WO2010091629A1

WO2010091629A1 - Chemical complexing directional separation and purification method for preparing high-purity beta-elemene raw material medicament

Info

Publication number: WO2010091629A1
Application number: PCT/CN2010/070577
Authority: WO
Inventors: 孙敏鸽; 李淑斌
Original assignee: 吕青松
Priority date: 2009-02-16
Filing date: 2010-02-09
Publication date: 2010-08-19
Also published as: CN101531563A

Abstract

Method for producing highly pure beta-elemene used as pharmaceutical raw material by chemical complexing directional separation and purification method, involves subjecting raw material containing 1% or more beta-elemene to silica gel column chromatography, removing volatile oil composition having high polarity, and removing impurity composition having low polarity from the remaining oil-phase by performing silver nitrite complex extraction process or silica gel column chromatography method involving silver nitrate binding, finally obtaining 95-99.9% content of beta-elemene through vacuum distillation or rectification. The pharmaceutical raw material containing beta-elemene can be blended with suitable excipients and formulated into oral delivery dosage form, such as oral emulsion, capsules, parenteral drug delivery formulation, such as injection, transdermal delivery drug, spray and suppository. The method is simple, low cost and high yield.

Description

Method for preparing high-purity elemene bulk drug by chemical complexation separation and purification method

The invention relates to a method for preparing high-purity ^-elemene bulk drug by chemical complexation separation and purification method.

Background technique

Elemene is isolated from zedoary turmeric oil and citronella oil. It has been widely used in the treatment of cancer. The earliest anticancer drug was made from zedoary turmeric oil, which can only be used locally. The treatment of cervical cancer in the form of tumor administration has a long course of treatment and inconvenient administration, but it cannot be effectively treated with this injection for various other cancers. In order to understand the limitations of the use of sputum oil, people have separated the elemene with a fixed ratio from zedoary turmeric oil and citronella oil to make elemene injection. In addition to local tumor administration and regional administration, the milk injection can also be intravenously administered to treat cervical cancer, brain tumors, digestive tract malignant tumors, malignant pleural effusion, malignant ascites and leukemia. Cancer, a wide range of clinical applications.

The main active ingredient of elemene to exert anti-tumor effect is ^-elemene, the Latin name of β-elemene

-曰enenum English name β-el en3⁄4ne, natural plant-derived elemene is generally (-) elemene, its chemical name is (1S 2S 4 ) 1-methyl-1-vinyl-2, 4- Diisopropenylcyclohexane, the structural formula is:

The molecular weight is 204; its content is directly related to the therapeutic effect, so people are looking for a method for preparing high-purity-elemene. Patent No. 93110091. 7 Separation of zedoary oil by silica gel column chromatography to obtain medicinal elemene, wherein the total elemene component is at 85 ° / ^, but this standard is far less than the current elemene raw material The requirements of the drug; Patent No. 200310121760. X was purified by two-step rectification combined with silica gel column chromatography to determine the content of 80% 92% 5-elemene, although the average content was obtained.

99. The probability of 9% elemene is small, because in this method, the isomer of ^-elemene is difficult to separate, and the patent is also vague about the source of the raw material; After analyzing the patents of other aspects of the olefinic drug substance, most of the patents are available. According to the boiling point of ^-elemene, it is separated by distillation column, the separation efficiency is low, the time is long, the operating conditions are very unstable, and the obtained elemene is generally the elemene isomer. mixture.

Ag is a group IB element, and its valence electron outer structure is 4 d ¹ ^^. It easily loses electrons and exhibits a +1 oxidized state. Ag has an ionic radius of 126 pm. At present, the Dewar-Chatt-Duncanson model (DCD model) is commonly used for the bonding of silver ions to carbon-carbon double bonds. The model considers that the bonding between silver ions and carbon-carbon double bonds involves two aspects of interdependence: First, the unsaturated electrons in the carbon-carbon double bond form a σ-coordination bond with the 5s orbital of the silver ion, which is a bond of the double bond to Ag ⁺ ; secondly, Ag ⁺ in turn gives a pair of d electrons to the carbon On the π* anti-bond orbit of the carbon double bond, a feedback π bond is formed, which is the bonding of Ag ⁺ to the double bond. Ag ⁺ complex extraction is a separation method based on the complexation of silver ions with unsaturated organic carbon-carbon bonds. In the aqueous solution of AgN0 ₃ , the silver ion can be complexed with an unsaturated organic substance having a carbon-ene ratio of 6 or less and having different types of carbon-carbon double bonds and having no steric hindrance under certain conditions. Due to the specificity of the chemical reaction, this method is highly selective, but has a small scope of application. This patent utilizes this rule to extract directional extraction of elemene from volatile oil.

