CN1430966A - Medicine combination contg. effective part of astragalus root - Google Patents
Medicine combination contg. effective part of astragalus root Download PDFInfo
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- CN1430966A CN1430966A CN 03112649 CN03112649A CN1430966A CN 1430966 A CN1430966 A CN 1430966A CN 03112649 CN03112649 CN 03112649 CN 03112649 A CN03112649 A CN 03112649A CN 1430966 A CN1430966 A CN 1430966A
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- radix astragali
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Abstract
A composite medicine containing the active components of astragalus root is prepared from astragalosaponin, astraglose and medical carrier. Its advantage is high content of astragalosaponin.
Description
Technical field
The present invention relates to treat the pharmaceutical composition that contains Chinese medicine astragalus effective site of cardiovascular disease, be specially pharmaceutical composition, especially drip liquid that astragaloside, astragalus polysaccharides and pharmaceutical carrier or adjuvant are formed, also be called Radix Astragali drip liquid.
Background technology
The Radix Astragali is a Chinese medicine, is used for clinical have liquid drugs injection, oral liquid, tablets and other formulations at present.It mainly contains Saponin, polysaccharide, contains compositions such as aminoacid, flavone in addition.Astragaloside and polysaccharide have the myocardium shrinkage function of improvement to the anxious Terrier heart, dwindle myocardial infarction area, alleviate the effect of myocardial damage.Astragalus polysaccharides also has significant protective effect to the rat heart muscle ischemia that pituitrin causes, can obviously resist BaCl
2Rat ventricular that brings out and CHCl
3Quivering in the mice chamber of bringing out, can improve platelet adhesion rate, decreasing heart rate; Hematodinamics studies show that microcirculation is had certain improvement effect.The Sanitation Ministry medicine standard " Radix Astragali injection " (small-volume injection) (WS
3-point out in B-3335-98) its have Yiqiyangyuan, strengthening vital QI to eliminate pathogenic factors, nourish heart promote blood circulation, the function of invigorating spleen to remove dampness.Can be used for that the motive is deficient, the treatment of the hepatitis of the viral myocarditis of blood-vessel obstructive, cardiac insufficiency and stagnation of dampness due to deficiency of the spleen.
The existing little pin of the commercially available Radix Astragali only contains Saponin in the Radix Astragali injection as Chengdu buchu, the production of Fuda, Shanghai, does not contain polysaccharide, and adopts the decocting in water alcohol deposition method to extract the Saponin constituents, and the content of active ingredient astragaloside is on the low side.Because Saponin is a water soluble ingredient, general preparation method all adopts the decocting in water alcohol deposition method, but impurity is very many in the aqueous extract, for content and the purity that improves astragaloside, often need to handle (referring to CN1283482A, CN1330082A) with n-butanol extraction and resin column.Medicinal n-butyl alcohol price is expensive, and resin column just need carry out Regeneration Treatment after with a period of time, and these factors have not only increased production cost, need corresponding apparatus, and has increased processing step and operation requirement, therefore is unfavorable for the suitability for industrialized production of formulation of astragalus root.
Be Radix Astragali small injection to be added in the glucose injection of 100-500ml or the sodium chloride injection dilute clinically always, use through intravenous drip again, because the liquid of getting before instiling mixes, not only formality is loaded down with trivial details, and be subjected to the pollution of environment, apparatus easily, user produce infusion reaction as have a fever, feel sick, feel cold, tachycardia or delay excessively etc., (intravenous drip Radix Astragali injection pyrogen reacts 1 example can to jeopardize patient's life when serious, Sun Yanwen, " Shandong nursing magazine " 1999,5 (1): 67 pages).So far still to adopt small-volume injection to be mixed with the reason of drip liquid a lot of temporarily, but, infusion solutions is very strict to the requirement of the quality of the pharmaceutical preparations especially effective component content, stability, clarity, impurity, and this does not have one of major reason of Radix Astragali drip liquid finished product production beyond doubt so far.
Summary of the invention
The technical problem to be solved in the present invention is a kind of pharmaceutical composition of being made up of astragaloside, polysaccharide and pharmaceutical carrier or adjuvant substantially of preparation, improve the water extracting method of astragaloside, n-butanol extraction and the resin column got rid of in the separating step are handled, use simple technological operation, obtain higher astragaloside extraction ratio.The present invention will prepare yield and all higher astragaloside, the astragalus polysaccharides of purity, so that mix with pharmaceutical carrier or adjuvant, prepare all kinds of oral formulations, injection, especially the drip liquid of venoclysis, it should meet the strict demand of drip liquid at aspects such as effective component content, stability, clarity, Control of Impurities.
