ligation dog serum LDH (P＜0.01), significantly reduces by 120 minutes ligation dog serum LDH (P＜0.05).
The cardiac hemodynamic result of the test shows that (dp/dtmax), myocardial oxygen consumption index TTI (mmHg.beats) did not all have obviously influence (P＞0.05) for left ventricle maximum shrinkage force (Vpm), myocardial relaxation parameter when Danhong for injection 8g crude drug/kg, 4g crude drug/kg, 2g crude drug/kg pressed LVED, zero load to the left ventricular diastolic end.
Danhong for injection 4g crude drug/kg can obviously reduce by 5 minutes dog systolic pressures (SAP) (P＜0.05).Danhong for injection 8g crude drug/kg can obviously reduce by 1 minute, 5 minutes, 10 minutes, 15 minutes, 45 minutes, 60 minutes dog diastolic pressures (DAP) (P＜0.05); Danhong for injection 4g crude drug/kg can extremely obviously reduce by 5 minutes, 10 minutes, 15 minutes, 30 minutes dog diastolic pressures (DAP) (P＜0.01), can significantly reduce by 45 minutes, 60 minutes, 90 minutes, 120 minutes dog diastolic pressures (DAP) (P＜0.05).Danhong for injection 2g crude drug/kg can extremely obviously reduce by 30 minutes 45 minutes dog diastolic pressures (DAP) (P＜0.01), obviously reduces by 1 minute, 5 minutes, 10 minutes, 45 minutes dog diastolic pressures (DAP) (P＜0.05).Danhong for injection 8g crude drug/kg can obviously reduce by 1 minute, 5 minutes, 10 minutes, dog mean arterial pressure (MAP) (P＜0.05); Danhong for injection 4g crude drug/kg can extremely significantly reduce by 5 minutes, 10 minutes dog mean arterial pressure (MAP) (P＜0.01) can obviously reduce by 1 minute, 15 minutes, 30 minutes dog mean arterial pressures (MAP) (P＞0.05).
Danhong for injection 8g crude drug/kg can extremely significantly increase by 10 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes dog coronary flow (CF) (P＜0.01) can obviously increase by 15 minutes, 120 minutes dog coronary flows (CF) (P＜0.05); Danhong for injection 4g crude drug/kg can extremely significantly increase by 30 minutes, 45 minutes dog coronary flows (CF) (P＜0.01), significantly increases by 1 minute, 15 minutes, 60 minutes, 90 minutes, 120 minutes dog coronary flows (CF) (P＜0.05); Danhong for injection 2g crude drug/kg can obviously increase by 1 minute, 10 minutes, 15 minutes, 90 minutes dog coronary flows (CF) (P＜0.05).
Danhong for injection 8g crude drug/kg can extremely significantly reduce by 1 minute, 5 minutes, 10 minutes, 15 minutes, 45 minutes, 60 minutes dog total peripheral resistances (TPR) (P＜0.01), significantly reduces by 30 minutes, 90 minutes, 120 minutes dog total peripheral resistances (TPR) (P＜0.05); Danhong for injection 4g crude drug/kg can extremely significantly reduce by 1 minute, 5 minutes, 10 minutes, 15 minutes, 45 minutes dog total peripheral resistances (TPR) (P＜0.01), significantly reduces by 60 minutes dog total peripheral resistances (TPR) (P＜0.05).
Danhong for injection 4g crude drug/kg can extremely significantly reduce by 1 minute, 15 minutes dog hearts rate (HR) (P＞0.01).
Danhong for injection 8g crude drug/kg can obviously increase by 1 minute dog cardiac output (CO) (P＜0.05); Danhong for injection 4g crude drug/kg can obviously increase by 1 minute, 30 minutes, 45 minutes, 60 minutes dog cardiac outputs (CO) (P＜0.05).
Danhong for injection 8g crude drug/kg can extremely significantly increase by 60 minutes dog stroke volume (SV) (P＜0.01) can obviously increase by 1 minute, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 90 minutes dog stroke volumes (SV) (P＜0.05); Danhong for injection 4g crude drug/kg can extremely significantly increase by 1 minute, 15 minutes, 30 minutes, 45 minutes dog stroke volumes (SV) (P＜0.01), can obviously increase by 5 minutes, 10 minutes, 60 minutes, 90 minutes dog stroke volumes (SV) (P＜0.05).
