CN100586420C - Astragaloside injection and preparation method thereof - Google Patents
Astragaloside injection and preparation method thereof Download PDFInfo
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- CN100586420C CN100586420C CN200610008492A CN200610008492A CN100586420C CN 100586420 C CN100586420 C CN 100586420C CN 200610008492 A CN200610008492 A CN 200610008492A CN 200610008492 A CN200610008492 A CN 200610008492A CN 100586420 C CN100586420 C CN 100586420C
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Abstract
The invention relates to an injection using astragalus root glycosides extract as the active ingredient, which also comprises pharmaceutically acceptable adjunct for injection, the content of the astragalus root glycosides in the total astragalus root extract is 80-100%, each unit of the preparation contains astragalus root glycosides 90-300mg.
Description
Technical field
The present invention relates to a kind of astragaloside injection, particularly, is that Radix Astragali total glycosides is injection of being prepared from of active component and preparation method thereof, belongs to drug world.
Background technology
The virus myocarditis is one of clinical common heart disease, its sickness rate is obvious ascendant trend closely during the last ten years, increases nearly 10 times, often leaves over sequela (, cardiac insufficiency not normal as the rhythm of the heart) in various degree, the serious harm human health does not still have specific medicament at present.Therefore, it is very important and necessary carrying out new drug development and study at viral myocarditis.Modern medicine thinks, its cause of disease is due to the multiple viral infection, and most clinically viral myocarditis system is caused by Coxsackie virus and echo, enteric cytopathogenic human orphan virus.At viral myocarditis, the main at present medicine that promotes myocardial metabolism that adopts of actual clinical is as adenosine triphosphate, coenzyme A, inosine, cyclic adenosine monophosphate (cAMP), cytochrome C etc.
Chinese medicine astragalus derives from the root of leguminous plant Radix Astragali Astragalus membranaceus (Fisch.) Bge., Chinese medicine astragalus and Radix Astragali Chinese patent medicine product (comprising Radix Astragali injection and Radix Astragali oral formulations) have significant curative effect to the treatment and the auxiliary treatment of viral myocarditis, accept comparatively widely and adopt for the clinician.Simultaneously, along with to the deepening continuously of Radix Astragali medicineization, pharmacology and clinical research, can obtain Radix Astragali total glycosides by Chinese medicine astragalus extraction separation total glycosides.Existing a large amount of experiment and clinical researches confirms that fully the contained Radix Astragali total glycosides of the Radix Astragali is the main active of Radix Astragali treatment viral myocarditis.The existing certain antivirus action of Chinese medicine astragalus class preparation have many-sided pharmacological actions such as the immunity of adjusting, protecting myocardial cell, improvement and cardiac function enhancing again, thereby it has bigger advantage and potentiality aspect treatment of viral myocarditis.Clinical application practice and a large amount of modern pharmacological research fully confirm at all times, and Chinese medicine astragalus and extract Radix Astragali saponin thereof are the active drugs of clinical treatment viral myocarditis, and its curative effect is reliable, and the mechanism of action is clear and definite.
Present clinical use Radix Astragali injection mostly is Radix Astragali extract and makes, and adopts the venous transfusion administration, and wherein Astragaloside content is low, difference is big, and drug effect is wayward, and impurity is more, and untoward reaction is many after patient's medication; Before each clinical application, must use the sodium chloride solution prepared and diluted, thereby make troubles to clinical application, increase the opportunities for contamination of venous transfusion especially easily.Preparation astragaloside injection (small-volume injection, injectable powder, glucose infusion liquid and sodium chloride transfusion) is difficult for making Radix Astragali total glycosides content height, stability is high, clarity is good, impurity content is low, satisfactory preparation.Patent CN1481806 discloses the pharmaceutical composition of Radix Astragali saponin, astragalus polysaccharides, patent CN1481806 discloses the Radix Astragali total glycosides injection, adopt water carry-alcohol deposition method obtains Radix Astragali extract, wherein the content of effective ingredient Radix Astragali total glycosides is 5-50mg, the content of effective ingredient Radix Astragali total glycosides accounts for 30-90% in the Radix Astragali total extract, and needs to add cosolvent and help diluent; Patent CN 1515295 discloses Radix Astragali injection, is equivalent to 40g Radix Astragali crude drug/250ml, and the astragaloside amount is not less than 8mg/250ml; Patent CN1543976 astragaloside injection preparation and preparation method thereof, the weight concentration that discloses astragaloside in the astragaloside raw material is 90-100%, the content of astragaloside is 1-100mg in every bottle of injection, has also added cosolvent and has helped diluent.Add cosolvent in the injection and help diluent can increase the risk that side effect takes place, increase the risk of venous transfusion generation side effect especially easily.
Summary of the invention
Technical scheme of the present invention has provided a kind of astragaloside injection, and another technical scheme of the present invention has provided the preparation method of this astragaloside injection.
The invention provides a kind of astragaloside injection, it is to be active component with the Radix Astragali total glycosides extract, does not contain cosolvent and helps diluent, adds pharmaceutically acceptable injection additive, the injection that is prepared from.
The content of effective ingredient Radix Astragali total glycosides accounts for 80-100% in the above-mentioned Radix Astragali total extract, and the content of total glycosides is that every preparation unit contains 90～300mg.
