CN101402544A - Industrial production method of high-purity beta-elemi alkene bulk medicament - Google Patents
Industrial production method of high-purity beta-elemi alkene bulk medicament Download PDFInfo
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Abstract
The invention provides a method for preparing high-purity beta elemene from natural plants containing the beta elemene such as curcuma zedoary (earthnuts or tubers of the curcuma zedoary), cedronella (fresh leaves of the cedronella), yellowtop (roots, stems, leaves, flowers and seeds of the yellowtop) and so on, which can improve the production efficiency from starting materials to the high-purity beta elemene and reduce the production cost. Compared with the prior art, the method is mainly different in that the roots, stems, leaves, flowers and seeds of the natural plants are taken as raw materials; oleum volatile of specific parts of the natural plants is obtained by methods for extracting different oleum volatiles, and is rectified by the rectification method to obtain the beta elemene with high content; impurity compositions are removed by the macroporous adsorption resin separation method or macroporous adsorption resin combined with the ethanol extraction method, and the silver nitrate complex extraction method in turn; and finally the beta elemene with the content between 95.0 and 99.9 percent is obtained through reduced pressure distillation or rectification. The bulk pharmaceutical chemicals not only can be prepared into oral dosing preparation such as emulsion oral liquid, self-emulsifying/ self-microemulsifying capsules, soft capsules and so on, but also can be prepared into non-alimentary dosing preparation such as emulsion injection, liquid drugs injection, transdermal absorbent, lung sprays, suppository and so on. The method has the advantages of novel design, simple apparatus, concise operating steps, obvious shortened operating time, improvement of the production efficiency and high yield coefficient, and is suitable for industrialized production.
Description
Technical field:
The present invention relates to a kind of industrialized preparing process that obtains the high-purity beta-Elemene bulk drug.
Background technology:
Elemenum is separating in zedoary turmeric oil, the pamorusa oil, now be widely used in the treatment cancer, the cancer therapy drug of Ying Yonging is to make Oleum Curcumae injection with zedoary turmeric oil the earliest, this injection liquid can only be treated cervical cancer with the mode of local knurl body administration, its course of treatment, long, administration operation inconvenience then can't effectively be treated with this injection liquid for other various cancers.Use circumscribed problem in order to solve Oleum Curcumae injection, people will have the Elemenum of fixed mixing ratio composition and separate from zedoary turmeric oil, pamorusa oil, make elemene injection.This emulsion injection except that can the administration of local knurl body, the regional administration, but also intravenous injection can be treated multiple cancers such as cervical cancer, brain tumor, malignant tumor of digestive tract, malignant pleural effusion, malignant abdominal cavity effusion and leukemia, clinical application range is wider.
The Herba Solidaginis main component of essential oil of discovering in recent years is terpenes and alcohols material, mainly contains δ-Elemenum, beta-elemene, caryophyllene, β-farnesene, β one cadinene, different big myrcene D etc.Contain high-load anti-tumor function composition Elemene vinyl compound in the volatile oil of Herba Solidaginis leaf texture.Therefore Herba Solidaginis can be used as the new raw material sources of beta-elemene and is developed.
