CN1270769C - Cinobufotalin lyophilized powder for injection and its preparation method - Google Patents
Cinobufotalin lyophilized powder for injection and its preparation method Download PDFInfo
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- CN1270769C CN1270769C CN 200410083994 CN200410083994A CN1270769C CN 1270769 C CN1270769 C CN 1270769C CN 200410083994 CN200410083994 CN 200410083994 CN 200410083994 A CN200410083994 A CN 200410083994A CN 1270769 C CN1270769 C CN 1270769C
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Abstract
The present invention discloses a cinobufagin lyophilized powder injection and a preparation method thereof. The cinobufagin lyophilized powder injection is prepared from cinobufagin active parts extracted from dry toad skins and pharmaceutic adjuvants, wherein the cinobufagin active parts are obtained by the methods of ethanol extraction, centrifugation and macroporous resin separation and purification, and the content of the main effective ingredient-indole total alkaloids is greater than 30%. As indicated by content assay results and pharmacological experiment results, the cinobufagin lyophilized powder injection of the present invention has the advantages of high effective ingredient content and strong pharmacological action.
Description
Affiliated technical field
The invention belongs to technical field of traditional Chinese medicine pharmacy, be specifically related to a kind of cinobufotalin lyophilized powder and preparation method thereof.
Background technology
Cinobufacin is the preparation that the dry maxima skin of Bufonidae animal Bufo siccus or Bufo melanostictus etc. makes through extraction, the tool detoxifcation, detumescence, the pain relieving effect, be used for the middle and advanced stage tumor, diseases such as chronic hepatitis B, in its water soluble ingredient except that containing the effective ingredient indoles alkaloid, as 5-hydroxy tryptamine, bufotenine, the special Buddhist nun of Bufo siccus, Bufo siccus sulfur etc., also contain a certain amount of aminoacid in addition, reducing sugar, the steroid class, the peptide class, bufotalis unit and arginine complex, studies show that the bufogenin constituents that contains in the Cutis Bufonis is its antineoplastic important activity composition, is again toxic component.In recent years pharmacology and clinical research prove: cinobufacin also can be used for intractable singultus, meningitis, verruca plana and psoriasis etc. except that being used for antitumor and hepatitis etc.The preparation that with the cinobufacin is main component at present has cinobufacin oral liquid, cinobufacin sheet, HUACHANSU ZHUSHEYE etc.
HUACHANSU ZHUSHEYE (WS3-B-30) is that dry maxima skin is through extracting the sterile water solution of processing, this injection preparation fails effectively to extract the bufogenin constituents, only measured amount in the quality standard in the indoles total alkaloids of 5-hydroxy tryptamine, and not to another important be toxicity be that the bufogenin constituents of active component is measured and controlled, be difficult to guarantee the quality and the curative effect of injection, injection is to the stability requirement height, and the inherent shortcoming that aqueous injection exists is exactly a stability problem and carry, store, broken easily when transporting, result in hand cramps.
Patent (application number 98103562) " a kind of cinobufacin capsule and preparation method thereof " is made capsule with the decoction and alcohol sedimentation technique effective component extracting, and this invented technology is simple, does not have novelty; Patent (application number 00136668) " a kind of nanometer cinobufacin preparation medicine and preparation method thereof " adopts microwave extracting, concentrating under reduced pressure, supersonic jet technology to make nanometer cinobufacin preparation medicine, the greatest drawback of this technology is to make with extra care, harmful and invalid impurity is many in the extract, make relatively difficulty of injection type, simultaneously the exploitativeness of this technology existing problems.
In data-searching, find no any report that closes cinobufotalin lyophilized powder.
Summary of the invention
The objective of the invention is to disclose a kind of active constituent content height, good effect, little, the convenient cinobufogenin freeze-drying powder injection preparation that uses of toxicity.
Another object of the present invention provides the preparation method of above-mentioned freeze-dried powder.
The present invention is achieved through the following technical solutions.
One, preparation method
(1) crude drug: dry maxima skin.
(2) get dry maxima skin, clean, add 5～6 times of 80% alcohol reflux secondary, 45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, centrifugal 30 minutes of concentrated solution (2500r/min), get supernatant, last macroporous adsorptive resins absorption is earlier with 3-4 times of column volume water elution, reuse 3-5 times of column volume 30%-50% ethanol elution, get the ethanol elution concentrating under reduced pressure, drying gets the cinobufacin ethanol extract.
(3) preparation prescription: cinobufacin ethanol extract 5.5-7.5 weight portion, pharmaceutic adjuvant 90-100 weight portion.
(4) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water, regulate pH value to 6.0-7.0 to ormal weight, ultrafiltration, fill, lyophilization, promptly.