The percentage composition of described astragaloside accounts for the 6-50% of Radix Astragali total glycosides extract.Or the content of astragaloside is that every preparation unit must not be less than 20mg in the described injection.Described every preparation unit is meant by every bottled amount and limits, is 100ml/ bottle or 250ml/ bottle.
Wherein, the extracting method of described Radix Astragali total glycosides is:
A, Milkvetch Root is adopted decoction and alcohol sedimentation technique or alcohol dipping, percolation, collects percolate, concentrate, concentrated solution;
B, the concentrated solution of a step is added ethanol reach 50%-80%, leave standstill 0 ℃～5 ℃ cold preservations to containing the alcohol amount, 24～48 hours, filter, filtrate is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and cold preservation is left standstill, and 24～48 hours, filters; Get filtrate by macroporous adsorptive resins, be washed to closely colourlessly, use the Diluted Alcohol eluting, collect eluent, filter, reclaim ethanol and also be concentrated into and do not have the alcohol flavor, cold preservation is left standstill, and filters, and gets filtrate;
C, with the described filtrate of b step, add ethanol and reach 70%～95% to containing the alcohol amount, cold preservation is left standstill, and filters, and reclaims ethanol, boils, and filters, and promptly gets Radix Astragali total glycosides extract.
Wherein, described injection is: injectable powder, instillation, injection.
The pH value of described injection is: 5.5～7.5.
Described injection is to be prepared from by following weight proportion raw material extract and additives:
Radix Astragali total glycosides extract 1-5 part, injection are used additives 8-25 part.
Further, described injection additives are: isotonic agent: pH value regulator, described isotonic agent are a kind of or mixing in sodium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol or the levulose acid anhydride; Described pH value regulator is a kind of in hydrochloric acid, acetic acid, lactic acid, NaOH, sodium dihydrogen phosphate, sodium hydrogen phosphate, the sodium citrate.
Further, described injection is to be prepared from by following materials of weight proportions and additives:
Radix Astragali total glycosides extract 0.40-3.50 part, 9.00 parts in sodium chloride, 0.5 part of sodium dihydrogen phosphate.
The present invention also provides the preparation method of this astragaloside injection, and it comprises the steps:
A. Milkvetch Root is adopted decoction and alcohol sedimentation technique or alcohol dipping, percolation, collect percolate, concentrate, get concentrated solution;
B, the concentrated solution of a step is added ethanol reach 60%-70% to containing the alcohol amount, leave standstill 0 ℃ of-5 ℃ of cold preservation, filter, filtrate is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and cold preservation is left standstill, and filters; Get filtrate by macroporous adsorptive resins, be washed to closely colourlessly, use ethanol elution, collect eluent, filter, reclaim ethanol and also be concentrated into and do not have the alcohol flavor, cold preservation is left standstill, filtration; Add ethanol and reach 80%-90% to containing the alcohol amount, cold preservation is left standstill, and filters; Reclaim ethanol, boil, filter, promptly get Radix Astragali total glycosides extract;
C, to get Radix Astragali total glycosides, sodium chloride and sodium dihydrogen phosphate an amount of, adds the injection water to 200-800ml, adds the 0.1%-0.2% active carbon, boil 30 minutes after, filter, add the injection water, transfer pH to 7.2-8.2, ultrafiltration with saturated sodium hydroxide solution to 1000ml, embedding, sterilization, check, promptly.
PH value might slowly descend and pH value influences clarity in long-term put procedure, and adjust pH is 7.2-8.2 before sterilization, to increase preparation stability.
Wherein, the used macroporous resin of step b is nonpolar or/and the low pole macroporous adsorbent resin, and model is the macroporous adsorbent resin of HPD100A, HPD700, LD140 and other types, or the macroporous adsorbent resin of above different model mixes by a certain percentage.The used ultrafilter membrane of step c is 5000-10000 dalton.
Particularly, Radix Astragali total glycosides of the present invention is to be prepared from by following method:
1. the extraction of Radix Astragali total glycosides
A. get Milkvetch Root, decoct with water three times, merge decoction liquor, filter, filtrate decompression is concentrated into no ethanol, gets Radix Astragali concentrated solution, and proportion is 1.15-1.25,60 ℃ of surveys;
B. get the Milkvetch Root coarse powder, Diluted Alcohol is a solvent, floods percolation after 24 hours, collects percolate, and filtrate decompression is concentrated into no ethanol, gets Radix Astragali concentrated solution, and proportion is 1.15-1.25,60 ℃ of surveys.
2. Radix Astragali total glycosides is refining
Above-mentioned Radix Astragali concentrated solution is added ethanol reach 50%-80% to containing alcohol amount, left standstill 24-36 hour 0 ℃ of-5 ℃ of cold preservation, filter, filtrate recycling ethanol also is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and cold preservation was left standstill 24-36 hour, filtered.Get filtrate by macroporous adsorptive resins, be washed to closely colourlessly, use the Diluted Alcohol eluting, collect eluent, filter, reclaim ethanol and also be concentrated into and do not have the alcohol flavor, cold preservation was left standstill 24-36 hour, filtration; Add ethanol and reach 70%-90% to containing the alcohol amount, cold preservation was left standstill 24-36 hour, filtered; Reclaim ethanol, boiled 30 minutes, add water to 1000ml, sealing, cold preservation filtered more than 24 hours, check, promptly.