The main effective constituent of Elemenum performance antitumor action is beta-elemene, the Latin of beta-elemene is called β-Elemenum, English β-elemene by name, chemistry (1S, 2S, 4R) 1-methyl isophthalic acid-vinyl-2 by name, 4-diisopropenyl hexanaphthene, structural formula is:
Molecular weight is 204, and its content size is directly connected to the quality of therapeutic action, so people are in the method for seeking to prepare high-purity beta-Elemene.In the patent No. is to adopt the rectifying column curcuma zedoary oil to carry out precision fractional distillation in 93110091.7 first, but the content of Elemenum only is 0.4～1.5g/mL; The patent No. is in 98106848.0, and beta-elemene content is adopted secondary rectifying at the pamorusa oil offal more than 80%, and obtaining content is 96.4% beta-elemene; The patent No. is 02132984.2 to have announced a kind of high nurity elemene anti-cancer medicine and preparation method thereof, and the content of beta-elemene is 75%～99.9%, but obtains the content instability of beta-elemene in this way; The patent No. is among the 200310121760.X it to be optimized on this basis, though obtained average content at 98%～99.9% beta-elemene, its raw material is the 80%-92% beta-elemene, and to originate very limited.The factor that influences the beta-elemene content in the above patent is more, and the extraction yield circulation ratio of beta-elemene is relatively poor.The patent No. is to adopt supercritical fluid extraction-rectifying column coupling technique that the beta-elemene in curcuma zedoary medicinal material and the zedoary turmeric oil is extracted in 200410064570.3 first, simplified the experimental implementation step greatly, shortened extraction time, but the extraction content of Elemenum only is 25%～33%, far do not reach the requirement of production of raw medicine, supercritical extraction equipment and instrument operational stability is relatively poor simultaneously; The patent No. is that the synchronous rectifier unit of 200510049615.4 employing G-row's formulas separates the beta-elemene in the Rhizoma Curcumae volatile oil, though content has reached more than 93%, but because this apparatus structure complexity, and a rectifying column goes wrong and directly can have influence on the separating effect of next rectifying column, so suitability for industrialized production can run into very big problem; The patent No. is 200610129740.0 to adopt molecular distillation methods that two pairs of versions are received the pamorusa oil submember to extract, the content that obtains beta-elemene is 85%-95%, but, use so be unsuitable for suitability for industrialized production because the backwardness of molecular distillation fundamental research and the research of mass-and heat-transfer mechanism has restricted the popularization of molecular distillation technique greatly.The patent No. is 200610052575.3 to be raw material with the Herba Solidaginis medicinal material, adopt the method for silica gel column chromatography to obtain beta-elemene content and be up to 97.4%, but the production of sample needs a large amount of silica gel and organic solvent in batches, is not adapted to industrial production.
Sum up above extracting and purifying method, major part is the boiling point difference according to beta-elemene, adopts rectifying column to separate, and separation efficiency is low, and length consuming time, operational condition are very unstable, and can not get highly purified beta-elemene.This patent considers that from the constructional feature of beta-elemene itself it can carry out complexing with Silver Nitrate, thus can be from volatile oil effective single-minded extraction beta-elemene, this is an important feature of this patent.
Ag is an IB family element, and its valence electron shell structure is 4d
105s
1, it is easy to lose electronics and presents+1 valency oxidation state, and the ionic radius of Ag is 126pm.At present, to the Cheng Jian of silver ions and carbon-carbon double bond, generally adopt Dewar-Chatt-Duncanson model (DCD model).This model thinks that the Cheng Jian of silver ions and carbon-carbon double bond comprises complementary two aspects on: one, and the 5s track of unsaturated electronics and silver ions forms a σ coordinate bond in the carbon-carbon double bond, and this is that two keys are to Ag
+Bonding; Its two, Ag
+Provide the π of a pair of d electronics conversely to carbon-carbon double bond
*On the antibonding(molecular)orbital, form feedback π key, this is Ag
+Bonding to two keys.Ag
+Complexing abstraction is based on the separation method of silver ions and the complex reaction of unsaturated compounds carbon-carbon double bond.At AgNO
3In the aqueous solution, silver ions can with carbene than smaller or equal to 6, contain dissimilar carbon-carbon double bonds and do not have sterically hindered unsaturated compounds to carry out complex reaction under certain condition.Because the specificity of chemical reaction, this method selectivity is strong, but the scope of application is little.This patent is to utilize this rule from oil phase beta-elemene to be carried out directed complexometric extraction.
The roughly processing step of this patent is: with the natural phant that contains beta-elemene is raw material, after the process different methods extracts volatile oil, obtain content and be the beta-elemene raw material more than 1%, after low-boiling monoterpene and sesquiterpenoid are removed in the process rectification under vacuum, the gained cut removed in conjunction with the alcohol extraction method by macroporous adsorbent resin partition method or macroporous adsorbent resin contain the big compound of oxygen terpenes polarity, the gained oil phase adopts silver nitrate aqueous solution to carry out the orientation extraction, strip with normal hexane, sample behind the concentrating under reduced pressure adopts the vacuum decompression distillation to obtain content at 95.0%～99.9% beta-elemene product again.
