CN1305999A - Process for extracting taxol from filtrate of enqlish yew cell culturing liquid - Google Patents
Process for extracting taxol from filtrate of enqlish yew cell culturing liquid Download PDFInfo
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- CN1305999A CN1305999A CN 01107410 CN01107410A CN1305999A CN 1305999 A CN1305999 A CN 1305999A CN 01107410 CN01107410 CN 01107410 CN 01107410 A CN01107410 A CN 01107410A CN 1305999 A CN1305999 A CN 1305999A
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- taxol
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Abstract
A process for extracting taxol from the filtrate of enqlish yew cell calturing liquid includes fully mixing the macroreticular adsorption resin with said filtrate or passing said filtrate through the macroreticular adsorption resin column, eluting the taxusol adsorbed by said resin with organic solvent and concentrating. Its advantages include simple process, and no environmental pollution.
Description
The present invention relates to a kind of method of from yew plant cells nutrient solution filtrate, extracting taxol.
Taxol is a kind of anticarcinogen for the treatment of cancers such as mammary cancer, ovarian cancer, lung cancer clinically, have good efficacy, and toxic side effect is less, multinational approved production in the China and the world and application, and demand increases day by day.But at present, its main source is a plant, and the plant resources amount is very limited, and is protected, and is far apart with requirement.For opening up the new source of taxol, we utilize Plant Biotechnology, have carried out yew plant cells and have cultivated the research of producing taxol, obtain the expection progress, have shown the realization manufacturing feasibility.By evidence, under substratum and culture condition that we set, yew cell synthetic taxol in culturing process constantly is discharged in the nutrient solution, and about 80% amount is attracted on the colloidal particle of nutrient solution.In the case, if use organic solvent CH
2CL
2Wherein taxol is extracted, not only consume a large amount of CH
2CL
2Solvent, extraction efficiency is low, and needs main equipment, consumes a large amount of energy.We use flocculation agent that nutrient solution is carried out rapid flocculation clarification, filters, and have solved the particulate solid substance that adsorbs a large amount of taxols and the separation problem (this institute patent applied for, application number are 00122083.7) of liquid effectively.The solids of the highly enriched taxol of processing small volume is more convenient, much economical than a large amount of nutrient solutions of extraction.Because a large amount of filtrates of carrying out after the solid-liquid separation still contain a certain amount of taxol, but volume is big, content is low.Use conventional organic solvent extracting access method, will run into above-mentioned mentioned same rough sledding.
Purpose of the present invention just provide a kind of from yew cell nutrient solution filtrate enrichment extract the method for taxol, that is to say, with macroporous adsorbent resin from the filtered liquid of the yew cell nutrient solution that contains taxol or other methods that contain the aqueous solution of taxol and contain adsorbing and extracting taxol in the methanol aqueous solution of yew cell nutrient solution extract of taxol.
The present invention can be realized by following mode: macroporous adsorbent resin is put into the test solution that contains taxol, shake absorption 5～6 hours, the pH value of test solution is 5.5～6.5, after absorption is finished,, can be obtained height after concentrating and contain the taxol enriched material by the taxol of resin absorption with the organic solvent wash-out.Also macroporous adsorbent resin can be adorned post, the macroporous adsorbent resin that allows test solution flow through in the post adsorbs, and after absorption is finished, by the taxol of resin absorption, equally can obtain enriched material that height contain taxol after concentrated with the organic solvent wash-out.Macroporous adsorbent resin is S-8, AB-8, X-5, D4020, NKA-9 (Chemical Plant of Nankai Univ.), LD605 (China LanXing morning twilight chemical research institute), XAD-4 (import packing).The LD605 resin with methyl alcohol or 50% ethanol elution by the taxol of absorption with macroporous adsorbent resin.S-8, AB-8, X-5, D4020, NKA-9 or XAD-4 resin use the dehydrated alcohol wash-out by the taxol of absorption with macroporous adsorbent resin.Test solution is 50% methanol solution that contains taxol, perhaps contains the filtrate of the yew cell nutrient solution of taxol, and pH value is 5.6～5.8.The yew cell nutrient solution comprises the cell culture fluid of Chinese Ramulus et folium taxi cuspidatae, taxus chinensis in northeast, taxusyunnanensis, southerm yew, Xizang Taxus chinensis, yewtree or hybrid Chinese yew.