3. the preparation of Radix Astragali total glycosides injection
It is an amount of to get Radix Astragali total glycosides, sodium chloride and sodium dihydrogen phosphate, adds the injection water to 200-800ml, adds the 0.1%-0.2% active carbon, boil 30 minutes after, filter, add the injection water, transfer pH to 7.2-8.2, ultrafiltration with saturated sodium hydroxide solution to 1000ml, embedding, sterilization, check, promptly.
The present invention also provides the application of this astragaloside injection in preparation treatment viral myocarditis, heart failure drugs.
Every bottle of Radix Astragali total glycosides content of Radix Astragali total glycosides injection of the present invention height is (in every preparation unit, 100ml/ bottle or 250ml/ bottle, the content of effective ingredient astragaloside must not be less than 20mg, the content of total glycosides is 90～300mg), quality controllable, stability high (commercially available back stability was greater than 2 years), and clarity is good, do not contain cosolvent and help diluent, the risk that side effect takes place is low, for the clinical treatment viral myocarditis provides a kind of more convenient effectively Chinese medicine preparation, satisfies the needs of clinical application.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
Further specify content of the present invention below in conjunction with embodiment:
Embodiment 1 Radix Astragali total glycosides injection 1 preparation method of the present invention:
Milkvetch Root meets pertinent regulations under first 249 pages of Radix Astragali item of Chinese Pharmacopoeia version in 2000, and astragaloside detects according to high performance liquid chromatography in the Milkvetch Root, and Milkvetch Root contains astragaloside (C
41H
68O
14) must not be less than 0.06%.
Get 500 kilograms of Radix Astragali decoction pieces (2-4mm sheet, produce in the Inner Mongol), add 8 times of amounts of water and decoct three times, each 1.5 hours, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum :-0.08Mpa) to relative density be 1.15 (60 ℃ of surveys), reach 80% with 95% ethanol precipitation to containing alcohol amount, cold preservation was left standstill 24 hours, filtered, and got filtrate recycling ethanol and be concentrated into every milliliter to be equivalent to 0.75 gram crude drug, cold preservation was left standstill 48 hours, filtered.Get filtrate by the LD140 macroporous adsorptive resins, be washed to closely colourlessly, use 80% ethanol elution, collect eluent, filter, reclaiming ethanol and being concentrated into relative density is 1.25 (60 ℃ of surveys), and cold preservation was left standstill 28 hours, filtration; Add 95% ethanol and reach 90% to containing the alcohol amount, cold preservation was left standstill 36 hours, filtered; Reclaim ethanol, boiled 30 minutes, add water to 50 liters, sealing, cold preservation filtered more than 24 hours, check, promptly.
Get 13 liters of Radix Astragali total glycosidess, 9.0Kg sodium chloride and 500 gram sodium dihydrogen phosphate, add injection water to 400 liter, add 0.08% active carbon, boil 30 minutes after, filter, add injection water to 1000 liter, transfer pH to 7.2, filtration with saturated sodium hydroxide solution, embedding is the 250ml/ bottle, sterilization, check, promptly.
Embodiment 2 Radix Astragali total glycosides injection 2 preparation methoies of the present invention:
Get 500 kilograms of Radix Astragali decoction pieces (2-4mm sheet, is produced from Shaanxi Province), add 12 times of amounts of water and decoct 2 times, each 2 hours, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum :-0.08Mpa) to relative density be 1.25 (60 ℃ of surveys), reach 90% with 95% ethanol precipitation to containing alcohol amount, cold preservation was left standstill 27 hours, filtered, and got filtrate recycling ethanol and be concentrated into every milliliter to be equivalent to 0.75 gram crude drug, cold preservation was left standstill 36 hours, filtered.Get filtrate by the HPD700 macroporous adsorptive resins, be washed to closely colourlessly, use 80% ethanol elution, collect eluent, filter, reclaiming ethanol and being concentrated into relative density is 1.15 (60 ℃ of surveys), and cold preservation was left standstill 24 hours, filtration; Add 95% ethanol and reach 80% to containing the alcohol amount, cold preservation was left standstill 24 hours, filtered; Reclaim ethanol, boiled 30 minutes, add water to 50 liters, sealing, cold preservation filtered more than 24 hours, check, promptly.
Get 25.4 liters of Radix Astragali total glycosidess, 9Kg sodium chloride and 500 gram sodium dihydrogen phosphate, add injection water to 400 liter, add 0.10% active carbon, boil 30 minutes after, filter, add injection water to 1000 liter, transfer pH to 7.5, filtration with saturated sodium hydroxide solution, embedding is the 250ml/ bottle, sterilization, check, promptly.
Embodiment 3 Radix Astragali total glycosides injection 3 preparation methoies of the present invention:
Get 500 kilograms of Radix Astragali decoction pieces (2-4mm sheet, is produced from the Shanxi Province), add 8 times of amounts of water and decoct three times, each 1.5 hours, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum :-0.08Mpa) to relative density be 1.25 (60 ℃ of surveys), reach 65% with 95% ethanol precipitation to containing alcohol amount, cold preservation was left standstill 27 hours, filtered, and got filtrate recycling ethanol and be concentrated into every milliliter to be equivalent to 0.75 gram crude drug, cold preservation was left standstill 24 hours, filtered.Get filtrate by the LD140 macroporous adsorptive resins, be washed to closely colourlessly, use 75% ethanol elution, collect eluent, filter, reclaiming ethanol and being concentrated into relative density is 1.20 (60 ℃ of surveys), and cold preservation was left standstill 28 hours, filtration; Add 95% ethanol and reach 85% to containing the alcohol amount, cold preservation was left standstill 36 hours, filtered; Reclaim ethanol, boiled 30 minutes, add water to 50 liters, sealing, cold preservation filtered more than 24 hours, check, promptly.