For solving the problems of the technologies described above, the invention provides following technical scheme.
A kind of pharmaceutical composition that contains astragaloside, astragalus polysaccharides is characterized in that preparing as follows:
Get the Radix Astragali, with 65～75% ethanol extractions, medicinal residues keep standby, reclaim pure liquid to the extractum shape, add ethanol and leave standstill for behind the 70-80% to containing the alcohol amount, filtering precipitates, and filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, adding ethanol again leaves standstill for behind the 80-90% to containing pure amount, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, leaves standstill behind the water for injection of 4 times of amounts of adding, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, leaves standstill the filtering precipitation after adding the water for injection of 4 times of amounts again, filtrate being concentrated into contains the astragaloside concentrated solution that the Radix Astragali is the 5g/ milliliter, gets the astragaloside refined liquid;
With the medicinal residues behind the Radix Astragali ethanol extraction, decocting concentrates, add ethanol and leave standstill for behind the 75-85 to containing the alcohol amount, the dissolving of precipitation adding distil water is got in filtration, filter, use membrane ultrafiltration, concentrate, concentrated solution adds ethanol again and leaves standstill for behind the 75-85 to containing pure amount, filter, reclaim ethanol to the greatest extent,, get the astragalus polysaccharides refined liquid that every ml contains crude drug 5 grams with the water for injection dissolving;
By volume, astragaloside refined liquid 0.8～16.0%, astragalus polysaccharides refined liquid 0.8～16.0% are mixed with pharmaceutically acceptable carrier or adjuvant 68.0～98.4%, and routine is made injection, injectable powder, drop pill, electuary, slow releasing tablet, tablet, capsule or microgranule.
The described pharmaceutical composition that contains astragaloside, astragalus polysaccharides is characterized in that: by volume, astragaloside refined liquid 0.8～8.0%, astragalus polysaccharides refined liquid 0.8～8.0% are mixed with pharmaceutically acceptable carrier or adjuvant 91.0～98.4%.
The described pharmaceutical composition that contains astragaloside, astragalus polysaccharides is characterized in that: by volume, astragaloside refined liquid 4.0%, astragalus polysaccharides refined liquid 4.0% are mixed with pharmaceutically acceptable carrier or adjuvant refined liquid 92.0%.
The aforementioned pharmaceutical composition that contains astragaloside, astragalus polysaccharides, it is characterized in that: by volume, astragaloside refined liquid 0.8～16.0%, astragalus polysaccharides refined liquid 0.8～16.0% are mixed with the conventional adjuvant of 68.0～98.4% drip liquid, regulate pH to 7.5～8.0, make drip liquid routinely.
The conventional adjuvant of drip liquid is isotonic agent, antioxidant and water for injection.
Isotonic agent is sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol or dextran; Antioxidant is sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate.
A kind of preparation method of astragaloside is characterized in that preparing as follows:
Get the Radix Astragali, with 65～75% ethanol extractions, reclaim pure liquid to the extractum shape, adding ethanol leaves standstill for behind the 70-80% to containing pure amount, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, adds ethanol again and leaves standstill for behind the 80-90% to containing the alcohol amount, and filtering precipitates, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, leave standstill behind the water for injection of 4 times of amounts of adding, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, leave standstill after adding the water for injection of 4 times of amounts again, the filtering precipitation, filtrate is reclaimed solvent, gets Radix Astragali total saponins.
The present invention repeatedly tests and shows, without the water extraction astragaloside, uses 65-75% ethanol extraction astragaloside instead, can make astragaloside content improve 3-5 doubly, has improved the content of Saponin constituents in the injection greatly.
And the present invention has got rid of n-butanol extraction and the resin column in the separating step and has handled, and not only greatly reduces production cost, simplified technology, reduced demand, thereby more helped suitability for industrialized production, and obtained higher, purer astragaloside extraction ratio equipment.
Yield and all higher astragaloside, the astragalus polysaccharides of purity that the present invention obtains, can mix with pharmaceutical carrier or adjuvant, prepare all kinds of oral formulations, injection, be particularly suitable for preparing the drip liquid of venoclysis, multinomial pharmacological evaluation proves, the Radix Astragali drip liquid of mainly being made up of astragaloside, astragalus polysaccharides of the inventive method preparation meets the strict regulations of drip liquid at aspects such as effective component content, stability, clarity, Control of Impurities fully.
The invention provides the pharmaceutical composition that contains astragaloside and astragalus polysaccharides, especially contain the drip liquid of astragaloside and astragalus polysaccharides, it can be directly used in venoclysis.