In the preparation of cinobufotalin lyophilized powder, we adopt alcohol reflux, the macroporous resin separation and purification obtains the cinobufacin ethanol extract, this extraction process both can have been extracted the water miscible indoles total alkaloids of dry maxima skin, can extract the bufogenin constituents in the dry maxima skin again, farthest kept the active component that plays a role, adopt purification by macroporous resin simultaneously, farthest removed the impurity that contains in the extract, make that the indoles total alkaloid contents reaches more than 30% in the cinobufacin ethanol extract, bufogenin constituents cinobufagin and bufogenin content reach 0.02% and 0.014% respectively.Because the bufogenin class is important active component, is again toxic component, we carry out detection by quantitative to cinobufagin and bufogenin, can better guarantee effectiveness, safety and the stability of preparation.
The concentration of macroporous resin ethanol elution is preferably 35%-45% among the preparation technology.
Hyperfiltration technique is that the microcellular structure by the film surface carries out Selective Separation to material.When liquid mixture is flowed through the film surface under certain pressure, the micromolecule solute sees through film (being called ultrafiltrate), macromolecular substances then is trapped, and makes that macromole concentration improves (being called concentrated solution) gradually in the stock solution, thereby realizes the separation of large and small molecule, the purpose that concentrates, purifies.Effective ingredient in the Chinese medicine such as alkaloid, flavonoid, glycoside equimolecular quantity are less, and invalid components is big as protein, the matter of mixing, resin, starch equimolecular quantity usually, and complex structure is held back by selectivity, better the purification effective ingredient.For more effectively removing antibacterial, pyrogen and some the macromole impurity in the medicinal liquid, the present invention is through repetition test, adopt the ultrafilter membrane of molecular cut off 10000-30000 to carry out ultrafiltration in the preparation process, further improved the quality of the pharmaceutical preparations, what wherein the ultrafilter membrane material can be in polyacrylonitrile (PAN) or the polyether sulfone (PES) is a kind of.
Pharmacological evaluation shows that cinobufotalin lyophilized powder of the present invention has better pharmacological action.
Two, formulation content analysis
1, the indoles total alkaloid content in the preparation
1.1 instrument and reagent: Hitach UV-2000 ultraviolet spectrophotometer, HUACHANSU ZHUSHEYE (Anhui gold toad Pharmaceutical head office); Cinobufotalin lyophilized powder of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); 5-hydroxy tryptamine reference substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute).
1.2 experimental technique: measure with reference to the content assaying method in HUACHANSU ZHUSHEYE (WS3-B-30) quality standard, the results are shown in Table 1.
Indoles total alkaloids (in 5-hydroxy tryptamine) content in table 1 preparation
| Group | Indoles total alkaloid content (mg/ props up) |
| HUACHANSU ZHUSHEYE cinobufotalin lyophilized powder of the present invention | 2.62 3.90 |
Above formulation content measurement result explanation, cinobufotalin lyophilized powder of the present invention is owing to adopt new preparation method, and main effective ingredient indoles total alkaloids (in 5-hydroxy tryptamine) content is significantly increased than HUACHANSU ZHUSHEYE.
2, bufalin and bufogenin constituents content in the preparation
2.1 instrument and reagent: Waters high performance liquid chromatograph (600 pumps, 2487 detectors), Millinium32 chromatography software; HUACHANSU ZHUSHEYE (Anhui gold toad Pharmaceutical head office); Cinobufotalin lyophilized powder of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); Cinobufagin reference substance and bufogenin reference substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute).
2.2 experimental technique: with reference to " content assaying method is measured under 2000 editions 316 pages of Venenum Bufonis items of Chinese pharmacopoeia, the results are shown in Table 2.
Cinobufagin and bufogenin content in table 2 preparation
| Group | Cinobufagin (μ g/ props up) | Bufogenin (μ g/ props up) |
| HUACHANSU ZHUSHEYE cinobufotalin lyophilized powder of the present invention | 0.318 1.203 | 0.220 0.814 |
Above assay result shows that cinobufagin and bufogenin content are less in the HUACHANSU ZHUSHEYE, and cinobufotalin lyophilized powder cinobufagin of the present invention and bufogenin content obviously improve.
Three, cinobufacin ethanol extract content analysis
Extract 1 (cinobufacin ethanol extract of the present invention); Extract 2 (according to the preparation method preparation of HUACHANSU ZHUSHEYE).
Content assaying method according to preparation is measured, the assay result such as the table 3 of cinobufacin ethanol extract.