Get 95 liters of Radix Astragali total glycosidess, 8.1Kg sodium chloride and 450 gram sodium dihydrogen phosphate, add injection water to 300 liter, add 0.12% active carbon, boil 30 minutes after, filter, add injection water to 900 liter, transfer pH to 7.9, filtration with saturated sodium hydroxide solution, embedding is the 100ml/ bottle, sterilization, check, promptly.
Embodiment 4 Radix Astragali total glycosides injection 4 preparation methoies of the present invention:
Get 500 kilograms of Radix Astragali decoction pieces (2-4mm sheet, the Gansu south of Gansu Province produces) (section), add 10 times of amounts of water and decoct three times, each 1 hour, merge decoction liquor, filter, filtrate decompression concentrates (temperature: 70 ℃; Vacuum :-0.08Mpa) to relative density be 1.15 (60 ℃ of surveys), reach 60% with 95% ethanol precipitation to containing alcohol amount, cold preservation was left standstill 27 hours, filtered, and got filtrate recycling ethanol and be concentrated into every milliliter to be equivalent to 0.75 gram crude drug, cold preservation was left standstill 24 hours, filtered.Get filtrate by the D101 macroporous adsorptive resins, be washed to closely colourlessly, use 80% ethanol elution, collect eluent, filter, reclaiming ethanol and being concentrated into relative density is 1.15 (60 ℃ of surveys), and cold preservation was left standstill 28 hours, filtration; Add 95% ethanol and reach 85% to containing the alcohol amount, cold preservation was left standstill 36 hours, filtered; Reclaim ethanol, boiled 30 minutes, add water to 50 liters, sealing, cold preservation filtered more than 24 hours, check, promptly.
Get 40 liters of Radix Astragali total glycosidess, 8.1Kg sodium chloride and 450 gram sodium dihydrogen phosphate, add injection water to 300 liter, add 0.15% active carbon, boil 30 minutes after, filter, add injection water to 900 liter, transfer pH to 7.9, filtration with saturated sodium hydroxide solution, embedding is the 100ml/ bottle, sterilization, check, promptly.
The detection of astragaloside, Radix Astragali total glycosides in the embodiment 5 Radix Astragali total glycosides injection of the present invention:
In order to control the quality of the pharmaceutical preparations, astragaloside adopts high performance liquid chromatography-evaporat light scattering method to detect; Radix Astragali total glycosides adopts ultraviolet spectrophotometry to detect, with astragaloside (C
41H
68O
14) meter.
The content of Radix Astragali total glycosides, astragaloside in the table 1 Radix Astragali total glycosides extract injection of the present invention
| Embodiment | Radix Astragali total glycosides content % in the extract | Radix Astragali total glycosides mg/ bottle in the injection | Astragaloside content % in the injection |
| Embodiment 1 | 95.0 | 97 | 42.3 |
| Embodiment 2 | 86.4 | 189 | 35.3 |
| Embodiment 3 | 89.1 | 285 | 9.5 |
| Embodiment 4 | 81.6 | 122 | 24.7 |
Prepare test sample by crude drug, Radix Astragali total glycosides and finished product test sample preparation method respectively.Other gets the astragaloside reference substance, adds methanol and makes the solution that every 1ml contains 1mg, in contrast product solution.Lower floor's solution with chloroform-methanol-water (volume ratio 13: 7: 2) is developing solvent, and spray is with 10% ethanol solution of sulfuric acid, dries by the fire to speckle at 105 ℃ and develops the color.Three's collection of illustrative plates basically identical illustrates that this technology has kept astragaloside homologue in the Milkvetch Root to greatest extent.The dissolubility of astragaloside homologue in water is far longer than astragaloside, and the dissolubility in water greatly in pharmacy advantage be conspicuous.