The preparation method that pharmaceutical composition that contains astragaloside and astragalus polysaccharides provided by the invention such as Radix Astragali drip liquid are more detailed is as follows:
(1) preparation astragaloside constituents refined liquid
(1) extraction of astragaloside constituents
Get Milkvetch Root, remove impurity after, with 10 times of amount 65-75% alcohol reflux 2 hours, filter, keep alcohol extract for the first time, 8 times of amounts of medicinal residues reuse 65-75% alcohol reflux 2 hours filters, and keeps the alcohol extract second time, medicinal residues are standby.
Merge alcohol extract twice, decompression recycling ethanol is to most.
(2) the astragaloside constituents is refining
(+)-Astragenol is carried concentrated solution to be added ethanol and placed 12-36 hour under 0 ℃ of-5 ℃ of condition for 70-80% to containing alcohol amount, filter and remove precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, adding ethanol again placed 12-36 hour under 0 ℃ of-5 ℃ of condition for 80-90% to containing the alcohol amount, filter and remove precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, the water for injection that adds 4 times of amounts was placed 12-36 hour under 0 ℃ of-5 ℃ of condition, filter and remove precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, the water for injection that adds 4 times of amounts was again placed 36-60 hour under 0 ℃ of-5 ℃ of condition, filter and remove precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, makes the refined liquid of astragaloside constituents.
(2) preparation astragalus polysaccharides refined liquid
(1) extraction of Astragalus Polysaccharides in Astragalus:
Get the astragalus root dregs after the alcohol extraction, the purified water that adds 8 times of amounts decocted 2 hours, filtered, keep decocting liquid for the first time, the purified water of 6 times of amounts of medicinal residues reuse decocted 2 hours, filtered, and kept decocting liquid for the second time, the purified water of 6 times of amounts of medicinal residues reuse decocted 2 hours, filter, keep decocting liquid for the third time, remove medicinal residues, merge decoction liquor then three times, be concentrated into and contain the concentrated solution that the Radix Astragali is the 1g/ milliliter.
(2) astragalus polysaccharides is refining
Radix Astragali water extracting liquid is added ethanol to be placed 12-36 hour under 0 ℃ of-5 ℃ of condition for 75-85% to containing the alcohol amount, filter, get the precipitation vacuum drying, precipitation is added the water heating for dissolving, filter,, keep concentrated solution with the membrane ultrafiltration of molecular weight 100,000, the reuse molecular weight is that 3000 membrane ultrafiltration concentrates, keep concentrated solution, add ethanol and reach 75-85%, under 0 ℃ of-5 ℃ of condition, placed 12-36 hour to containing the alcohol amount, filter, reclaim ethanol to the greatest extent, dissolve, filter, promptly get the astragalus polysaccharides refined liquid, every ml contains crude drug 5 grams.
(3) preparation waits and oozes concentrated wiring liquid:
Get isotonic agent and add 3 times of amount waters for injection, regulate pH to 7.5-8.0, add active carbon, boiled 15 minutes, filter through the sand rod and make concentrated wiring liquid with sodium hydroxide or hydrochloric acid.
(4) preparation Radix Astragali drip liquid
The concentrated wiring liquid of getting above-mentioned astragaloside constituents refined liquid, astragalus polysaccharides refined liquid and isotonic agent merges by the prescription proportional quantity, add 8 times of amount waters for injection, adding active carbon boiled 15 minutes, filter through the sand rod, filtrate is regulated pH to 7.5-8.0 with sodium hydroxide or hydrochloric acid, adds to the full amount of water for injection, test intermediate content, behind 0.45 μ m microporous filter membrane fine straining, fill gets Radix Astragali drip liquid finished product after sterilization, lamp inspection, quality inspection in washed glass infusion bottle or transfusion bag.
Radix Astragali drip liquid of the present invention is applicable to the infusion solutions of all size.
The survey report of the Radix Astragali drip liquid that makes with method of the present invention is as follows:
The name of an article: Radix Astragali drip liquid
Preparation unit: Tianyang Pharmaceutical Co., Ltd., Anhui Prov.
Detect unit: the institute for drug control, Anhui Province
Test item and result:
Character: this product is fallow clear liquid
Differentiate: be positive reaction
pH：5.0-7.0
Other: meet requirement under the injection item
Aseptic: qualified
Pyrogen: qualified
Astragaloside content (TLCS method): qualified
Polyoses content (UV method): qualified
Isotonic agent content is labelled amount % 95-105%
About two class Chinese medicine injection requirements, Radix Astragali drip liquid after the process modification has been carried out irritant test, hypersensitive test, hemolytic test and acute toxicity test according to National Drug Administration, has been reported as follows:
Sample: Radix Astragali drip liquid.