Summary of the invention:
The objective of the invention is for overcome existing high-content beta-elemene raw material sources limitation in the prior art, production unit is complicated and involve great expense and plant and instrument extracts problems such as poor stability, providing a kind of is starting raw material with the natural phant that contains beta-elemene, the novel method of preparation high-purity beta-Elemene bulk drug.Important breakthrough of the present invention is from the constructional feature of anti-cancer active compound beta-elemene itself, adopt corresponding separation purification method, realized that directly preparing content from low levels beta-elemene raw material is high-purity beta-elemene of 95.0%～99.9%, broken through the limitation of only coming it is carried out separation and purification in traditional extracting and purifying method from the angle of beta-elemene boiling point, this method preparation technology is simple simultaneously, the separation and purification favorable reproducibility, obvious raising of production efficiency and yield are higher, adapt to need of industrial production.
Technical solution of the present invention is: the volatile oil that methods such as employing wet distillation will contain in the beta-elemene plant's root leaf flower seed extracts; Gained volatile oil adds in the rectifying tower and carries out high vacuum rectification, collects beta-elemene content at 16.0%～60.0% cut; Then the gained cut is passed through macroporous adsorbent resin partition method or macroporous adsorbent resin in conjunction with the alcohol extraction method, the Silver Nitrate complexing abstraction is removed other impurity; The final content that obtains under molecular distillation is at 95.0%～99.9% beta-elemene product.Compare with previous method, these method raw material sources are extensive, and plant and instrument is simple, and the production operation step is succinct and yield is higher, and production efficiency obviously improves.
A kind of suitability for industrialized production implementation method of high-purity beta-Elemene bulk drug comprises the steps:
A. be raw material to contain beta-elemene natural phant rhizome leaf flower seed, it mainly comprises stem tuber or piece root, the bright leaf of Herba Cymbopogonis Citrari and root, stem, leaf, flower and the seed of Herba Solidaginis of curcuma zedoary;
B. above raw material is adopted wet distillation, solvent extraction, methods such as supersound extraction or supercritical extraction are extracted, and obtain containing the volatile oil raw material of beta-elemene more than 1.0%;
C. the raw material of b gained is put into the rectifying tower still and carry out rectifying, control vacuum tightness is 1～7mm Hg, and the temperature of tower still is 110 ℃～124 ℃, is 1: 1 o'clock in reflux ratio, removes temperature at the impurity cut below 75 ℃; The control reflux ratio is between 1: 1～5: 1, collects temperature at 77 ℃～82 ℃ cut, obtains content and be 16.0%～60.0% beta-elemene;
D. the aqueous ethanolic solution of c gained cut with the long-pending amount 80%～95% of diploid diluted, be to carry out column chromatography on 20 times the macroporous adsorbent resin in weight, earlier with 30%～65% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 70%～80% ethanol water towards two retention volume of post again, gained oil phase behind the aqueous ethanolic solution concentrating under reduced pressure of 70%-80% is standby;
E. d step gained oil phase is passed through liquid-phase chromatographic analysis, if the big basic Ex-all of composition of polarity before the beta-elemene retention time, then d step gained oil phase carries out next step operation; If the big composition of polarity does not have Ex-all in addition on a small quantity, then d step gained oil phase is passed through the further Ex-all of part that its Semi-polarity is big of alcohol extraction method, be 50%～80% aqueous ethanolic solution extraction three times with the above concentration of the long-pending amount of diploid, the collection upper oil phase;
F. with equal-volume concentration the aqueous solution extraction three times of 1.0～4.0mol/L Silver Nitrate with e step gained oil phase, separatory takes off a layer water, continues with isopyknic n-hexane extraction three times, with upper strata normal hexane concentrating under reduced pressure, obtain colourless oil liquid, the omnidistance nitrogen protection of this extraction process;
G.. be raw material with f step gained beta-elemene sample, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 1～7mm Hg, tower still temperature is 115 ℃～126 ℃, the collection temperature is 63 ℃～80 ℃ a cut, obtains the beta-elemene of content at 95.0%～99.9% (weight percent).
Used natural plant raw material has the stem tuber or the piece root of curcuma zedoary among the step a of the present invention, the blade of Herba Cymbopogonis Citrari, one or more in the Herba Solidaginis rhizome leaf flower seed etc.