This patent is based on the structural characteristics of β-elemene containing three terminal double bonds, separating β-elemene from a mixture of its isomers, followed by vacuum distillation or rectification. - The removal of silver or silver ions in elemene effectively ensures the purity of elemene, which is an important feature of this patent.

Summary of the invention

The object of the present invention is to overcome the problems of high content of elemene raw materials, complicated production equipment, high cost and poor extraction stability of instruments and equipments, and provide a low content of elemene. As a starting material, a method for preparing a high-purity ^-elemene bulk drug by chemical complexation separation and purification is used. The major breakthrough of the present invention lies in the fact that the anti-cancer active compound - elemene contains three terminal double bonds, and is prepared by silver nitrate aqueous solution complex extraction or silver nitrate-bonded silica gel column chromatography from the same as elemene. Separating the elemene from the isomer mixture effectively, 95.0%~99.9% high purity ^-elemene was prepared from the low content of elemene, which broke through the traditional extraction and purification methods. The separation and purification of elemene from the point of view of the boiling point of elemene, the separation of elemene and isomers is achieved, and the preparation process is simple, the reproducibility of separation and purification is good, and the production efficiency is obvious. improve.

The technical solution of the present invention is: removing the polar portion from the elemene starting material of different natural plant sources at a content of 1% by weight or more, and then extracting the polar portion by silica gel column chromatography, followed by silver nitrate complex extraction Or silver nitrate-bonded silica gel column chromatography to remove other polar isomer impurities; finally, the content of elemene in the range of 95.0% to 99.9% is obtained under vacuum distillation or rectification. Compared with the previous methods, the method has a wide range of raw materials, simple equipment, simple operation steps and high yield, and the production efficiency is obviously improved.

The method for preparing high-purity ^-elemene bulk drug by chemical complexation separation and purification comprises the following steps: a. using 1% or more of elemene as a raw material from natural plant sources;

b. The raw material obtained in step a is subjected to silica gel column chromatography to remove a portion having a large polarity, and a portion having a small polarity is collected; c. The portion obtained by the step b having a small polarity is extracted three times with an aqueous solution of an equal volume of 1.0 to 4.0 mol/L of silver nitrate, and the lower aqueous layer is separated by liquid separation, and extraction is continued two to five times with an equal volume of n-hexane. The mixture is extracted three times, and the upper layer of n-hexane is concentrated under reduced pressure to obtain a colorless oily liquid; or the portion of the polar portion obtained in step b is separated by a silver nitrate-bonded silica gel column chromatography, eluted with a solvent having a small polarity, and collected. The fraction containing elemene is reserved;

d.. taking the elemene sample obtained in step c as a raw material, performing vacuum distillation or rectification under high vacuum conditions, controlling the degree of vacuum to be l~7 mm Hg, and the temperature of the column is 115 ° C to 126 ° C, collecting The fraction having a temperature of from 63 ° C to 80 ° C gives -elecilene in an amount of from 95.0% to 99.9%.

The natural plant material used in the step a of the present invention has one or more of the roots, stems, leaves, flowers and seeds of the tubers and roots of the scutellaria, the leaves of the lemongrass and the yellow flowers; more than 1% of the elemene It is obtained by steam distillation, ultrasonic extraction, organic solvent extraction, supercritical fluid extraction or further vacuum distillation under vacuum distillation and molecular distillation.

The portion having a high polarity in the step b of the present invention means a component having a retention time shorter than that of elemene under the conditions of GC or HPLC detection; the component having a small polarity is a component having a retention time longer than elemene and the elemene. .

The elution solvent used in the silica gel column chromatography in step b, including one or more of petroleum ether, cyclohexane and diethyl ether; the polar component obtained by silica gel column chromatography needs to be detected by GC or HPLC to determine the ratio of The impurity components with low retention time of the olefin are removed. If there is residue in this part, this step should be repeated.