Detect unit: national Shenyang new drug safety evaluation key lab.
Test a Radix Astragali drip liquid local irritation test, hypersensitive test and hemolytic test
Test objective is investigated the clinical research that is used for that Radix Astragali drip liquid whether can safety.
Test material is subjected to the reagent thing: Radix Astragali drip liquid is provided by Tianyang Pharmaceutical Co., Ltd., Anhui Prov..
Animal subject: rabbit, body weight 2.0-2.5kg, outer auricular concha is normal.Provide by Shenyang Pharmaceutical University Animal Experimental Study center.The quality certification number: 033.
The Cavia porcellus order is male, and body weight 250g-350g is provided by Shenyang Pharmaceutical University zooscopy center, the quality certification number: 033
1, local irritation test
Get 6 of rabbit, wherein 3 left ears are given Radix Astragali drip liquid (administration volume 10ml/kg), 3 left ears are given and are waited the capacity normal saline in contrast in addition, successive administration three days, once a day, after the last administration 24 hours, put to death animal, clip injection site auricular concha, about 5cm is long, and perusal has or not redness, edema, mound speckle to form.And with after 10% formaldehyde fixed, perusal has or not redness, edema, mound speckle to form.And with after 10% formaldehyde fixed, censorship pathology, microscopically is observed blood vessel endothelium, subendothelial tissue and thrombosis situation.
2, sensitivity test
Get 18 of male guinea pigs, body weight 250g-350g, 6 every group, totally 3 groups.Experimental group i.p. is tried Radix Astragali drip liquid; Blank group i.p. normal saline; Positive controls i.p.1% fresh egg white; The administration volume only is 1.0ml/.The every other day administration, continuous three times.Every then component is each 3 of two groups, injecting back 14 days and 21 days for the first time respectively, tried Radix Astragali drip liquid by vena femoralis injection again, normal saline, 1% fresh egg white 2ml/ only, observe immediately that animal has or not sneeze after the administration, scratch nose, retch or cough, anaphylaxiss such as perpendicular hair, tic, dyspnea, gatism, shock and death were observed 1 hour.
3, external hemolytic test
Get 1 of rabbit, ear edge vein exploitating blood 5-10ml adds in the clean small beaker, uses the bamboo let stirring and removes fibronectin.Add normal saline 5-10ml again, shake up, centrifugal, the supernatant that inclines, so repeatedly do not take on a red color to supernatant several times till.Measure blood cell, add normal saline and be diluted to 2% suspension and be for experiment.
Get 7 in test tube, add various solution in the following order.
The external hemolytic test application of sample of table 1 table
Test tube numbers 1234567
Check medicinal liquid (ml) 0.2 0.4 0.6 0.8 1.0 00
Normal saline (ml) 2.3 2.1 1.9 1.7 1.5 2.5 0
2% red blood cell suspension (ml) 2.5 2.5 2.5 2.5 2.5 2.5 2.5
The wherein negative contrast of the 6th pipe, the positive contrast of the 7th pipe.Each pipe haemolysis is shaken up gently, put in 37 ℃ of calorstats the result when observing and writing down 1,2,3,4 hours.Observe the phenomenon whether haemolysis and red blood cell condensation are arranged, clear and red colouration is promptly represented haemolysis as solution becomes.
The local irritation experiment shows: the local nothing redness of the administration of administration group and matched group, edema and tissue necrosis occur, and blood vessel endothelium is continuous, and is complete, and surrounding tissue is not seen inflammatory infiltration and edema, and no thrombosis forms in the tube chamber.Can think that Radix Astragali drip liquid intravenously administrable does not have obvious irritation.
Sensitivity test shows: Radix Astragali drip liquid and normal saline level began the back the 14th day and 21 days in sensitization, and venous pulse injection is subjected to there is no dyspnea after the reagent, twitched, and sneeze is scratched reaction such as nose and also do not had dead generation.1% Ovum Gallus domesticus album matched group 14 days and 21 days quiet notes give dyspnea to occur behind the Ovum Gallus domesticus album, and it is all dead in 15 minutes to twitch.
External hemolytic test shows: give for 1-5 number be subjected to reagent pipe and No. 6 each time points of saline tube all not transparent red dye and blood cell is assembled.No. 7 distillation water pipe 1-4 hour obvious red dying, and prolongation in time and redness increases the weight of to deepen.The result thinks that Radix Astragali drip liquid do not have external haemolysis.
Above result of the test shows that Radix Astragali drip liquid can not cause that to rabbit auricular vein injection nonirritant the pathologic of ear tissue changes; Radix Astragali injection does not have sensitization to Cavia porcellus; Radix Astragali drip liquid does not have haemolysis and makes erythroagglutination rabbit external.