Embodiment 6 Radix Astragali total glycosides injection of the present invention are investigated the result:
Carried out examine stability by three batch samples that embodiment 1-4 method system makes, result of the test shows that the quality of the pharmaceutical preparations is stable in 2 years, is to investigate the result by three batch samples that make by embodiment 4 method systems (1,2, No. 3 sample) below:
The investigation result of No. 1 sample of table 2
| Period of storage | Character | Differentiate | Clarity | PH value | Aseptic | Pyrogen | Haemolysis | Zest | Astragaloside content (mg/ml) |
| 0 month | Light yellow clear liquid | + | ∨ | 6.68 | ∨ | ∨ | ∨ | ∨ | 0.3014 |
| January | Light yellow clear liquid | + | ∨ | 6.65 | ∨ | ∨ | ∨ | ∨ | 0.3015 |
| February | Light yellow clear liquid | + | ∨ | 6.66 | ∨ | ∨ | ∨ | ∨ | 0.3021 |
| March | Light yellow clear liquid | + | ∨ | 6.63 | ∨ | ∨ | ∨ | ∨ | 0.3034 |
| June | Light yellow clear liquid | + | ∨ | 6.62 | ∨ | ∨ | ∨ | ∨ | 0.3046 |
| 24 months | Light yellow clear liquid | + | ∨ | 6.60 | ∨ | ∨ | ∨ | ∨ | 0.3052 |
+-be positive reaction, ∨-expression is up to specification
The investigation result of No. 2 samples of table 3
| Period of storage | Character | Differentiate | Clarity | PH value | Aseptic | Pyrogen | Haemolysis | Zest | Astragaloside content (mg/ml) |
| 0 month | Light yellow clear liquid | + | ∨ | 6.71 | ∨ | ∨ | ∨ | ∨ | 0.3070 |
| January | Light yellow clear liquid | + | ∨ | 6.69 | ∨ | ∨ | ∨ | ∨ | 0.3065 |
| February | Light yellow clear liquid | + | ∨ | 6.69 | ∨ | ∨ | ∨ | ∨ | 0.3064 |
| March | Light yellow clear liquid | + | ∨ | 6.73 | ∨ | ∨ | ∨ | ∨ | 0.3068 |
| June | Light yellow clear liquid | + | ∨ | 6.68 | ∨ | ∨ | ∨ | ∨ | 0.3052 |
| 24 months | Light yellow clear liquid | + | ∨ | 6.65 | ∨ | ∨ | ∨ | ∨ | 0.3055 |
The investigation result of No. 3 samples of table 4
| Period of storage | Character | Differentiate | Clarity | PH value | Aseptic | Pyrogen | Haemolysis | Zest | Astragaloside content (mg/ml) |
| 0 month | Light yellow clear liquid | + | ∨ | 6.85 | ∨ | ∨ | ∨ | ∨ | 0.3068 |
| January | Light yellow clear liquid | + | ∨ | 6.87 | ∨ | ∨ | ∨ | ∨ | 0.3065 |
| February | Light yellow clear liquid | + | ∨ | 6.84 | ∨ | ∨ | ∨ | ∨ | 0.3062 |
| March | Light yellow clear liquid | + | ∨ | 6.80 | ∨ | ∨ | ∨ | ∨ | 0.3078 |
| June | Light yellow clear liquid | + | ∨ | 6.87 | ∨ | ∨ | ∨ | ∨ | 0.3113 |
| 24 months | Light yellow clear liquid | + | ∨ | 6.83 | ∨ | ∨ | ∨ | ∨ | 0.3098 |
Below prove beneficial effect of the present invention by pharmacodynamics test.
Test example 1 drug injection of the present invention causes the therapeutic test of cat acute heart failure to pentobarbital sodium:
(Beijing tonneau animal feeding factory provides body weight to 2～4kg animal cat, the male and female dual-purpose) is divided into dosage and Radix Astragali total glycosides injection low dose in normal control group, positive drug group (cedilanid), the heavy dose of group of Radix Astragali total glycosides injection, the Radix Astragali total glycosides injection, 5 groups altogether, 7～8 every group.3% pentobarbital sodium (Beijing chemical reagents corporation, lot number 020402, be mixed with normal saline) lumbar injection 30mg/kg anesthesia, the jugular vein intubate is used for constant infusion 3% pentobarbital sodium, and femoral venous catheter is used for constant infusion and is subjected to the reagent thing, connect that electrocardiogram (ECG) limb is led, tracheal intubation, connection artificial respirator, respiratory frequency is 26 times/min, and tidal volume is 29～70ml, opens breast, left ventricular cannulation connects pressure transducer.ECG, left ventricular pressure (LVP) and left ventricular pressure differential (LVdp/dt) through Rm6240C bio signal acquisition processing system continuous record in computer.Every numerical value of stablizing 30 minutes behind the animal surgery is as the arm's length basis value.
With the maximum climbing speed (LVdp/dt of left ventricular pressure
Max) as the myocardial contractility index, behind vein constant infusion 3% pentobarbital sodium, LVdp/dt
MaxDescend gradually, when dropping to 26.6～66.5kPa (200～500mmHg), 5min does not have the tendency of rising, be considered as forming acute heart failure, vein constant infusion 0.2ml/min is subjected to the reagent thing then, blank group instillation normal saline, positive drug group instillation deacetyllanatoside injection (cedilanid, Shanghai Xudong Hipu Medicine Co., Ltd, lot number 010901, face with preceding be diluted to desired concn with physiological saline solution) 0.1mg/ml, Radix Astragali total glycosides (Radix Astragali total glycosides injection, make by embodiment 4) heavy dose of 12g medical material/ml, dosage 1g medical material/ml in the Radix Astragali total glycosides injection, the low dose of 0.5g medical material/ml of Radix Astragali total glycosides injection.
After 3% pentobarbital sodium constant speed intravenous injection causes the cat heart failure, three concentration of constant speed intravenous injection Radix Astragali total glycosides (12g crude drug/ml, 1g crude drug/ml, the 0.5g crude drug/ml), cedilanid 0.1mg/ml and normal saline matched group, the maximum rising difference of LVSP and LVdp/dtmax sees Table 5.
The quiet influence of annotating front and back of table 5 Radix Astragali total glycosides constant speed to heart failure cat LVdp/dtmax and the maximum rising difference of LVSP
Annotate: with normal saline matched group ratio
*P＜0.05.