The present invention has simplified technology, has reduced the cost of extraction separation taxol, has easy, efficient and is easy to industrialized advantage, can save a large amount of organic solvents, reduces main equipment expense and save energy, avoids contaminate environment.
Below in conjunction with embodiment, the invention will be further described.
Method of the present invention is: 1. macroporous adsorbent resin is successively handled the washing impurity elimination with the HCL solution of the NaoH of distilled water, 1mol and 1mol, distilled water, dehydrated alcohol, distilled water etc.2. the macroporous adsorbent resin that will quantitatively handle well is put into the filtrate of the quantitative yew plant cells nutrient solution that contains taxol or is contained methanol aqueous solution or other aqueous solution that contains taxol of the yew plant cells nutrient solution extract of taxol, shake absorption 5～6 hours, the test solution pH value is 5.5～6.5, or after macroporous adsorbent resin loaded chromatography column, above-mentioned test solution is adsorbed to taxol by chromatography column.3. filter, collect macroporous adsorbent resin that has adsorbed taxol and the test solution that was adsorbed taxol respectively.4. adsorbed the macroporous adsorbent resin of taxol and used CH with dehydrated alcohol or methanol-eluted fractions
2CL
2The test solution of taxol was adsorbed in extraction, and dehydrated alcohol or meoh eluate constant volume are equipped with survey; Reclaim CH
2CL
2To doing, with dissolve with methanol washing and constant volume.5. HPLC detects the dehydrated alcohol of constant volume or the taxol amount in the meoh eluate.6. by above-mentioned detection by taxol residual quantity in the elution amount of the taxol of absorption with macroporous adsorbent resin and the test solution and the original content of taxol in the test solution, calculate adsorptive capacity, eluting rate of adsorptive capacity, the unit weight resin of macroporous adsorbent resin etc.
Embodiment one
Macroporous adsorbent resin is to the absorption property test of 50% methanol solution of the paclitaxel extract of taxus chinensis cell nutrient solution.It is operating as: measure the methanol solution that certain volume contains the taxus chinensis cell nutrient solution paclitaxel extract of quantitative taxol (detecting with HPLC) and add in the triangular flask, add equivalent distilled water (pH value is 6) again, shake up, make it become 50% methanol solution that contains taxol, add the macroporous adsorbent resin (institute's macroporous adsorbent resin that tries is handled according to its medical use technology requirement fully) of anticipating through weighing again, the macroporous adsorbent resin of this test has S-8, AB-8, X-5, XAD-4, D4020, NKA-9, LD605 etc.The test solution that adds resin is positioned over and shakes absorption 5 hours on the shaking table.Filter, separate the resin that has adsorbed taxol,, detect the elution amount of taxol behind the constant volume with HPLC except LD605 is that other resins that adsorbed taxol all adopt the dehydrated alcohol wash-out 5 times with methyl alcohol or its taxol of 50% ethanol elution; Crossed the test solution CH of taxol by resin absorption
2CL
2Extract 3 times, be concentrated into driedly, dissolve with methanol and washing detect taxol residual quantity in this test solution with HPLC behind the constant volume, by the original content of taxol in the test solution, calculate adsorptive capacity, the eluting rate of macroporous adsorbent resin.