The assay of table 3 extract
| Group | Extract 1 | Extract 2 |
| Indoles total alkaloids (%) | 32.5 | 15.4 |
| Cinobufagin (%) bufogenin (%) | 0.020 0.014 | 0.0037 0.0026 |
Above assay result shows that cinobufacin lyophilized powder extract purity of the present invention obviously improves, and wherein indoles total alkaloids (in 5-hydroxy tryptamine) content is greater than 30%.
Four, pharmacological toxicology embodiment
1. anti-hepatitis B virus experimentation
Laboratory animal: adopt vertical transmission to infect the positive sheldrake of DHBV DNA (deoxyribonucleic acid) (DNA), every group is 10 5 monthly age sheldrakes of selecting at random.It is close with sex ratio that each organizes the sheldrake body weight.All raise under the same conditions.
Experiment medicine: normal saline (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); HUACHANSU ZHUSHEYE (Anhui gold toad Pharmaceutical head office); Cinobufotalin lyophilized powder of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
Experimental technique: sheldrake leg muscle drug administration by injection dosage is 1.5g crude drug/kg, continuous 12 weeks, administration 3 times next day the weekly, injection 2ml/kg normal saline during the administration of DHBV positive controls, more than each group respectively before administration, the 2nd all venous blood collections after the 4th week, the 8th week, the 12nd week and the drug withdrawal after the administration, do the experiment of serum dot blot hybridization with the HBV DNAt probe of 32p labelling, the results are shown in Table 4.
Table 4 sheldrake serum DHBV DNA measurement result
| Group | Blood sampling time | |||||
| Before the administration | The 4th week | The 8th week | The 12nd week | 2 weeks after the drug withdrawal | ||
| Control group cinobufagin injection group | A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 B1 B2 | + + + + ++ + + +++ + + + + | ++ + ++ + +++ + + ++ + + - - | + + ++ + ++ + + + + + - - | + + + ++ + + + + + + - - | + + + + + + + + + + - - |
| B3 B4 B5 B6 B7 B8 B9 B10 | +++ ++++ + + + + + + | ++ +++ - + + - - + | + ++ - + - - - + | + + - + - - - - | + + - - - - - - | |
| Cinobufogenin freeze-drying powder injection group of the present invention | C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 | + + + ++ + + + + + ++++ | - - - ++ + - - - - ++ | - - - + + - - - - + | - - - + + - - - - - | - - - + - - - - - - |
++ ++ being equivalent to the DHBV dna content is 100pg, +++be 50pg, ++ be 25pg ,+be 10pg,
2. to the growth inhibited effect of mice transplanted tumor S180
Laboratory animal: healthy mice, body weight 18-22g, male and female half and half.
Tumor strain: sarcoma S180 is introduced by the Guangdong medicine, the inoculation of going down to posterity of institute of oncology, Guangzhou.
Experiment medicine: normal saline (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides); HUACHANSU ZHUSHEYE (Anhui gold toad Pharmaceutical head office); Cinobufotalin lyophilized powder of the present invention (Tianzhijiao Medication Development Co., Ltd., Guangdong's laboratory provides)
Experimental technique: get health, the vigorous sarcoma S180 tumor-bearing mice of tumor growth, put to death the back and take out the tumor piece, in homogenizer, add normal saline, make the tumor homogenate, again with normal saline dilution in 1: 3, it is subcutaneous to get oxter, a 0.2ml injection mice left side then, weighs in 24 hours, and treating excess syndrome is tested medicine, drug administration by injection dosage is 0.65g crude drug/kg, every day, mouse tail vein was administered once, injection 0.2m1 normal saline during the matched group administration, successive administration 10 days.Next day is put to death mice in drug withdrawal, weighs and carefully peels off the subcutaneous tumors piece, and it is heavy to take by weighing tumor in the EM50 electronic balance.The results are shown in Table 5.
The growth inhibited effect of table 5 couple murine sarcoma S180
| Group | Tumor body weight (g) | Tumour inhibiting rate % |
| Normal saline HUACHANSU ZHUSHEYE cinobufotalin lyophilized powder of the present invention | 2.0214 1.0476 0.9169 | 48.17 * 54.64 *# |
Annotate: compare * P＜0.01 with the normal saline group, compare #P＜0.05 with positive controls
Above The pharmacological results shows that cinobufotalin lyophilized powder of the present invention compares with HUACHANSU ZHUSHEYE and have better pharmacological action.