As seen from Table 5, cause the cat acute heart failure with 3% pentobarbital sodium, Radix Astragali total glycosides concentration 0.5g medical material/ml constant speed injection 0.2ml/min, the ascensional range of the maximum climbing speed of left ventricular pressure peak value (LVSP) and left ventricular pressure (LVdp/dtmax) is higher than normal saline matched group (P＜0.05), and the significant prolongation animals survived time (P＜0.01).Radix Astragali total glycosides 1g crude drug/ml concentration constant speed injection 0.2ml/min, the amplitude that heart failure cat LVSP and LVdp/dtmax rise and normal saline matched group are than no marked difference (P＞0.05), but the significant prolongation animals survived time (P＜0.01).Radix Astragali total glycosides 12g crude drug/ml does not all have obvious influence (P＞0.05) to LVSP, LVdp/dtmax and animals survived time.Therapeutic dose, toxic dose, lethal dose, treatment width, therapeutic index.
1. therapeutic dose: LVdp/dt
MaxRise to 1/2 o'clock cumulant of peak effect; 2. toxic dose: with the arrhythmia that occurs taking place frequently is index, calculates cumulant; 3. lethal dose: the cumulant during electrocardiogram disappearance 10s; 4. treat width=toxic dose/therapeutic dose; 5. therapeutic index=lethal dose/therapeutic dose.The results are shown in Table 6.
The quiet notes of table 6 Radix Astragali total glycosides constant speed are to the influence of heart failure cat therapeutic dose, toxic dose, lethal dose, treatment width, therapeutic index
Annotate: the normal saline group can't be obtained therapeutic dose, Radix Astragali total glycosides (the Radix Astragali total glycosides injection is made by embodiment 4) 1.0g/ml, and 12g/ml group and normal saline group are than no obvious therapeutic action.With normal saline matched group ratio
*P＜0.01,
* *P＜0.001.With the cedilanid group than #P＜0.05, ##P＜0.01, ###P＜0.001.
As seen from Table 6, Radix Astragali total glycosides 0.5g/ml group, 1.0g/kg group lethal dose are significantly higher than normal saline matched group (P＜0.01).The therapeutic index of Radix Astragali total glycosides 0.5g/ml group is significantly higher than cedilanid group (P＜0.05).
The more living normal saline matched group of the maximum ascensional range of Radix Astragali total glycosides 0.5g medical material/ml concentration constant speed intravenous drip 0.2ml/min LVSP and LVdp/dtmax significantly raise (P＜0.05).Prolong the animals survived time (P＜0.001) with normal saline group, cedilanid group than highly significant.Radix Astragali total glycosides 0.5g medical material/ml concentration group therapeutic index is significantly higher than cedilanid group (P＜0.05).
Radix Astragali total glycosides 1g medical material/ml concentration constant speed intravenous drip 0.2ml/min and instillation normal saline group specific energy highly significant prolong the animals survived time (P＜0.01).
Radix Astragali total glycosides does not have obvious influence at 0.5g medical material/ml, 1.0g medical material/ml, 12.0g medical material/ml concentration constant infusion and normal saline group comparison cat heart rate.
Radix Astragali total glycosides injection hypersensitive test result shows that administration does not cause the Cavia porcellus systemic anaphylaxis.Hemolytic test does not find that the Radix Astragali total glycosides injection has haemolysis.Test shows that the rabbit vein blood vessel is not had obvious irritation to the Radix Astragali total glycosides injection to the rabbit vein blood vessel irritation.
Test example 2 drug injection interior therapeutic mice CV B of the present invention
3The myocarditis test
Mice CVB
3The foundation of myocarditis model
BALB/C mice (in 6 ages in week, body weight 16-18g/ is only provided the animal quality certification by West China Center of Medical Sciences management of laboratory animal center: No. the 75th, the real kinoplaszm pipe in (1996) river) 10 every group, and totally three groups.Adopt 10 respectively
-2/ ml, 10
-4/ ml and 10
-6The CV B of three concentration of/ml
3Virus liquid injects mouse peritoneal, and 0.2ml/.Heart rate, survival condition and the myocardial pathology of observing mice on the 7th day detect, and determine injection CV B
3ID
50Be 10
-4/ ml virus liquid 0.2ml can cause typical mice viral myocarditis.
Radix Astragali total glycosides treatment mice CV B
3The myocarditis test
Being divided into is six experimental grouies: (1) normal control group, 10, do not do any processing; (2) infection group and viral infection group, 20, the abdominal cavity injects CV B
310
-4/ ml 0.2ml, not medication; (3) Radix Astragali total glycosides experimental group A:20 only injects CVB
30.2ml behind the 2h, with 0.63g/ml Radix Astragali total glycosides (the Radix Astragali total glycosides injection is made by embodiment 4), the 0.1ml/10g body weight; (4) Radix Astragali total glycosides experimental group B:20 only injects CV B
30.2ml behind the 2h, use the 1.25g/ml Radix Astragali total glycosides, the 0.1ml/10g body weight; (5) Radix Astragali total glycosides experimental group C:20 only injects CV B
30.2ml behind the 2h, use the 2.5g/ml Radix Astragali total glycosides, the 0.1ml/10g body weight; (6) medicine matched group, injects CV B by 10
30.2ml behind the 2h, inject virazole 0.1g/kg, once a day.
At the 8th day, get mouse orbit blood, separation of serum is for detecting serum paraoxonase creatine phosphate kinase (CK), lactic acid deaminase (LDH) and virucidin.After putting to death mice, weigh, it is dirty to core.
The Radix Astragali total glycosides of iv various dose is to CV B continuously
3The influence of myocarditis mouse heart weight and heart surface pathological changes the results are shown in Table 7.
Table 7 Radix Astragali total glycosides is to the influence of myocarditis mouse heart weight and heart surface pathological changes (X ± S)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01.