Danhong for injection 8g crude drug/kg can extremely obviously increase the acting (LVSWJ/beat) (P＜0.01) of whenever fighting of 15 minutes dog left ventriclies, can obviously increase by 1 minute, 5 minutes, 10 minutes left ventriclies are whenever fought acting (LVSWJ/beat) (P＜0.05); Danhong for injection 4g crude drug/kg can obviously increase the acting (LVSW J/beat) (P＜0.05) of whenever fighting of 30 minutes dog left ventriclies; Danhong for injection 2g crude drug/kg can obviously increase the acting (LVSW J/beat) (P＜0.05) of whenever fighting of 30 minutes 90 minutes left ventriclies.
Danhong for injection 4g crude drug/kg can reduce by 10 minutes, 15 minutes dog left ventricle maximum internal pressure LVP (P＜0.05).
Danhong for injection 8g crude drug/kg can obviously increase by 1 minute, 5 minutes, 30 minutes dog myocardial contraction parameter (+dp/dtmax) (P＜0.05); Danhong for injection 4g crude drug/kg can obviously increase by 30 minutes, 45 minutes, 60 minutes, 120 minutes dog myocardial contraction parameter (+dp/dtmax) (P＜0.05).
1 minute, 5 minutes myocardium of left ventricle oxygen consumption (mlO of Danhong for injection 8g crude drug/Kg
2/ min/g) significantly reduction (P＜0.05); 1 minute myocardium of left ventricle oxygen consumption of Danhong for injection 4g crude drug/Kg (mlO
2/ min/g) extremely significantly reduction (P＜0.01); 5 minutes, 10 minutes myocardium of left ventricle oxygen consumption (mlO of 4g crude drug/Kg
2/ min/g) significantly reduction (P＜0.05).
The rat pituitary pituitrin causes myocardial ischemia experiment and shows, before and after the administration self more as can be known, model group 5sec, 10secT ripple are obviously raised, 30sec, 1min, 5minT ripple obviously reduce.The positive drug group has only the 1minT ripple significantly to reduce.High dose group, middle dosage group all do not have obvious reduction, and low dose group 10sec, 30sec, 1min, 2minT ripple obviously reduce.By between the group of difference before and after the administration more as can be known, high dose difference (mv) behind 5sec, 10secT wavefront all has significance to reduce (P＜0.05), 30sec has significance rising (P＜0.05); Middle dosage has extremely significantly reduction (P＜0.01) at 5sec, 10sec, and 30sec and 5min have significance to raise (P＜0.05), and low dosage extremely significantly reduces (P＜0.01) at 5sec, and 10see has significance to reduce (P＜0.05).
Before and after the administration self more as can be known, model group 5sec, 10sec, 2min, 5min, 10min, 20min J point after administration are all obviously raised.High dose group 5min, 10min, middle dosage group 10sec, 2min, 5min, 10min, the J point of low dose group 10min is obviously raised.By between the group of difference before and after the administration more as can be known, high dose group all has utmost point significance reduction (P＜0.01) in 5sec, 10sec J point front and back differences (mv); Difference (mv) has significance to reduce (P＜0.05) before and after 5min, 10min, the 20min J point.Middle dosage has extremely significantly reduction (P＜0.01) at 5sec, and 10sec and 20min have significance to reduce (P＜0.05).Low dosage extremely significantly reduces (P＜0.01) at 5sec, and 10sec has significance to reduce (P＜0.05).
Each dosage group p-p interval (s) of Danhong for injection does not relatively have significant difference with model group.
Guinea pig isolated heart perfusion experiment shows, with model group relatively, high dose group, middle dosage group all have significant difference (P＜0.05, P＜0.01) irritating 10min, 20min, 30min again, can strengthen ischemia and irritate myocardial contraction again.
Compare with model group, high agent group amount is being irritated 10min, 20min, 30min again, and middle dosage is being irritated 10min, 20min, 30min again, and low dosage all has significant difference (P＜0.05 irritating 30min again, P＜0.01), can increase the isolated heart ischemia and irritate coronary flow again.