1. the former content of adsorptive capacity=test solution-test solution residual quantity
2. eluting rate=elution amount/adsorptive capacity * 100% test-results such as table one:
| The resin title | Amount of resin (dry weight) (g) | Taxol amount (mg/ml) in the test solution | Taxol residual quantity (mg) in the test solution | Adsorptive capacity (mg) | 1 gram resin absorption amount (mg) | Elution amount (mg) | Eluting rate (%) |
| ???S-8 | ??0.13 | ?2.12mg/12ml | ?????0.9562 | ??1.1638 | ?????8.9 | ???0.978 | ????84.03 |
| ???AB-8 | ??0.22 | ?2.136mg/40ml | ?????0.2792 | ??1.8568 | ?????8.4 | ???1.7436 | ????93.90 |
| ???X-5 | ??0.20 | ?2.165mg/40ml | ?????0.4488 | ??1.7162 | ?????7.8 | ???1.6820 | ????98.0 |
| ???XAD-4 | ??0.58 | ?3.576mg/50m1 | ?????0.291 | ??3.285 | ?????5.66 | ???3.125 | ????95.59 |
| ???D4020 | ??0.20 | ?2.136mg/40ml | ?????0.621 | ??1.515 | ?????7.58 | ???1.423 | ????93.92 |
| ???NKA-9 | ??0.15 | ?0.9381mg/10ml | ?????0.0693 | ??0.8688 | ?????5.79 | ???0.815 | ????93.81 |
| ???LD605 | ??0.30 | ?1.4145mg/20ml | ?????0.190 | ??1.2245 | ?????4.08 | ???1.181 | ????96.44 |
Find out that from table one data 7 kinds of macroporous adsorbent resins all can adsorb taxol in the methanol solution (50%) of the paclitaxel extract of taxus chinensis cell nutrient solution, but the adsorptive capacity of every gram dried resin there are differences; Wherein the adsorptive capacity of S-8 and two kinds of every grams of resin of AB-8 is high than other resins, is respectively 8.9mg and 8.4mg.The adsorptive capacity of 3 kinds of every grams of resin such as LD605, NKA-9, XAD-4 is lower, is respectively 4.08mg, 5.79mg and 5.66mg.And the eluting rate of 7 kinds of adsorbed taxols of macroporous adsorbent resin is 84% except that S-8, and remaining resin is all more than 93%.X-5 is 98%, and LD605 is 96.44%, and XAD-4 is 95.59%.
Embodiment two
Macroporous adsorbent resin is used for the taxol that the flocculate and clarify filtrate filtered of taxus chinensis cell nutrient solution is extracted in enrichment.Its operating process is as follows: measure the taxus chinensis cell nutrient solution and add in the triangular flask through the filtered liquid (the HPLC method is measured its content of taxol) of flocculate and clarify, pH value is 5.8, adds the wet basis macroporous adsorbent resin of weighing again, is placed on shaking table and shakes absorption 5 hours, filter, gained filtrate is used CH
2CL
2Extract 3 times, reclaim CH
2CL
2To doing, with dissolve with methanol washing and constant volume, the HPLC method detects content of taxol, is in the test solution residual quantity of taxol behind absorption with macroporous adsorbent resin; Resin dehydrated alcohol wash-out 5 times of having adsorbed taxol, constant volume.Detect the elution amount that is adsorbed taxol with the HPLC method.Go out macroporous adsorbent resin adsorptive capacity, elution amount, eluting rate and rate of recovery to taxol in the flocculate and clarify filtrate filtered of taxus chinensis cell nutrient solution by above data computation.
The former content of the rate of recovery=elution amount/test solution * 100% test-results such as table two:
| The resin title | Amount of resin (dry weight) (g) | Taxol amount (mg/ml) in the test solution | Taxol residual quantity (mg) in the test solution | Adsorptive capacity (mg) | Elution amount (mg) | Eluting rate (%) | The rate of recovery (%) |
| ??S-8 | ???5.44 | ????2.52mg/400ml | ????0.1 | ??2.42 | ??2.40 | ??99.2 | ??95.2 |
| ??AB-8 | ???0.82 | ????0.325mg/100ml | Do not detect | ??0.325 | ??0.3172 | ??97.6 | ??97.6 |
| ??X-5 | ???0.39 | ????0.1625mg/50ml | Do not detect | ??0.1625 | ??0.1368 | ??84.2 | ??84.2 |
| ??XAD-4 | ???2.3 | ????1.26mg/200ml | ????0.376 | ??0.889 | ??0.831 | ??93.5 | ??65.95 |
| ??D4020 | ???0.25 | ????0.2255mg/50ml | Do not detect | ??0.2255 | ??0.2230 | ??98.89 | ??98.89 |
| ??NKA-9 | ???1.68 | ????1.26mg/200ml | ????0.123 | ??1.134 | ??1.122 | ??98.9 | ??82.69 |
| ??LD605 | ???0.15 | ????0.1625mg/50ml | Do not detect | ??0.1625 | ??0.1585 | ??97.54 | ??97.54 |
Find out that from table two data on embodiment one experimental basis, when 7 kinds of macroporous adsorbent resins were used for the taxol of enrichment extraction taxus chinensis cell nutrient solution filtrate, under the excessive slightly situation of resin, taxol can be adsorbed fully in the test solutions more than half; By the eluting rate of resin absorption taxol, except that X-5 is 84.2%, all more than 93.5%, S-8 is up to 99.2% for all the other; By the rate of recovery of original taxol in resin absorption and the relative test solution of wash-out taxol, remove XAD-4 and X-5 and be respectively 65.9% and 84.2%, NKA-9 is beyond 82.69%, all the other rate of recovery are all up between 95.2%～97.6%, illustrate that suitable macroporous adsorbent resin can efficiently concentrating extracts and reclaim the taxol in the test solution.