Test two: Radix Astragali drip liquid passive cutaneous anaphylaxis test.
Test objective is investigated Radix Astragali drip liquid and whether is had IgE sample antigenic action, is reference data for clinical drug use.
Test material is subjected to the reagent thing: Radix Astragali drip liquid.Provide by Tianyang Pharmaceutical Co., Ltd., Anhui Prov..
Egg protein (Albumin Egg): Beijing nation decides Tyke biotech company, Sigma A 5253.
Absorption pertussis, diphtheria, cholera and Typhoid-Paratyphoid A and B Vaccine and Tetanus Toxoid Complex: Changchun Biological Products Institute, Ministry of Public Health, lot number: 991008-1-3;
Azovan blue: (0589-60) Koch-Light import packing.
Experimental animal: the Wistar rat, the 150-200g body weight is provided by Shenyang Pharmaceutical University experimental animal center, the quality certification number: 033.
The preparation of test method 1, sensitization serum: 12 of Wistar rats (male and female half and half), body weight 150-200g is divided into egg protein group and Radix Astragali drip liquid group at random.Egg protein group rat is in the white normal saline 0.05ml of back leg both sides intramuscular injection 1% incubation, and 0.1ml/ rat of Radix Astragali drip liquid group intramuscular injection Radix Astragali drip liquid (0.2g/ only) distinguished the lumbar injection DPT vaccine simultaneously and (include pertussis 2 * 10
10), with the sensitization time first time be the 1st day, respectively at the 5th, 10 day sensitization 2 times again.The blood sampling of 14 days rear neck arteries, separation of serum, after each group merges respectively, put preserve in the refrigerator standby.
2, passive sensitization of skin: other gets 16 of rats, male and female half and half, and body weight 160-180g is divided into 2 groups at random, i.e. egg protein group and Radix Astragali drip liquid group.After rat is used the shallow fiber crops of ether, in the cropping of abdominal part both sides, every side 2 points.Get that above-mentioned two groups of antiserums are diluted to 1: 5 with normal saline and 1: 10 two kinds of concentration.Two treated animals are in each 0.1ml of antiserum of the corresponding two kinds of concentration of cropping place difference intradermal injection.After 48 hours, the egg protein group with the white normal saline of 1% incubation (containing 0.5% azovan blue) tail vein injection 1ml/ is only carried out antigen and is attacked after the sensitization; Radix Astragali drip liquid group tail vein injection Radix Astragali drip liquid (containing 0.5% azovan blue) 1ml/ only carries out antigen and attacks.Attack back 30min and put to death rat, the upset skin of abdomen, observation has or not locus coeruleus to form.
Result of the test is incubated the protein groups skin injection and was all formed locus coeruleus behind the antiserum in 1: 5 and 1: 10, and equal locus coeruleus forms under two kinds of serum-concentrations of Radix Astragali drip liquid group.The results are shown in 2,3.
Two treated animal locus coeruleus form situation under 1: 5 serum-concentration of table 2
The group positive (locus coeruleus is arranged) negative (no locus coeruleus)
Incubate protein groups 16 0
Radix Astragali drip liquid group 0 16
Table 31: two treated animal locus coeruleus form situation under 10 serum-concentrations
The group positive (locus coeruleus is arranged) negative (no locus coeruleus)
Incubate protein groups 16 0
Radix Astragali drip liquid group 0 16
Annotate: X
2Check, compare with matched group p＜0.01
Conclusion: Radix Astragali drip liquid does not have IgE sample antigenic action.
Test three: Radix Astragali drip liquid acute toxicity test
After test objective is observed abdominal cavity and tail vein shot Radix Astragali drip liquid, acute toxic reaction symptom and death condition that mice produced, and calculate the mice LD of intraperitoneal injection and tail vein injection administration
50And 95% fiducial limit.
The tested medicine Radix Astragali of test material drip liquid is provided by Tianyang Pharmaceutical Co., Ltd., Anhui Prov., and the drug level of lumbar injection is 15.00g/ml, 12.00g/ml, 9.60g/ml, 7.68g/ml, 6.14g/ml crude drug.The drug level of tail vein injection is 10.00g/ml, 8.00g/ml, 6.40g/ml, 5.12g/ml, 4.10g/ml crude drug.
Each mouse inbred lines of animal Kunming, intraperitoneal injection mice body weight 20-22g, age in 5-6 week, male and female half and half.Tail vein injection administration mice body weight 24-26g, in age in 7-8 week, male and female half and half are provided by Shenyang Pharmaceutical University Animal Experimental Study center, the quality certification number: 033.