Each administration group all has no significant effect (P＞0.05) to heart rate.
The experiment of mice anoxia enduring shows that Danhong for injection 48 and 24g crude drug/kg can the utmost point significant prolongation mice normobaric hypoxia death time (P＜0.01).
Influence experiment to rat blood rheological characteristic and rabbit extracorporeal platelet aggregation rate shows that high, medium and low three dosage of Danhong for injection all can obviously reduce the rat model whole blood viscosity, with the model group comparing difference significance (P＜0.05, P＜0.01) is arranged all.
High and low two dosage groups can reduce the rat erythrocyte aggregation index, with the model group comparing difference significance (P＜0.05) are arranged all.
Each administration group all has remarkable inhibition ADP to induce the effect of the maximum platelet aggregation rate of rat.
The Danhong for injection treated in vitro, final concentration is 444.4,222.2,111.1,55.6, each dosage of 27.8mg crude drug/ml induces tame rabbit platelet maximum agglutination rate that the obvious suppression effect is all arranged to ADP, final concentration is 444.4,222.2, three dosage of 111.1mg crude drug/ml can also suppress platelet 1min and 5min aggregation rate, these the effect all be dose-dependence (Y=-11.24X+427.3, r=0.814).
The Danhong for injection treated in vitro, final concentration is 444.4,222.2,111.1, each dosage of 55.6mg crude drug/ml induces tame rabbit platelet maximum agglutination rate that the obvious suppression effect is all arranged to PAF, final concentration is 444.4,222.2, three dosage of 111.1mg crude drug/ml can also suppress platelet 1min and 5min aggregation rate, these the effect all be dose-dependence (Y=-10.037X+524.07, r=0.963).
Two, the experimental study of general pharmacology research
This test has been inquired into Danhong for injection to the neural influence of domesticated dog cardiovascular system, respiratory system and mice.The result shows, three dosage groups of Danhong for injection 16g crude drug/kg, 8g crude drug/kg and 4g crude drug/kg and negative control group (5% glucose injection) are behind the femoral vein dropleting medicine-feeding in the 180min, tried each time point blood pressure of each dosage group of anesthetized dog, respiratory frequency, amplitude of respiration and every electrocardiogram index administration front and back own control, no significance statistical significance (P＞0.05).Showing that this medicine does not all have obviously domesticated dog cardiovascular and respiratory system in being subjected to the amount of reagent scope influences.
Danhong for injection shows the result of mice nervous system test, after three dosage groups of this medicine 96g/kg, 48g/kg and 24g/kg and negative control group (5% glucose injection) the tail vein injection administration, three dosage groups do not have obvious influence to mice auricular concha blood vessel and tail color and luster, high dose group has part animal appearance activity to reduce, in, the low dose group mice do not see and movablely obviously reduces.This medicine does not have obvious influence to the mice coordination of function.The pentobarbital sodium of each dosage group of Danhong for injection and sub-threshold dose does not have synergism.This medicine high dose group extremely significantly reduces spontaneous activity in mice number of times (P＜0.01), in, low dose group is to not obviously influence (P＞0.05) of spontaneous activity in mice.
Three, acute toxicity testing
Danhong for injection intraperitoneal administration mice LD50 is 270.00g/kg, the 95% credible 229.35～317.86g/kg that is limited to.
Danhong for injection intravenously administrable mice LD50 is 151.88g/kg, the 95% credible 131.20～175.81g/kg that is limited to.
Four, rat long term toxicity test research
Danhong for injection 160g/kg, 80g/kg, 40g/kg (be equivalent to human dosage 80 times, 40 times, 20 times) crude drug intraperitoneal injection, once a day, successive administration three months, measure hematological indices, the blood biochemical index of animal in administration three months and convalescent period, and in experimentation, observe the general performance of animal, record food consumption and body weight change.Get 20,10 animals respectively in every group of administration three months and convalescent period and carry out system and become celestial, calculate organ index, and internal organs are carried out histopathology detect.
Experimental result shows that Danhong for injection does not all have obviously influence in administration three months and convalescent period to general performance, food-intake, body weight, organ index and organs and tissues of animal.