Embodiment three
Measure the paclitaxel extract methanol solution of 2 parts of each 5ml taxus chinensis cell nutrient solutions, (it is 0.76mg/5ml that the HPLC method is measured its content of taxol) adds in the triangular flask, adds 5ml distilled water again, shakes up standbyly, and pH value is 5.8.Take by weighing wet basis macroporous adsorbent resin X-5 and each 1g of AB-8 (0.4g dry weight) of having handled well in addition respectively.Be respectively charged in the glass column of 2 40cm * 0.8cm, with after the distilled water balance, above-mentioned 2 parts of test solutions getting ready adsorbed for 5 times respectively by the macroporous adsorbent resin in the pillar, HPLC detects effluent liquid and does not contain till the taxol.By the taxol of resin absorption 6 times, ethanol eluate constant volume 50mml detects wherein taxol elution amount with HPLC with the desorb of dehydrated alcohol wash-out.
Test-results such as table three:
| The resin title | Taxol amount (mg) in the test solution | Adsorptive capacity (mg) | Elution amount (mg) | Eluting rate (%) | The rate of recovery (%) |
| ????X-5 | ?????0.76 | ??0.76 | ?????0.703 | ????92.5 | ????92.5 |
| ?AB-8 | ?????0.76 | ??0.76 | ?????0.70 | ????92.1 | ????92.1 |
Find out from table three data, utilize macroporous adsorbent resin that taxol in the test solution is adsorbed and wash-out, under the excessive slightly situation of resin with test solution in taxol adsorb fully, the elution amount and the rate of recovery are all more than 92%.With the effect basically identical that utilizes macroporous adsorbent resin to be dispersed among the embodiment one, two to shake in the test solution absorption and wash-out.
Claims (8)
1, the method for enrichment extraction taxol from yew cell nutrient solution filtrate, it is characterized in that macroporous adsorbent resin is put into the test solution that contains taxol, shake absorption 5～6 hours, the pH value of test solution is 5.5～6.5, after absorption is finished, by the taxol of resin absorption, can obtain enriched material that height contain taxol after concentrating with the organic solvent wash-out.
2, the method for enrichment extraction taxol from yew cell nutrient solution filtrate, it is characterized in that macroporous adsorbent resin is adorned post, the macroporous adsorbent resin that allows test solution flow through in the post adsorbs, after absorption is finished, by the taxol of resin absorption, can obtain enriched material that height contain taxol after concentrating with the organic solvent wash-out.
3, according to claim 1 or 2 described from yew cell nutrient solution filtrate enrichment extract the method for taxol, it is characterized in that macroporous adsorbent resin is S-8, AB-8, X-5, XAD-4, D4020, NKA-9 or LD605.
4, according to claim 1 or 2 described from yew cell nutrient solution filtrate enrichment extract the method for taxol, it is characterized in that test solution is 50% methanol solution that contains taxol.
5, according to claim 1 or 2 described from yew cell nutrient solution filtrate enrichment extract the method for taxol, it is characterized in that test solution is the filtrate that contains taxol yew cell nutrient solution, PH is 5.5～6.5.
6, according to claim 3 described from yew cell nutrient solution filtrate enrichment extract the method for taxol, it is characterized in that with methyl alcohol or 50% ethanol elution by the taxol of LD605 resin absorption.