3. long term toxicity test
Get 80 of healthy rats (wistar kind), the branch heavy dose (the 3g crude drug/kg), in dosage (1.5g crude drug/kg) and low dose of (0.8g crude drug/kg) and 4 groups of blank groups, every group 20, male and female half and half, every day the tail intravenously administrable once, administration stopped after 7 days one day, continue administration, 7 weeks of successive administration, matched group gives normal saline, observe predrug period, mid-term, later stage, the outward appearance behavior of drug withdrawal after 15 days, movable, fur, appetite, variations such as explanation, go forward side by side promoting the circulation of blood routine test and liver, kidney function test, recording ecg, weighed every 10 days, adjust dosage, each is organized experimental rat and puts to death in batches, put to death half in 2 days after first drug withdrawal, put to death in 15 days after all the other drug withdrawals, core after the execution liver taste lung kidney adrenal gland's lymph node pancreas thymus and testis or uterus, organs such as ovary, and routine paraffin wax section, the painted pathological section of HE carries out light microscopy checking, and the result shows, each dosage group blood parameters, hepatic and renal function and the section of each organ-tissue are compared with matched group, all belong to normal range, do not see obvious poisoning pathological changes.
Five, preparation embodiment
Embodiment 1:
(1) crude drug is: dry maxima skin 500g.
(2) get dry maxima skin, clean, add 5 times of 80% alcohol reflux secondary, 45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, centrifugal 30 minutes of concentrated solution (2500r/min), get supernatant, last D101 absorption with macroporous adsorbent resin is earlier with 3 times of column volume water elutions, 4 times of column volume 40% ethanol elutions of reuse, get the ethanol elution concentrating under reduced pressure, drying gets cinobufacin ethanol extract 6.1g.
(3) preparation prescription: cinobufacin ethanol extract 6.1g, mannitol 90g.
(4) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water, regulate pH value, with the ultrafilter membrane ultrafiltration of molecular cut off 10000, fill, lyophilization, promptly to 6.0-7.0 to ormal weight.
Embodiment 2:
(1) the crude drug crude drug is: dry maxima skin 450g.
(2) get dry maxima skin, clean, add 6 times of 80% alcohol reflux secondary, 45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, centrifugal 30 minutes of concentrated solution (2500r/min), get supernatant, last AB-8 absorption with macroporous adsorbent resin is earlier with 4 times of column volume water elutions, 3 times of column volume 35% ethanol elutions of reuse, get the ethanol elution concentrating under reduced pressure, drying gets cinobufacin ethanol extract 5.5g.
(3) preparation prescription: cinobufacin ethanol extract 5.5g, polyvinylpyrrolidone 95g.
(4) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water, regulate pH value, with the ultrafilter membrane ultrafiltration of molecular cut off 20000, fill, lyophilization, promptly to 6.0-7.0 to ormal weight.
Embodiment 3:
(1) the crude drug crude drug is: dry maxima skin 550g.
(2) get dry maxima skin, clean, add 6 times of 80% alcohol reflux secondary, 45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, centrifugal 30 minutes of concentrated solution (2500r/min), get supernatant, last NKA-9 absorption with macroporous adsorbent resin is earlier with 4 times of column volume water elutions, 5 times of column volume 30% ethanol elutions of reuse, get the ethanol elution concentrating under reduced pressure, drying gets the cinobufacin ethanol extract.
(3) preparation prescription: cinobufacin ethanol extract 7.5g, fructose 90g.
(4) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water, regulate pH value, with the ultrafilter membrane ultrafiltration of molecular cut off 30000, fill, lyophilization, promptly to 6.0-7.0 to ormal weight.
Embodiment 4:
(1) the crude drug crude drug is: dry maxima skin 500g.
(2) get dry maxima skin, clean, add 6 times of 80% alcohol reflux secondary, 45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, centrifugal 30 minutes of concentrated solution (2500r/min), get supernatant, last AB-8 absorption with macroporous adsorbent resin is earlier with 4 times of column volume water elutions, 3 times of column volume 50% ethanol elutions of reuse, get the ethanol elution concentrating under reduced pressure, drying gets the cinobufacin ethanol extract.
(3) preparation prescription: cinobufacin ethanol extract 6.4g, lactose 100g.
(4) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water to ormal weight, regulate pH value to 6.0-7.0, ultrafiltration is with the ultrafilter membrane fill of molecular cut off 10000, lyophilization, promptly.
Embodiment 5:
(1) the crude drug crude drug is: dry maxima skin 480g.
(2) get dry maxima skin, clean, add 6 times of 80% alcohol reflux secondary, 45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, centrifugal 30 minutes of concentrated solution (2500r/min), get supernatant, last D101 absorption with macroporous adsorbent resin is earlier with 4 times of column volume water elutions, 4 times of column volume 40% ethanol elutions of reuse, get the ethanol elution concentrating under reduced pressure, drying gets the cinobufacin ethanol extract.