1, intraperitoneal injection air-conditioning constant temperature laboratory, laboratory transfers to 25 ℃ of constant temperature, and is indoor sunny, the exhaust fan air draft, clean environment, less to the result of the test influence.
Buy mice the last week by test, strengthen and raise, the pass conforms.
Choose 50 of mices, body weight 20-22g, male and female half and half, by sex, body weight is divided into 5 groups at random, and 10 every group, the male and female equalization.With the Radix Astragali drip liquid lumbar injection of variable concentrations, the 0.5ml/10g body weight, dosage is respectively 750g/kg, 600g/kg, 480g/kg, 384g/kg, 307g/kg, the group spacing is 1: 0.8.
Normally raise after the administration, observe continuously, write down the symptom and the dead routine number of animal toxicity reaction when pursuing day by day.When surviving animals recovers normal, mortality rate during no change, calculates LD with the Bliss statistic law
50And 95% fiducial limit.
2, the selection of tail vein injection medicine-feeding test condition and animal is with the intraperitoneal injection method.
Choose 50 mices, body weight 24-26g is divided into 5 groups at random by sex, body weight, and 10 every group, male and female half and half.With the Radix Astragali drip liquid tail vein injection of variable concentrations, the 0.3ml/10g body weight, dosage is respectively 300g/kg, 240g/kg, 192g/kg, 154g/kg, the 123g/kg crude drug, the group spacing is 1: 0.8.
Normally raise after the administration, observe continuously, write down the symptom and the dead routine number of animal toxicity reaction when pursuing day by day.When surviving animals recovers normal, mortality rate during no change, calculates LD with the Bliss statistic law
50And 95% fiducial limit.
Intraperitoneal injection The acute toxicity tests: behind the mouse peritoneal drug administration by injection, the different inhibitory state that successively carry out according to dosage, it is fast that the high dose group reaction symptom occurs, and the most serious, mice reposes very soon, motionless, respiratory frequency is slack-off, with the formula intermittent breathing of panting, the all cyanosis of mouth, table is purple, tic of the limbs or the one-tenth shape of crawling, dead before most mices have to faint from fear and scurry the jumping phenomenon.The high dose group mice is all dead in 12 hours.Symptom also appears suppressing in the low dose group mice, and spontaneous activity reduces, and repose and do not start building, but respiratory frequency is not seen change, after 5-8 hour, all can recover normal activity and foraging behavior gradually, all survivals, and none example is dead.Middle each dosage group, the heavy test example of reaction then continues to be inhibition and finally causes death.The test example of response light is recovered normally gradually, healthy survival.Dead example in time performs an autopsy on sb, and main organs is not seen macroscopic pathological change.LD
50And fiducial limit sees Table 4
The LD of table 4 Radix Astragali drip liquid mouse peritoneal drug administration by injection
50Dosage death time probability LD
50(g/kg logarithm number of animals death toll death rate unit 95% credible crude drug) dosage, (only) 1h 2h 3h 6h 8h 12h 24h, (only), (%), (Y) limit, (mg/kg) 750 2.8751 10-1,143 1-10,100 6.86600 2.7782 10--1,32 1-7,70 5.77 512.37480 2.6812 10----1 214 40 4.68, (464.02-384 2.5843 10-----1-1 10 3.59 565.77) 307 2.4871 10-------0 0 2.5
2, tail vein injection administration The acute toxicity tests
What tail vein injection toxic reaction symptom occurred is fast and serious, and behind the high dose group drug administration by injection, that reposing appears in all animals very soon is motionless, tic, respiratory frequency are slack-off, the intermittent breathing of panting, the all cyanosis table purples of mouth, or scurry the jumping phenomenon with convulsions before dead, most animals is dead in 1 hour.Symptom also appears resisting in the low dose group mice, and it is motionless to repose, but tangible respiration inhibition do not occur, all can recover normal activity and foraging behavior gradually after 3-4 hour, all survivals, and none example is dead.Middle each dosage group, the heavy test example of reaction continues to present inhibition, and is finally dead at short notice.The test example of response light is recovered normal activity gradually at short notice, healthy survival.Dead example in time performs an autopsy on sb, and main organs is not seen the visible pathological change of eye.LD
50And 95% fiducial limit sees Table 5
The LD of table 5 Radix Astragali drip liquid mouse tail vein injection administration
50Dosage death time probability LD
50And, (g/kg logarithm number of animals death toll death rate unit 95% credible crude drug) dosage, (only) 1h 2h 3h 6h 8h 12h 24h, (only), (%), (Y) limit, (mg/kg) 300 2.4771 10 4221 1--10,100 7.00240 2.3802 10 2311 1--8,80 6.04 512.37192 2.2833 10 112 1---5 50 5.09, (464.02-154 2.1875 10---1 1 1-3 30 4.15 565.77) 123 2.0899 10-------0 0 3.19
Conclusion: Radix Astragali drip liquid is given the measured LD of Kunming mouse intraperitoneal injection
50Be the 512.37g/kg crude drug, the 95% credible 464.02-565.77g/kg crude drug that is limited to.The LD of tail vein injection administration
50Be the 187.89g/kg crude drug, the 95% credible 168.89-209.03g/kg crude drug that is limited to.