The method used in the extraction in step c is a combination of silver nitrate aqueous solution complex extraction and n-hexane extraction method; the concentration of silver nitrate used for extraction is 1.0~4.0 mol/L _; the whole process is nitrogen protection; the n-hexane used for extraction can be replaced with petroleum Ether, an organic solvent with a small polarity of ether.

The silver nitrate-bonded silica gel mentioned in the step c is prepared by the following method: 100 g of silica gel of 200 to 300 mesh is weighed, 160 mL of an aqueous solution containing 10 g of silver nitrate is added (soaked with silica gel), and heated in a boiling water bath for 30 min. (When stirring). After cooling and suction filtration, it was activated in a vacuum oven at 120 ° C for 20 hours for use.

Step c can also be separated on the silver nitrate-bonded silica gel column based on the sample obtained in step b, using a solvent having a small polarity as an elution solvent, and the solvent having a small polarity mainly includes petroleum ether, cyclohexane. One or more of n-hexanes are collected, and a fraction containing elemene is collected.

Step d is purified by vacuum distillation or rectification operation on the basis of the sample obtained in step c; the temperature of the distillation column or the rectification column is 115 ° C to 126 ° C _; the temperature of the collected fraction is 63 ° C to 80 ° C _;

In each step of the extraction method, extraction is carried out two to five times, preferably three times; the final preparation of elemene is from 95.0% to 99.9%.

The raw material obtained by the method of chemical complexation separation and purification method for preparing high-purity elemene bulk drug can be prepared into an oral administration preparation together with a pharmaceutically acceptable auxiliary material, and includes a conventional, sustained-release or controlled-release preparation; Or made into a non-gastrointestinal tract Formulations for administration include conventional, sustained release, controlled release or targeted formulations.

DRAWINGS

1 is a process flow diagram of the implementation of the present patent, wherein a is a raw material containing more than 1.0% of elemene from different natural plant sources; b is a silica gel column separation device; c is a silver nitrate extraction device; d is an organic solvent extraction device e is a vacuum rectification unit; f is a vacuum distillation unit; g is a high purity end product; h and i are organic solvent recovery units; j is a silver nitrate bonded silica gel column chromatography apparatus; (1) means vacuum The method of distillation; (2) refers to the method of vacuum distillation; (1) and (2) two parallel methods, one of which can meet the requirements.

detailed description

Example 1

a. The volatile oil is extracted from the tubers of the scorpion by steam distillation, wherein - the content of elemene is 8.1%, and 100 g of the volatile oil is used as a raw material;

b. After the above raw materials are freeze-filtered in a refrigerator at -4 ° C, the remaining oil phase is mixed with 100 g of 100-200 mesh silica gel, and the sample is applied to 1000 g of 200-300 mesh silica gel by wet packing. On the column, eluted with petroleum ether (60~90 ° C), the fractions with small polarity were collected, and the components with high polarity were found to be substantially removed by GC or HPLC. The content of elemene was 68.2%;

c 68.2% of the elemene obtained in step b is extracted three times with an aqueous solution of an equal volume of 1.0 mol/L silver nitrate, and the lower aqueous phase is separated by liquid separation, and the extraction is continued three times with an equal volume of n-hexane. The alkane is concentrated under reduced pressure to give a colorless oily liquid;

d. The colorless oil obtained in step c is used as a raw material, and vacuum distillation is performed by a high vacuum oil pump, and the vacuum degree is controlled to be 1 to 2 mm Hg, the temperature of the column is 115 ° C to 116 ° C, and the collection temperature is 63 ° C. The fraction of ~64 ° C gave -elecene at a content of 96.0%.

Example 2:

a. Take the fresh leaves of the citronella citronella as raw materials, and obtain the volatile oil of Java by steam distillation. After vacuum distillation, the content of elemene is 16.5%, and 800 g is used as the raw material.

b. Mix the above raw materials with 1500g of 100~200 mesh silica gel, use a wet packed column, and mix the sample on a 15000g 200~300 mesh silica gel column, elute with cyclohexane to collect small polarity. The fractions were found to be substantially clean by HPLC or HPLC, and the elemene content was 70.5%.

c. Extract 70.5% of the elemene obtained in step b with an aqueous solution of an equal volume of 1.8 mol/L silver nitrate three times, separate the aqueous layer by liquid separation, and continue extracting with an equal volume of n-hexane three times to The alkane was concentrated under reduced pressure to give a colorless oil.

d. The colorless oil obtained in step c is used as a raw material, and a vacuum distillation is performed using a high vacuum oil pump to control the degree of vacuum to 4~ 5 mm Hg, the temperature of the column was 120 ° C to 121 ° C, and the fraction having a temperature of 70 ° C to 71 ° C was collected to obtain a content of 95.8% - elemene.