(3) preparation prescription: cinobufacin ethanol extract 5.8g, glucosan 94.2g.
(4) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water, regulate pH value, with the ultrafilter membrane ultrafiltration of molecular cut off 20000, fill, lyophilization, promptly to 6.0-7.0 to ormal weight.
Embodiment 6:
(1) the crude drug crude drug is: dry maxima skin 520g.
(2) get dry maxima skin, clean, add 5 times of 80% alcohol reflux secondary, 45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, centrifugal 30 minutes of concentrated solution (2500r/min), get supernatant, last NKA-9 absorption with macroporous adsorbent resin is earlier with 4 times of column volume water elutions, 5 times of column volume 35% ethanol elutions of reuse, get the ethanol elution concentrating under reduced pressure, drying gets the cinobufacin ethanol extract.
(3) preparation prescription: cinobufacin ethanol extract 7.2g, mannitol 92.8g.
(4) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water, regulate pH value, with the ultrafilter membrane ultrafiltration of molecular cut off 10000, fill, lyophilization, promptly to 6.0-7.0 to ormal weight.
Claims (3)
1. cinobufotalin lyophilized powder, it is characterized in that it is to be made by cinobufacin ethanol extract 5.5-7.5 weight portion and pharmaceutic adjuvant 90-100 weight portion, wherein the indoles total alkaloid content is more than or equal to 30% in the cinobufacin ethanol extract, and its preparation method is following steps:
(1) gets dry maxima skin, clean, add doubly 80% alcohol reflux secondary of 5-6,45 minutes for the first time, 30 minutes for the second time, merge ethanol liquid, filter, filtrate being concentrated into contains 1g crude drug/ml, with the 2500r/min rotating speed with centrifugal 30 minutes of concentrated solution, get supernatant, go up nonpolar or low pole absorption with macroporous adsorbent resin, earlier with 3-4 times of column volume water elution, reuse 3-5 times of column volume 30%-50% ethanol elution, get the ethanol elution concentrating under reduced pressure, drying gets the cinobufacin ethanol extract;
(2) get above-mentioned cinobufacin ethanol extract and pharmaceutic adjuvant and mix, add the dissolving of injection water, add the injection water to ormal weight, regulating pH value to 6.0-7.0, is that 10000-30000, membrane material are the ultrafilter membrane ultrafiltration of polyacrylonitrile or polyether sulfone with molecular cut off, fill, lyophilization, promptly.
2. cinobufotalin lyophilized powder according to claim 1, wherein pharmaceutic adjuvant is a kind of in mannitol, lactose, polyvinylpyrrolidone, the glucosan.
3. cinobufotalin lyophilized powder according to claim 1, wherein the concentration of alcohol of macroporous adsorbent resin eluting is 35%-45%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101396373B (en) * | 2007-09-29 | 2011-04-06 | 四川省中医药科学院 | Cinobufacini extract and preparation method thereof |
| CN102028710A (en) * | 2010-12-03 | 2011-04-27 | 浙江大学 | Method for measuring contents of indole alkaloids in cinobufagin alcohol precipitation liquid |
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| CN1319522C (en) * | 2005-11-03 | 2007-06-06 | 郭斌阁 | Method for preparing cinobufotalin lyophilized powder |
| CN1846712B (en) * | 2006-01-16 | 2012-01-11 | 西安安健药业有限公司 | Cinobufagin emulsion for injection and its preparation process |
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| CN102973604B (en) * | 2011-06-02 | 2015-05-27 | 江苏省中医药研究院 | Toad skin extract dry powder inhalant and preparation method and applications thereof |
| CN105884855B (en) * | 2016-05-25 | 2017-09-15 | 安徽华润金蟾药业股份有限公司 | A kind of cinobufagin freezing purification system and its control method |
| CN107397748B (en) * | 2017-08-09 | 2018-10-02 | 黄娇英 | A kind of toad cake extract and preparation method thereof with anti-infectious function |
| CN108142933A (en) * | 2018-01-09 | 2018-06-12 | 河南牧农生物科技有限公司 | A kind of extraction process of toad slurry |
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2004
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101396373B (en) * | 2007-09-29 | 2011-04-06 | 四川省中医药科学院 | Cinobufacini extract and preparation method thereof |
| CN102028710A (en) * | 2010-12-03 | 2011-04-27 | 浙江大学 | Method for measuring contents of indole alkaloids in cinobufagin alcohol precipitation liquid |
| CN102028710B (en) * | 2010-12-03 | 2012-05-16 | 浙江大学 | Method for measuring contents of indole alkaloids in cinobufagin alcohol precipitation liquid |
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