7, according to claim 3 described from yew cell nutrient solution filtrate enrichment extract the method for taxol, it is characterized in that with the dehydrated alcohol wash-out by the taxol of absorption with macroporous adsorbent resin such as S-8, AB-8, X-5, D4020, NKA-9 or XAD-4.
8, according to claim 1 or 2 described from yew cell nutrient solution filtrate enrichment extract the method for taxol, it is characterized in that the yew cell nutrient solution comprises the cell culture fluid of Chinese Ramulus et folium taxi cuspidatae, taxus chinensis in northeast, taxusyunnanensis, southerm yew, Xizang Taxus chinensis, yewtree or hybrid Chinese yew.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011074108A CN1166655C (en) | 2001-01-03 | 2001-01-03 | Process for extracting taxol from filtrate of enqlish yew cell culturing liquid |
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| CNB011074108A CN1166655C (en) | 2001-01-03 | 2001-01-03 | Process for extracting taxol from filtrate of enqlish yew cell culturing liquid |
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| CN1166655C CN1166655C (en) | 2004-09-15 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298712C (en) * | 2004-12-27 | 2007-02-07 | 梅县梅雁生物工程研究所 | Method for elementary separating 10-noracetyl Baccatins III from branches and leaves of yew |
| WO2008151526A1 (en) * | 2007-06-08 | 2008-12-18 | Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences | A method of inducing taxane production |
| CN101319199B (en) * | 2007-06-08 | 2010-10-27 | 中国科学院大连化学物理研究所 | Method for cell abduction generation of taxone with Chinese yew |
| CN101314597B (en) * | 2008-07-04 | 2010-12-01 | 华中科技大学 | Method for separating paclitaxel from yew cell suspending culture solution |
| CN101177421B (en) * | 2006-11-07 | 2010-12-15 | 上海天伟生物制药有限公司 | Method for preparing high-purity taxone compounds |
| CN102417492A (en) * | 2011-12-07 | 2012-04-18 | 福建紫杉园生物有限公司 | Method for separating and purifying paclitaxel |
| CN102653528A (en) * | 2012-04-19 | 2012-09-05 | 重庆市碚圣农业科技股份有限公司 | Method for separating purified paclitaxel and 10 diaminobenzidine (DAB) III by utilizing macroporous resin |
| CN103570647A (en) * | 2013-11-06 | 2014-02-12 | 湖南农业大学 | Method for preparing high-purity paclitaxel from taxus chinensis cell culture fluid |
-
2001
- 2001-01-03 CN CNB011074108A patent/CN1166655C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298712C (en) * | 2004-12-27 | 2007-02-07 | 梅县梅雁生物工程研究所 | Method for elementary separating 10-noracetyl Baccatins III from branches and leaves of yew |
| CN101177421B (en) * | 2006-11-07 | 2010-12-15 | 上海天伟生物制药有限公司 | Method for preparing high-purity taxone compounds |
| WO2008151526A1 (en) * | 2007-06-08 | 2008-12-18 | Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences | A method of inducing taxane production |
| CN101319199B (en) * | 2007-06-08 | 2010-10-27 | 中国科学院大连化学物理研究所 | Method for cell abduction generation of taxone with Chinese yew |
| CN101314597B (en) * | 2008-07-04 | 2010-12-01 | 华中科技大学 | Method for separating paclitaxel from yew cell suspending culture solution |
| CN102417492A (en) * | 2011-12-07 | 2012-04-18 | 福建紫杉园生物有限公司 | Method for separating and purifying paclitaxel |
| CN102653528A (en) * | 2012-04-19 | 2012-09-05 | 重庆市碚圣农业科技股份有限公司 | Method for separating purified paclitaxel and 10 diaminobenzidine (DAB) III by utilizing macroporous resin |
| CN102653528B (en) * | 2012-04-19 | 2014-07-16 | 重庆市碚圣农业科技股份有限公司 | Method for separating purified paclitaxel and 10 diaminobenzidine (DAB) III by utilizing macroporous resin |
| CN103570647A (en) * | 2013-11-06 | 2014-02-12 | 湖南农业大学 | Method for preparing high-purity paclitaxel from taxus chinensis cell culture fluid |
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| CN1166655C (en) | 2004-09-15 |
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