Example 3:

a. Take the fresh leaves of a yellow flower as raw material, and extract it from the supercritical fluid of carbon dioxide to obtain the volatile oil of the yellow flower, wherein the content of ^-elemene is 14.3%, and the content of the elemene is 40.6% after continuous distillation. Take 500g as raw material. b. Mix the above raw materials with 800g of 100~200 mesh silica gel, use a wet packed column, and mix the sample on 8000g of 200~300 mesh silica gel column, elute with petroleum ether, collect small polarity. The composition, GC or HPLC detection: Some of the polar components are not removed; the components containing elemene are collected, passed through the silica gel column again, and the polar components are completely removed by GC or HPLC. The olefin content was 85.6%.

c. 85.6% of the elemene obtained in step b is extracted three times with an aqueous solution of an equal volume of 2.0 mol/L silver nitrate, and the lower aqueous layer is separated by liquid separation, and the extraction is continued three times with an equal volume of n-hexane. The alkane was concentrated under reduced pressure to give a colorless oil.

d. The colorless oil obtained in step c is used as a raw material, and the vacuum distillation is performed by a high vacuum oil pump, and the vacuum degree is controlled to be 3 to 4 mm Hg, and the temperature of the column is 117 to 118 ° C, and the reflux ratio is: 1 : 1. A fraction having a temperature of 66 ° C to 67 ° C was collected to obtain a content of 99.9% of elemene.

Example 4:

a. The volatile oil of Rhizoma Curcumae is obtained by steam distillation of the root of the medicinal material, wherein the content of ^-elemene is 7.5%, and then the content of 60.2% of elemene is obtained by molecular distillation, and 500 g is taken.

b. Mix the above materials with 1000g of 100~200 mesh silica gel, use a wet packed column, and place the sample on a 15000g 200~300 mesh silica gel column, elute with ether to collect a small polarity stream. According to GC or HPLC, it was found that the polar component was almost removed, and the elemene content was 87.2%.

c. 87.2% of the elemene obtained in step b is extracted three times with an aqueous solution of an equal volume of 1.0 mol/L silver nitrate, and the lower aqueous layer is separated by liquid separation, and the extraction is continued three times with an equal volume of n-hexane. The n-hexane was concentrated under reduced pressure to give a colorless oily liquid.

d. The colorless oil obtained in step c is used as a raw material, and the vacuum distillation is performed by a high vacuum oil pump, and the vacuum degree is controlled to be 1 to 2 mm Hg, the temperature of the column is 116 ° C to 117 ° C, and the collection temperature is 64 ° C. The fraction of ~65 ° C gave -elecene at a content of 99.1%.

Example 5

a. The volatile oil of Rhizoma Curcumae is obtained by steam distillation of the root of the medicinal material, wherein the content of ^-elemene is 7.5%, and then the content of 60.2% of elemene is obtained by molecular distillation, and 700 g is taken.

b. Mix the above raw materials with 1300g of 100~200 mesh silica gel, use a wet packed column, and mix the sample on 17000g. On a 200-300 mesh silica gel column, the mixture was eluted with diethyl ether to collect a small polarity fraction. The detection by GC or HPLC revealed that the polar component was substantially removed, and the elemene content was 85.3%.

c. 85.3% of the elemene obtained in step b is dissolved in an appropriate amount of petroleum ether, and slowly added dropwise to the upper layer of the silver nitrate-bonded silica gel column. After the sample is completely adsorbed, a small amount of silica gel is added to protect the column liquid surface. Then, elution with petroleum ether, fractions containing elemene were collected and concentrated to give a colorless oily liquid.

d. The colorless oil obtained in step c is used as a raw material, and vacuum distillation is performed by a high vacuum oil pump, and the vacuum degree is controlled to 3 to 4 mm Hg, the temperature of the column is 118 ° C to 119 ° C, and the collection temperature is 67 ° C. The fraction of ~68 ° C gave a content of 99.3% of elemene.