The Danhong for injection high dose group made basophilic leukocyte significantly reduce (P＜0.05) in three months in administration, but its value is still within normal range; Each dosage group administration three months and the every index value of other hematologys of convalescent period are compared no significant difference with matched group.Danhong for injection high dose group blood urea nitrogen significantly reduces (P＜0.05), creatinine extremely significantly raise (P＜0.01); In the dosage group extremely significantly reduce (P＜0.01) in three months millet straw transaminases of administration and alkali phosphatase, creatinine extremely significantly raise (P＜0.01); Blood urea nitrogen and creatinine significantly reduce (P＜0.05).Convalescent period the low dose group glutamate pyruvate transaminase and alkali phosphatase significantly reduce (P＜0.05); But its value is still within normal range.In addition, other every indexs of each group are compared equal no significant difference with matched group.
Five, Beagle dog long term toxicity test
Danhong for injection 120g/kg, 60g/kg, 30g/kg crude drug (be equivalent to human dosage 60 times, 30 times, 15 times), the intravenous drip administration, once a day, successive administration three months, before administration, administration three months and convalescent period electrocardiogram, hematological indices, the blood biochemical of measuring animal learn index and routine urinalysis index, and in experimentation, observe general performance and the body weight change of animal.Get 4,2 animals respectively in every group of administration three months and convalescent period and carry out system and become celestial, calculate organ index, and internal organs are carried out histopathology detect.Experimental result shows that Danhong for injection is learned general performance, electrocardiogram, food-intake, body weight, organ index and the organs and tissues of animal does not all have obviously influence.
The routine blood test index detects and shows, the Danhong for injection low dose group finishes basophil in administration and extremely significantly raises (P＜0.01), but its value is still within normal range.Other hematological indices numerical value in animal each period is compared equal no significant difference with matched group.Blood biochemistry index detects and shows, the Danhong for injection high dose group finishes blood glucose value in administration and significantly reduces (P＜0.05), but its value is still within normal range.Other biochemical indexes numerical value in animal each period is compared equal no significant difference with matched group.
Routine urinalysis detects and to show, matched group before administration, administration three months and convalescent period have 4,2,1 Beagle dogs to occur occulting blood respectively, urine protein do not occur; High dose group before administration, administration three months and convalescent period have 4,1,0 Beagle dogs to occur occulting blood respectively, urine protein do not occur; In the dosage group before administration, administration three months and convalescent period have 3,2,1 Beagle dogs to occur occulting blood respectively, urine protein do not occur; Low dose group before administration, administration three months and convalescent period have 5,4,1 Beagle dogs to occur occulting blood respectively, urine protein do not occur.The above results shows, before the administration, administration three months and convalescent period the appearance and the medicine of occulting blood do not have obvious dependency.The result shows that three dosage groups of Danhong for injection (high, medium and low dosage group) do not have obvious influence in administration three months and convalescent period to every routine urinalysis index of dog.
Six, anaphylaxis, hemolytic and the research of local irritation test
1, vein irritating test
With sterile working's method to rabbit right, left auricular vein instillation Danhong for injection and 5% glucose injection 10ml/kg, be administered once every day, continuous 3 times, the vein of not finding administration has tangible stimulation, the vein blood vessel of injectable drug and 5% glucose injection matched group structure compared are normal, do not see endothelial cell damage, thrombosis and other pathological changes.
1. hemolytic test
Danhong for injection does not have haemolysis and agglutination to tame rabbit erythrocyte when maximum concentration is the 0.06g/ml crude drug in test tube.
2. anaphylaxis experiment
Whether this experiment discussion Cavia porcellus has anaphylaxis to Danhong for injection.The result shows that under this experiment condition, Danhong for injection does not have sensitization to the animal subject Cavia porcellus.
3. models of passive skin irritability experiment
The experiment of Danhong for injection models of passive skin irritability shows, ovalbumin group generation passive cutaneous anaphylaxis, PCA, and passive cutaneous anaphylaxis, PCA (two groups of skin inner layer speckle averages are all less than 5mm) does not all take place in negative control group and Danhong for injection group.