The specific embodiment
Embodiment:
Get Milkvetch Root 10kg, behind the removal impurity, with twice of 70% alcohol reflux (10,8), each 2 hours, merge extractive liquid, filtered, and medicinal residues are standby.With (+)-Astragenol extract decompression recycling ethanol extremely to the greatest extent, ethanol to the alcohol amount of containing is 75% to place 24 hours under 0 ℃ of condition, filter and remove precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, adding ethanol to the alcohol amount of containing again and be 85% placed 24 hours under 3 ℃ of conditions, filter and remove precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, the water for injection that adds 4 times of amounts was placed 24 hours under 0 ℃ of condition, filter and remove precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, the water for injection that adds 4 times of amounts was again placed 48 hours under 5 ℃ of conditions, filtered and removed precipitation, and filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, make 2000 milliliters of the refined liquid of astragaloside constituents, 5 gram crude drug/milliliters.
Get the astragalus root dregs after the alcohol extraction, decocting in water three times is removed medicinal residues, merge decoction liquor then three times, filter, be concentrated into and contain the concentrated solution that the Radix Astragali is the 1g/ milliliter, adding ethanol is 80% to place 16 hours under 0 ℃ of condition to containing the alcohol amount, filters, and gets the precipitation vacuum drying, precipitation is added the water heating for dissolving, filter,, keep concentrated solution with the membrane ultrafiltration of molecular weight 100,000, the reuse molecular weight is that 3000 membrane ultrafiltration concentrates, keep concentrated solution, add ethanol and reach 80%, under 5 ℃ of conditions, placed 36 hours to containing the alcohol amount, filter, reclaim ethanol to the greatest extent, dissolve, filter, promptly get 2500 milliliters of astragalus polysaccharides refined liquid, be equivalent to 5 gram crude drug/milliliters.
Get isotonic agent sodium chloride 565 grams, add 3 times of weight waters for injection, regulate pH to 7.5-8.0, add active carbon, boiled 15 minutes, filter through the sand rod and make concentrated wiring liquid with sodium hydroxide or hydrochloric acid.
The concentrated wiring liquid of getting above-mentioned astragaloside constituents refined liquid, astragalus polysaccharides refined liquid and isotonic agent merged in 20: 25: 17 by volume, add 8 times of amount waters for injection, adding active carbon boiled 15 minutes, filter through the sand rod, filtrate is regulated pH to 7.8 with sodium hydroxide or hydrochloric acid, adds the injection water to 62500ml, test intermediate content, behind 0.45 μ m microporous filter membrane fine straining, fill in 250 milliliters of glass infusion bottles cleaning or transfusion bag, after sterilization, lamp inspection, quality inspection Radix Astragali drip liquid finished product.Intravenous drip 250ml/ days, or follow the doctor's advice.
Claims (7)
1, a kind of pharmaceutical composition that contains astragaloside, astragalus polysaccharides is characterized in that preparing as follows:
Get the Radix Astragali, with 65～75% ethanol extractions, medicinal residues keep standby, reclaim pure liquid to the extractum shape, add ethanol and leave standstill for behind the 70-80% to containing the alcohol amount, filtering precipitates, and filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, adding ethanol again leaves standstill for behind the 80-90% to containing pure amount, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, leaves standstill behind the water for injection of 4 times of amounts of adding, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, leaves standstill the filtering precipitation after adding the water for injection of 4 times of amounts again, filtrate being concentrated into contains the astragaloside concentrated solution that the Radix Astragali is the 5g/ milliliter, gets the astragaloside refined liquid;
With the medicinal residues behind the Radix Astragali ethanol extraction, decocting concentrates, add ethanol and leave standstill for behind the 75-85 to containing the alcohol amount, the dissolving of precipitation adding distil water is got in filtration, filter, use membrane ultrafiltration, concentrate, concentrated solution adds ethanol again and leaves standstill for behind the 75-85 to containing pure amount, filter, reclaim ethanol to the greatest extent,, get the astragalus polysaccharides refined liquid that every ml contains crude drug 5 grams with the water for injection dissolving;
By volume, astragaloside refined liquid 0.8～16.0%, astragalus polysaccharides refined liquid 0.8～16.0% are mixed with pharmaceutically acceptable carrier or adjuvant 68.0～98.4%, and routine is made injection, injectable powder, drop pill, electuary, slow releasing tablet, tablet, capsule or microgranule.