Adopt wet distillation among the step b of the present invention, solvent extraction, methods such as supersound extraction and supercritical extraction obtain volatile oil after Chinese medicinal materials is extracted, and wherein the content of gained raw material beta-elemene is 1%～15%.
Described in the step c of the present invention under vacuum condition, cut comprises myrcene below 75 ℃, borneol, isocamphol, D-limonene, lemongrass alkane, geranial ， limonene, Geraniol, isopulegol, phantol, small molecules monoterpenes compounds such as firpene.
Reflux among the step c of the present invention and be meant that the cut that is arranged in heating kettle is heated and rise to condensing works after the gasification and meet cold liquefaction and be back to that heating kettle forms.
Description of drawings
Fig. 1 is the process flow sheet that this patent is implemented, and wherein a is the medicinal material in different natural phant source; B is a volatile oil extractor; C is a water-and-oil separator; D and i are vacuum rectifying apparatuss; E is the macroporous adsorbent resin tripping device; F is the alcohol extraction device; G is the Silver Nitrate extraction plant; H is the n-hexane extraction device; J is a vacuum distillation plant; K is high-purity finished product; L is the oil phase part that is dissolved in the ethanol; M reclaims the ethanol device; N is the upper oil phase part after the Silver Nitrate extraction; O is the device that reclaims normal hexane; (1) is meant the method that adopts rectification under vacuum; (2) be meant the method that adopts vacuum distilling; (1) parallel with (2) two kinds of methods, adopt both one all can reach requirement.
Embodiment:
Embodiment 1:
A, to get natural plant curcuma zedoary stem tuber be raw material;
B, the medicinal material curcuma zedoary is obtained Rhizoma Curcumae volatile oil by wet distillation, wherein the content of beta-elemene is 6.0%;
C, the raw material of b gained is put into the rectifying tower still carry out rectifying, control vacuum tightness is 5～6mm Hg, and the temperature of tower still is 123 ℃～124 ℃, is 1: 1 o'clock in reflux ratio, removes temperature at the impurity cut below 75 ℃; The control reflux ratio is 3: 1, collects temperature at 77 ℃～82 ℃ cut, obtains content and be 30.0% beta-elemene.
D. the beta-elemene with c step gained 30.0% dilutes with the aqueous ethanolic solution that diploid amasss amount 85%, on macroporous adsorbent resin, carry out column chromatography, earlier with 60% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 70% ethanol water towards two retention volume of post again, the laggard liquid phase analysis of aqueous ethanolic solution concentrating under reduced pressure with 70%, the result shows the big basic Ex-all of composition of polarity in the past of beta-elemene retention time.
E. be the aqueous solution extraction three times of 1.8mol/L Silver Nitrate with d step gained oil phase with equal-volume concentration, separatory takes off a layer water, continues with upper strata normal hexane concentrating under reduced pressure, to obtain colorless oil beta-elemene sample with isopyknic n-hexane extraction three times.
F. be raw material with e step gained beta-elemene sample, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 5～6mm Hg, tower still temperature is 125 ℃～126 ℃, the collection temperature is 67 ℃～68 ℃ a cut, obtains the beta-elemene of content at 96.3% (weight percent).
Embodiment 2:
A, to get the bright leaf of natural phant Cymbopogon winterianus grass be raw material;
B, medicinal material Cymbopogon winterianus grass is obtained Java volatile oil by wet distillation, wherein the content of beta-elemene is 5.0%;
C, the raw material of b gained is put into the rectifying tower still carry out rectifying, control vacuum tightness is 2～3mm Hg, and the temperature of tower still is 116 ℃～117 ℃, is 1: 1 o'clock in reflux ratio, removes temperature at the impurity cut below 75 ℃; The control reflux ratio is 3: 1, collects temperature at 78 ℃～81 ℃ cut, obtains content and be 16.0% beta-elemene.
D. the beta-elemene with c step gained 16.0% dilutes with the aqueous ethanolic solution that diploid amasss amount 80%, be to carry out column chromatography on 20 times the macroporous adsorbent resin in weight, earlier with 60% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 75% ethanol water towards two retention volume of post again, the laggard liquid phase analysis of aqueous ethanolic solution concentrating under reduced pressure with 75%, the result shows the big basic Ex-all of composition of polarity in the past of beta-elemene retention time.