As seen from Table 7, normal control group mice and model group mouse heart weight, there were significant differences for coefficient ratio (p＜0.01), model group mice weight loss, and the normal group body weight is weightening finish, there were significant differences for both, and no petechia, surface, shows that mice viral myocarditis model is reliable.Continuously iv Radix Astragali total glycosides 6.3,12.5,25g (crude drug)/kg.d are 7 days, the cardiac weight of three kinds of dosage Radix Astragali total glycosides mices, coefficient, petechia, ecchymosis all have obvious inhibition than model group as a result, body weight is also significantly increased (p＜0.01) than model group, show that Radix Astragali total glycosides is to CV B
3Causing the mice viral myocarditis has remarkable inhibitory action, and showing has good protective action to mouse heart.The power of protective effect and iv dosage have tangible dose dependent.
The Radix Astragali total glycosides of iv various dose is to CV B continuously
3The influence of myocarditis mice serum CK and LDH enzymatic activity the results are shown in Table 8.
Table 8 Radix Astragali total glycosides is to CK in the myocarditis mice serum, the LDH enzymatic activity (influence of X ± SD)
Annotate: compare with model group,
*P＜0.05,
*P＜0.01.
As seen from Table 8, the CK and the LDH of model group all significantly raise than normal group, and p is all less than 0.01.Show CV B
3Myocarditis can cause that CK, LDH significantly raise, and CK, LDH of each group of Radix Astragali total glycosides all have remarkable reduction than model group, shows that continuous iv Radix Astragali total glycosides can stop CK, LDH due to the myocarditis virus to raise.
The Radix Astragali total glycosides of iv various dose is to CV B continuously
3CV in myocarditis mice serum neutralizing antibody and the myocardial cell
3The influence of titre the results are shown in Table 9.
Table 9 Radix Astragali total glycosides is to mice serum neutralizing antibody and CV B
3The influence of titre
Annotate: compare with model group, when neutralizing antibody or titre difference reach 4 times, show diagnostic significance, i.e. p＜0.01.
As seen from Table 9, all do not find neutralizing antibody and CV B in the serum of normal group
3Virus, and the neutralizing antibody of model group and titre were respectively 1: 32,1: 16, showed CV
3Virus causes CV B in the neutralizing antibody of myocarditis mice and the myocardial cell
3Raise, the middle and high dosage group of Radix Astragali total glycosides in and antibody suppress equal highly significant (p＜0.01), the Radix Astragali total glycosides of three kinds of dosage is to myocardium CV B
3Titre suppresses equal highly significant.Show neutralizing antibody and the myocardial cell CV B of Radix Astragali total glycosides to the myocarditis mice
3Good regulating action is arranged.
The Radix Astragali total glycosides of iv various dose is to mice CV B continuously
3The influence of myocarditis cardiac muscle pathological tissue integration the results are shown in Table 10.
Table 10 Radix Astragali total glycosides is to the influence of mouse cardiac muscle pathological tissue integration
Annotate: compare with model group,
*P＜0.05,
*P＜0.01.
As known from Table 10, continuous iv Radix Astragali total glycosides 6.3,12.5,25g (crude drug)/kg.d are to CV B
3Myocarditis mice pathology integration (inflammatory infiltration and necrosis) has significant inhibition, shows that Radix Astragali total glycosides has good protective action to the pathology damage that myocarditis causes mice.
Can reduce serum paraoxonase creatine phosphate kinase, lactic acid deaminase level and neutralizing antibody with Radix Astragali total glycosides treatment mice coxsackie myocarditis, reduce the virus titer of myocardial cell, alleviate the damage of virus myocardial cell.Show that Radix Astragali total glycosides has lethal effect to Coxsackie virus, myocardial cell is had the better protect effect.
In vivo test shows: to infecting CV B
3The Radix Astragali total glycosides 6.3,12.5 of viral myocarditis BALB/C mice iv various dose, 25g (crude drug)/kg.d, continuous 7 days, CV B in the serum CK of myocarditis mice, LDH, neutralizing antibody, heart coefficient, the myocardial cell as a result
3Titre and inflammatory infiltration area degree of necrosis, with model group than p all less than 0.01, show that Radix Astragali total glycosides has anti-preferably CV B
3Due to the viral myocarditis effect.
Test example 3 toxicology tests
The median lethal dose(LD 50) that tail vein injection gives the mice Radix Astragali total glycosides is 184.2g (crude drug)/kg.Radix Astragali total glycosides rat long term toxicity test shows: in 7 weeks of administration, low dose group increases RBC number, content of hemoglobin and the packed cell volume of rat, blood glucose significantly increases, and all the other hematologys of each administration group, biochemical indexes are no abnormal.Do not find macroscopic pathological change when dissecting animal, organ coefficient is normal substantially, the pathologic finding well afoot.
The dog long term toxicity test shows: the symptom of scratching where it itches significant emesis appears and in middle and high dosage treated animal of administration initial stage, and the symptom of scratching where it itches is very fast disappearance after administration, and symptoms of emesis no longer appears in the most of animal in two week backs.Except that high, middle dosage cause that blood glucose reduces, blood parameters be there is no obvious influence.