Example 6:

Elemene liposome preparation: liposome was prepared by ethanol injection method. (1) Weigh 2.0 g of cholesterol, 5.0 g of soybean lecithin and 0.75 g of elemene raw material in a small beaker, then add an appropriate amount of absolute ethanol to stir. It is dissolved to form an oil phase. (2) Measure 100ml PBS buffer in a three-necked flask, slowly inject the oil phase into the water phase with a syringe at a water bath temperature of 50 ° C and a magnetic stirring speed of 30 r / min, and then vacuum for 10 minutes. 7.5mg/ml of the drug. Or (3) adding 25% trehalose to the above-mentioned elemene liposome suspension, and lyophilizing to obtain elemene liposome powder, which can be rapidly dissolved by dilution with water before use. The liposome obtained by the preparation method has a particle diameter of about 100 nm and can be used for oral or injection administration.

Example 7

Preparation of elemene emulsion: (1) Weigh 180g of soybean oil, 15g of egg yolk phospholipid, 35g of TPGS, 10g of elemene raw material medicine, put it in a water bath, stir and melt, keep the temperature at 70 °C, as oil phase; (2) P _O l _OX am _er 188 3.0 g and polyethylene glycol 400 50 g were added to an appropriate amount of water for injection, dissolved by heating and stirring, and kept at a temperature of 70 ° C as an aqueous phase. The aqueous phase is dripped into the oil phase under stirring, and stirring is continued to form colostrum; (3) The colostrum is hooked twice by a 700 bar high-pressure milk, and rapidly cooled and solidified to obtain a 10 mg/mL elemene emulsion, the emulsion The particle size is less than 100 nm and can be administered orally or by injection.

Example 8

Preparation of elemene microemulsion for injection: (1) Weigh 100g of medium chain oil (MCT), 15g of soybean phospholipid, 2.5g of oleic acid, 8.5g of β-elemene raw material in a water bath, stir and melt, keep the temperature 75 ° C, as the oil phase; (2) Weigh P ₀ l _OX am _er 188 3.0g, Tween-80 2.0g and glycerol 85g added to the appropriate amount of water for injection, heated to stir to dissolve, keep the temperature at 75 ° C , as the water phase. The aqueous phase is dripped into the oil phase with stirring, and stirring is continued to form the elemene microemulsion; or (3) 20% glucose is added to the above-mentioned elemene microemulsion, and lyophilized to obtain an injection? The solid powder of the enee microemulsion can be quickly dissolved by dilution with water before use.

Example 9

Preparation of elemene nanolipid carrier: (1) Weigh 62.5g of glyceryl monostearate, 25.5g of soybean oil, 75g of HS-15, 1.0g of oleic acid, 5.0g of elemene in a water bath, stir and melt , keep the temperature at 75 ° C, as the oil phase; (2) weigh Poloxamerl88 5.0g was added to an appropriate amount of water for injection, heated and stirred to dissolve, and maintained at a temperature of 75 ° C as an aqueous phase. The aqueous phase is dripped into the oil phase under stirring, and stirring is continued to form colostrum; (3) The colostrum is uncured by 1200 bar high pressure nipple for 6 times, and rapidly cooled and solidified to obtain a suspension of elemene nanolipid carrier; (4) Add 15% mannitol to the above elemene nano-lipid carrier suspension, and spray-dry to obtain a solid powder of elemene nano-lipid carrier, which can be quickly dissolved by dilution with water before use. . Spray drying conditions: inlet temperature 150 ° C, outlet temperature 85 ° C, air volume 100%, flow rate 0.01%, yield 37.8%. The preparation can be administered orally or by injection, and has a sustained release effect.