2, the pharmaceutical composition that contains astragaloside, astragalus polysaccharides according to claim 1, it is characterized in that: by volume, astragaloside refined liquid 0.8～8.0%, astragalus polysaccharides refined liquid 0.8～8.0% are mixed with pharmaceutically acceptable carrier or adjuvant 91.0～98.4%.
3, according to the described pharmaceutical composition that contains astragaloside, astragalus polysaccharides of claim 2, it is characterized in that: by volume, astragaloside refined liquid 4.0%, astragalus polysaccharides refined liquid 4.0% are mixed with pharmaceutically acceptable carrier or adjuvant refined liquid 92.0%.
4, according to the described pharmaceutical composition that contains astragaloside, astragalus polysaccharides of one of claim 1～3, it is characterized in that: by volume, astragaloside refined liquid 0.8～16.0%, astragalus polysaccharides refined liquid 0.8～16.0% are mixed with the conventional adjuvant of 68.0～98.4% drip liquid, regulate pH to 7.5～8.0, make drip liquid routinely.
5, the pharmaceutical composition that contains astragaloside, astragalus polysaccharides according to claim 4 is characterized in that: the conventional adjuvant of drip liquid is isotonic agent, antioxidant and water for injection.
6, the pharmaceutical composition that contains astragaloside, astragalus polysaccharides according to claim 5 is characterized in that: isotonic agent is sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol or dextran; Antioxidant is sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate.
7, a kind of preparation method of astragaloside is characterized in that preparing as follows:
Get the Radix Astragali, with 65～75% ethanol extractions, reclaim pure liquid to the extractum shape, adding ethanol leaves standstill for behind the 70-80% to containing pure amount, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, adds ethanol again and leaves standstill for behind the 80-90% to containing the alcohol amount, and filtering precipitates, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 3g/ milliliter, leave standstill behind the water for injection of 4 times of amounts of adding, the filtering precipitation, filtrate being concentrated into contains the concentrated solution that the Radix Astragali is the 5g/ milliliter, leave standstill after adding the water for injection of 4 times of amounts again, the filtering precipitation, filtrate is reclaimed solvent, gets Radix Astragali total saponins.
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| CN 03112649 CN1201745C (en) | 2003-01-10 | 2003-01-10 | Medicine combination contg. effective part of astragalus root |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005084689A1 (en) * | 2004-02-23 | 2005-09-15 | Hutchison Medipharma Enterprises Limited | Radix astragli extract and production method and use thereof |
| CN1305894C (en) * | 2003-10-17 | 2007-03-21 | 成都华森药物高新技术有限公司 | Process for extracting total saponin of American ginseng and powder injection thereof |
| CN100367969C (en) * | 2003-07-29 | 2008-02-13 | 上海博泰医药科技有限公司 | Injection formulation of astragalus root saponin and its preparation mehod |
| CN101904863B (en) * | 2009-06-04 | 2012-05-30 | 广州泽力医药科技有限公司 | Preparation process of medicinal composition compounded from astragaloside and astragalus polyose |
| CN104940277A (en) * | 2015-06-17 | 2015-09-30 | 中国农业科学院兰州畜牧与兽药研究所 | Preparation method of calcium astragalus polysaccharide |
-
2003
- 2003-01-10 CN CN 03112649 patent/CN1201745C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100367969C (en) * | 2003-07-29 | 2008-02-13 | 上海博泰医药科技有限公司 | Injection formulation of astragalus root saponin and its preparation mehod |
| CN1305894C (en) * | 2003-10-17 | 2007-03-21 | 成都华森药物高新技术有限公司 | Process for extracting total saponin of American ginseng and powder injection thereof |
| WO2005084689A1 (en) * | 2004-02-23 | 2005-09-15 | Hutchison Medipharma Enterprises Limited | Radix astragli extract and production method and use thereof |
| CN101904863B (en) * | 2009-06-04 | 2012-05-30 | 广州泽力医药科技有限公司 | Preparation process of medicinal composition compounded from astragaloside and astragalus polyose |
| CN104940277A (en) * | 2015-06-17 | 2015-09-30 | 中国农业科学院兰州畜牧与兽药研究所 | Preparation method of calcium astragalus polysaccharide |
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| Publication number | Publication date |
|---|---|
| CN1201745C (en) | 2005-05-18 |
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