From last data Radix Astragali total glycosides of the present invention as can be seen treat that the effective dose of viral myocarditis mice is 0.25,0.125,0.063g/kg days, and document: Chinese Journal of New Drugs and Clinical Remedies in JIUYUE, 2003,22 (9): 515-519, the report astragaloside is treated effective dose 0.5g/kg days of mouse core myositis mice, and 0.056g/kg days, treatment mouse core myositis mice was invalid in 0.17g/kg days.The effective dose of astragaloside treatment mouse core myositis is greater than Radix Astragali total glycosides as can be seen.Astragaloside homologue has synergistic function the viral myocarditis mice of treatment in the proof Radix Astragali total glycosides.
By the control of above-mentioned formulation parameters and the mensuration of medicine stability of the present invention, prove that injection of the present invention is not containing cosolvent and helping under the situation of diluent, can reach the prescription of preparation equally, common practise according to those skilled in the art, the selection of adjuvant is very big to the Safety Effect of preparation, the cosolvent in the injection and help diluent to cause allergy easily particularly, therefore, the resulting astragaloside injection of technical scheme of the present invention has reached beyond thought beneficial effect, do not contain cosolvent in its additives and help diluent, be that special nature by Radix Astragali total glycosides extract of the present invention is determined, prove by pharmacodynamics test, in the raw extract in the Radix Astragali total glycosides astragaloside homologue brought into play the effect of Synergistic, provide a kind of safer for clinical, the effectively new selection of treatment viral myocarditis drug injection.
Claims (4)
1, a kind of astragaloside injection, it is characterized in that: it is to be active component with the Radix Astragali total glycosides extract, do not contain cosolvent and help diluent, add pharmaceutically acceptable injection additive, the injection that is prepared from, wherein, the content of effective ingredient Radix Astragali total glycosides accounts for 80-100% in the described Radix Astragali total glycosides extract, and the content of Radix Astragali total glycosides is 90～300mg in every preparation unit; The content of astragaloside accounts for 6-50% in the described Radix Astragali total glycosides extract; The content of astragaloside is no less than 20mg in every preparation unit; Described every preparation unit is: 100ml/ bottle or 250ml/ bottle;
Wherein, the extracting method of Radix Astragali total glycosides extract is:
A, with Chinese medicine astragalus, decoct with water, merge decoction liquor, concentrating under reduced pressure, Radix Astragali concentrated solution;
B, the concentrated solution of a step is added ethanol reach 50%-80%, leave standstill 0 ℃～5 ℃ cold preservations to containing the alcohol amount, 24～48 hours, filter, filtrate is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and cold preservation is left standstill, and 24～48 hours, filters; Get filtrate by nonpolar or/and low pole macroporous adsorptive resins, be washed to closely colourlessly, the Diluted Alcohol eluting with 75% or 80% is collected eluent, filters, and reclaims ethanol and also is concentrated into and does not have the alcohol flavor, and cold preservation is left standstill, and filters, and gets filtrate;
C, with the described filtrate of b step, add ethanol and reach 70%-95% to containing the alcohol amount, cold preservation is left standstill, and filters, and reclaims ethanol, boils, and filters, and promptly gets Radix Astragali total glycosides extract;
Described injection is instillation or injection;
Described injection is to be prepared from by following weight proportion raw material extract and additives:
Radix Astragali total glycosides extract 0.4-3.5 part, 9.0 parts of isotonic agents, 0.5 part of pH value regulator; Wherein, described isotonic agent is a sodium chloride; Described pH value regulator is a sodium dihydrogen phosphate.
2, astragaloside injection according to claim 1 is characterized in that: the pH value of described injection is: 7.2～8.2.
3, a kind of method for preparing the described astragaloside injection of claim 1, it comprises the steps:
A, Milkvetch Root is adopted decoction and alcohol sedimentation technique, concentrating under reduced pressure, concentrated solution;
B, the concentrated solution of a step is added ethanol reach 50%-80% to containing the alcohol amount, left standstill 24～48 hours 0 ℃～5 ℃ cold preservations, filter, filtrate is concentrated into every milliliter and is equivalent to 0.5-1.0 gram crude drug, and cold preservation was left standstill 24～48 hours, filtered; Get filtrate by nonpolar or/and low pole macroporous adsorptive resins, be washed to closely colourlessly, the Diluted Alcohol eluting with 75% or 80% is collected eluent, filters, and reclaims ethanol and also is concentrated into and does not have the alcohol flavor, and cold preservation is left standstill, and filters, and gets filtrate; Add ethanol and reach 70%-95% to containing the alcohol amount, cold preservation is left standstill, and filters, and reclaims ethanol, boils, and filters, and promptly gets Radix Astragali total glycosides extract;
C, get Radix Astragali total glycosides, isotonic agent, pH regulator agent, add the injection water, add the active carbon of water for injection total amount 0.1%-0.2%, boil 30 minutes after, filter, transfer pH to 7.2-8.2, ultrafiltration, embedding, sterilization, check, promptly.
4, the preparation method of astragaloside injection according to claim 3, it is characterized in that: it is nonpolar or/and the low pole macroporous adsorbent resin that the used macropore of step b is inhaled resin, and model is a kind of or its mixing among D101, HPD100A, HPD700, the LD140.
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| CN103385913B (en) * | 2013-07-18 | 2015-04-15 | 成都标典生物科技开发有限公司 | Radix Astragali extract and its preparation method and preparation |
| CN105560173B (en) * | 2015-12-29 | 2019-02-05 | 江苏九旭药业有限公司 | A kind of high stability astragalus injection and preparation method thereof |
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