Example 10

Preparation of elemene solid lipid nanoparticles: (1) Weigh 95.0g stearic acid, 25g of soy lecithin, 3.0g of oleic acid, 7.5g of elemene raw material, placed in a water bath, heated and stirred to maintain a temperature of 85° C, as the oil phase; (2) Weigh P ₀ l _OX am _er 188 5.0g, and add TPGS 18g to an appropriate amount of water for injection, dissolve it by heating and stirring, and maintain the temperature at 85 ° C as an aqueous phase. The aqueous phase is dripped into the oil phase under stirring, and stirring is continued to form colostrum; (3) The colostrum is subjected to a high pressure emulsion of 800 bar for 7 times, and rapidly cooled and solidified to obtain a suspension of elemene solid lipid nanoparticles; Or (4) adding 15% sucrose to the above-mentioned elemene solid lipid nanoparticle suspension, and vacuum-drying to obtain a solid powder of elemene solid lipid nanoparticle for injection, which can be quickly diluted with water before use. Dissolved. The preparation can be administered orally or by injection, and has a sustained release effect.

Example 11:

Preparation of elemene self-emulsifying soft capsule: Weigh 80.0 g of elemene raw material into propylene glycol, dissolve it at 40 °C, add 25.0 g of ethyl oleate, and mix it with Tween-85 45.0 g. After the hook, make a soft capsule.

Example 12:

Preparation of elemene transdermal patch: weigh 5.0g of elemene, 15g of compound penetration enhancer azone, 30g of menthol, 50g of propylene glycol as a latent solvent, after grinding, add acrylate copolymer to 100%, grind Are they coated at 80 μ? The PVC film was dried at 70 ° C to form a transparent solid dispersion sheet.

Example 13

Preparation of elemene suppository: 18 g of stearic acid and 25 g of semi-synthetic fatty acid ester were weighed and heated and melted in a 65 ° C water bath. Weigh 9.5g of elemene into the molten matrix three times, stir constantly to spread the drug, and when the mixture is viscous, pour into the model with lubricant, cool and solidify and then cut off the die. Overflow part, demoulding, that is.

Example 14

Preparation of elemene nanospheres: Weigh 5.0g of elemene into a solution of 7% polylactic acid or lactic acid-glycolic acid copolymer in dichloromethane, ultrasonically disperse to make a suspension, and then suspend The solution was slowly added dropwise to a 2.5% aqueous solution of polyethylene glycol. The dichloromethane was completely evaporated at room temperature for 2 hours. The microspheres were collected by vacuum filtration, washed with distilled water for 5 times, and dried under vacuum at room temperature for 48 hours. A semi-finished product of eucryptene microspheres, which can be formulated into an injection or an implant after being compounded with other solvents. Example 15

Preparation of elemene nano-liposome nasal drops: Weigh 2.0 g of soy lecithin, 1.0 g of cholesterol, 0.5 g of sodium cholate O.Olg and 0.85 g of elemene dissolved in 40 mL of chloroform solution, and evaporated at 65 ° C under reduced pressure. The lipid membrane was added to a 40 rrL phosphate buffer to oscillate and dissolved, and the pH was adjusted to 6.0. 0, 1 g of stearic acid amine was added, and 0. 05 g of Tween-80 was obtained to obtain a liposome dispersion of elemene. After the high-pressure milk hook machine was hooked for 7 times, a liposome suspension having a particle diameter of less than 100 nm was obtained, and 0.8 g of phosphatidylglycerol was added thereto to obtain a nasal administration preparation.

Example 16:

Preparation of elemene liposome spray: weigh 37.5g of soy lecithin, 2.5g of cholesterol, 0.3g of oleic acid, 0.01g of azone, vitamin E 0.03g, peppermint oil 0.3g, elemene 8.0g added to 40mL ethanol Heat and stir until completely dissolved. Add the ethanol drug solution to 160mL water in high-speed stirring (3000r/min), stir for 30min under nitrogen protection condition, and then hook it 5 times through 700bar high-pressure milk hook machine to obtain elemene. Liposomal solution. It was filtered through a dry G6 glass frit filter and dispensed into a spray bottle to obtain an elemene liposome spray.

Claims

Rights request

1. A method for preparing a high-purity elemene bulk drug by chemical complexation separation and purification method, characterized in that the elemene raw material having a content of 1% or more is removed by a silica gel column chromatography to remove a volatile oil having a large polarity The component, and then the remaining oil phase is removed by silver nitrate complex extraction or silver nitrate-bonded silica gel column chromatography to remove other impurities of small polarity, and finally the obtained oil phase is subjected to distillation under reduced pressure or rectification to obtain a content of 95.0% to 99.9. % of ^-elemene bulk drug.