2, muscular irritation test
4 of extracting waste rabbit, wherein sentence sterile working's method intramuscular injection injection injection with DANHONG (0.6g/ml crude drug) 2ml respectively at the and arranged on left and right sides quadriceps femoris for two, two rabbit are injected isometric(al) 5% glucose injection in contrast in addition, be administered once, medicine-feeding part is not seen obvious hyperemia, redness, degeneration, necrosis.
Claims (6)
1. a Danhong freez-fried powder injecta is characterized in that, component and parts by weight before the lyophilizing comprise:
0.1～10 part of the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami
0.001～10 part of excipient
0.01～5 part in water
The pH that makes the preceding solution of lyophilizing is 5.0～6.0 pH regulator agent;
Said excipient is an acceptable lyophilizing excipient commonly used arbitrarily on the galenic pharmacy;
The effective ingredient of said Radix Salviae Miltiorrhizae and Flos Carthami is to adopt the crude drug of following parts by weight to prepare:
1～5 part of Radix Salviae Miltiorrhizae, 1～5 part on Flos Carthami.
2. Danhong freez-fried powder injecta according to claim 1 is characterized in that, excipient is one or more the mixture in mannitol, lactose, sucrose, glucose or the dextran.
3. Danhong freez-fried powder injecta according to claim 1 is characterized in that, said pH regulator agent is selected from a kind of or its mixture in sodium hydroxide, sodium bicarbonate, sodium carbonate or hydrochloric acid, phosphoric acid, nitric acid, the sulphuric acid.
4. Danhong freez-fried powder injecta according to claim 2 is characterized in that, said pH regulator agent is selected from a kind of or its mixture in sodium hydroxide, sodium bicarbonate, sodium carbonate or hydrochloric acid, phosphoric acid, nitric acid, the sulphuric acid.
5. according to each described Danhong freez-fried powder injecta of claim 1～4, it is characterized in that the preparation method of the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami comprises the steps:
(1) gets Radix Salviae Miltiorrhizae and Flos Carthami two flavor medical materials, add the water of 5～15 times of amounts respectively, decocted 1～3 hour, filter;
(2) be concentrated into the clear paste that relative density is 1.10-1.20 (about 1.16), add weight concentration and be 80～95% ethanol, make to contain the alcohol amount and reach 75%, cold preservation 15～30 hours;
(3) filter, the clear paste that ethanol to relative density is 1.00-1.10 (about 1.06) is flung in evaporation, adds weight concentration and be 80～95% ethanol, makes to contain the alcohol amount and reach 80%, cold preservation 15～30 hours;
(4) filter, the clear paste that ethanol to relative density is 1.00-1.10 (about 1.06) is flung in evaporation, with weight concentration is that 10～50% sodium hydroxide is regulated pH to 8.5～9.5, boiled 0.5～2 hour, 1M hydrochloric acid is regulated pH to 5.5～6.5, filters, and the adding weight concentration is 80～95% ethanol, make and contain alcohol amount and reach 85%, cold preservation 15～30 hours;
(5) filter, the clear paste that ethanol to relative density is 1.10-1.20 (about 1.14) is flung in evaporation, adds the water of gross weight 75%, promptly obtains the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami.
6. the preparation method of Danhong freez-fried powder injecta according to claim 5 is characterized in that comprising the steps:
With weight concentration is the pH to 5.0-6.0 that the effective ingredient of Radix Salviae Miltiorrhizae and Flos Carthami is regulated in 2～50% pH regulator agent, adds excipient, dissolving, and moisturizing is to full dose, mixing is crossed doughnut microporous filter membrane (molecular cut off 1000～10000), degerming, fill, lyophilizing, gland promptly obtains product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105920096A (en) * | 2016-06-12 | 2016-09-07 | 南京中医药大学 | Composition with salviae miltiorrhiza and safflower as well as preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105920096A (en) * | 2016-06-12 | 2016-09-07 | 南京中医药大学 | Composition with salviae miltiorrhiza and safflower as well as preparation method and application thereof |
| CN105920096B (en) * | 2016-06-12 | 2020-05-08 | 南京中医药大学 | Composition of red sage root and safflower, preparation method and application thereof |
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