The method for preparing a high-purity elemene bulk drug according to the chemical complexation separation and purification method according to claim 1, wherein the method comprises the steps of:

a. Containing more than 1% of elemene from natural plant sources;

b. The raw material obtained in step a is subjected to silica gel column chromatography to remove a portion having a large polarity, and a portion having a small polarity is collected; c the portion having a small polarity obtained in step b is used in an equal volume concentration of 1.0 to 4.0 mol/L of silver nitrate. The aqueous solution is extracted two to five times, preferably three times, and the lower aqueous layer is separated by liquid separation, and the extraction is continued two to five times with an equal volume of n-hexane, preferably three times, and the upper layer of n-hexane is concentrated under reduced pressure to obtain a colorless oily liquid; The fraction having a small polarity obtained in the step b is separated by a silver nitrate-bonded silica gel column chromatography, eluted with a solvent having a small polarity, and the fraction containing the elemene is collected for use;

d. The elemene sample obtained in step c is used as a raw material, and subjected to vacuum distillation or rectification under high vacuum conditions, the degree of vacuum is controlled to be 1 to 7 mm Hg, and the temperature of the column is 115 ° C to 126 ° C, and the collection temperature is The fraction of 63 ° C to 80 ° C gives -elecilene in an amount of from 95.0% to 99.9%.

3. The method for preparing a high-purity ^-elemene bulk drug according to the chemical complexation separation and purification method according to claim 2, wherein: 1% or more of the natural plant source of elemene is a tuber and root of the scorpion , one or more of the roots, stems, leaves, flowers and seeds of the leaves of the lemongrass and the yellow flowers; more than 1% of the elemene is subjected to steam distillation through different parts of the above natural plants, ultrasonic extraction , organic solvent extraction, supercritical fluid extraction or further by vacuum distillation, molecular distillation method for extraction and purification.

The method for preparing a high-purity elemene bulk drug according to the chemical complexation separation and purification method according to claim 2, wherein: the elution solvent used in the silica gel column chromatography in step b is low polarity. Solvent, including one or more of petroleum ether, cyclohexane, and diethyl ether; the polar component obtained by silica gel column chromatography needs to be detected by GC or HPLC to determine that the impurity component is less than the retention time of elemene. If this part has residuals, repeat this step.

The method for preparing a high-purity elemene bulk drug according to the chemical complexation separation and purification method according to claim 2, wherein the method for extracting in step c is silver nitrate aqueous solution complex extraction and n-hexane. The extraction method is combined; the concentration of silver nitrate used for the extraction is 1.0~4.0 mol/L _; the whole process is nitrogen protection; the n-hexane used for the extraction It can be replaced with petroleum ether, an organic solvent with a small polarity of ether.

6. The method for preparing a high purity ^-elemene bulk drug according to the chemical complexation separation and purification method according to claim 2, wherein: the silver nitrate-bonded silica gel mentioned in the step C is used in the following The method is made: Weigh 200~

300 g of silica gel 100 g, 160 mL of an aqueous solution containing 10 g of silver nitrate was added to immerse the silica gel, and the mixture was stirred for 30 minutes in a boiling water bath, stirred, filtered, and activated in a vacuum oven at 120 ° C for 20 hours.

The method for preparing a high-purity ^-elemene bulk drug according to the chemical complexation separation and purification method according to claim 2, wherein: step c is based on the sample obtained in step b, and is subjected to silver nitrate bonding. It is separated by a silica gel column, and a solvent having a small polarity is used as an elution solvent, and a fraction containing elemene is collected, and a solvent having a small polarity includes one or a kind of petroleum ether, cyclohexane and n-hexane. the above.

The method for preparing a high-purity elemene bulk drug according to the chemical complexation separation and purification method according to claim 2, wherein the step d is based on the sample obtained in the step c, and is subjected to vacuum distillation or Distillation operation to purify; the temperature of the distillation column or the rectification column is 115 ° C ~ 126 ° C _; the temperature of the collected fraction is 63 ° C ~ 80 ° C _;

The raw material obtained by the method for preparing a high-purity elemene bulk drug according to the chemical complexation separation and purification method according to claim 2, which is characterized in that it is orally administered together with a pharmaceutically acceptable adjuvant. Formulations, which include conventional, sustained release or controlled release formulations; or formulations for parenteral administration, which include conventional, sustained release, controlled release or targeted formulations.