E. be the aqueous solution extraction three times of 1.5mol/L Silver Nitrate with d step gained oil phase with equal-volume concentration, separatory takes off a layer water, continues with upper strata normal hexane concentrating under reduced pressure, to obtain the beta-elemene sample of colorless oil with isopyknic n-hexane extraction three times.
F. be raw material with e step gained beta-elemene sample, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 2～3mm Hg, tower still temperature is 117 ℃～118 ℃, the collection temperature is 64 ℃～65 ℃ a cut, obtains the beta-elemene of content at 95.5% (weight percent).
Embodiment 3:
A, to get the bright leaf of natural phant Herba Solidaginis be raw material;
B, the Herba Solidaginis blade pass is crossed supercritical extraction obtain Herba Solidaginis volatile oil, wherein the content of beta-elemene is 14.3%;
C, the raw material of b gained is put into the rectifying tower still carry out rectifying, control vacuum tightness is 6～7mm Hg, and the temperature of tower still is 123～124 ℃, is 1: 1 o'clock in reflux ratio, removes temperature at the impurity cut below 75 ℃; The control reflux ratio is 4: 1, collects temperature at 79 ℃～82 ℃ cut, obtains content and be 40.6% beta-elemene.
D. the beta-elemene with c step gained 40.6% dilutes with the aqueous ethanolic solution that diploid amasss amount 90%, be to carry out column chromatography on 20 times the macroporous adsorbent resin in weight, earlier with 60% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 75% ethanol water towards two retention volume of post again, the laggard liquid phase analysis of aqueous ethanolic solution concentrating under reduced pressure with 75%, the big composition of polarity still had not Ex-all of small amount of impurities before the result showed the beta-elemene retention time.
E. the ethanol water of d step gained oil phase with triplication 72% is extracted three times, the laggard liquid phase analysis of gained upper oil phase concentrating under reduced pressure is found the basic Ex-all of the composition of retention time before beta-elemene.
F. be the aqueous solution extraction three times of 2.0mol/L Silver Nitrate with e step gained oil phase with equal-volume concentration, separatory takes off a layer water, continues with upper strata normal hexane concentrating under reduced pressure, to obtain the beta-elemene sample of colorless oil with isopyknic n-hexane extraction three times.
G. be raw material with f step gained beta-elemene sample, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 2～3mm Hg, tower still temperature is 117 ℃～118 ℃, the collection temperature is 64 ℃～65 ℃ a cut, obtains the beta-elemene of content at 99.8% (weight percent).
Embodiment 4:
A, to get natural plant curcuma zedoary piece root be raw material;
B, the medicinal material curcuma zedoary is obtained Rhizoma Curcumae volatile oil by wet distillation, wherein the content of beta-elemene is 7.5%;
C, the raw material of b gained is put into the rectifying tower still carry out rectifying, control vacuum tightness is 5～6mm Hg, and the temperature of tower still is 123～124 ℃, is 1: 1 o'clock in reflux ratio, removes temperature at the impurity cut below 75 ℃; The control reflux ratio is 3: 1, collects temperature at 77 ℃～80 ℃ cut, obtains content and be 25.7% beta-elemene.
D, the beta-elemene of c step gained 25.7% aqueous ethanolic solution with the long-pending amount 85% of diploid is diluted, be to carry out column chromatography on 20 times the macroporous adsorbent resin in weight, earlier with 60% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 70% ethanol water towards two retention volume of post again, the laggard liquid phase analysis of aqueous ethanolic solution concentrating under reduced pressure with 70%, the big composition of polarity still had not Ex-all of small amount of impurities before the result showed the beta-elemene retention time.
E. the ethanol water of d step gained oil phase with quintuple 70% is extracted three times, the laggard liquid phase analysis of gained upper oil phase concentrating under reduced pressure is found the basic Ex-all of the composition of retention time before beta-elemene.
F. be the aqueous solution extraction three times of 1.0mol/L Silver Nitrate with e step gained oil phase with equal-volume concentration, separatory takes off a layer water, continues with upper strata normal hexane concentrating under reduced pressure, to obtain the beta-elemene sample of colorless oil with isopyknic n-hexane extraction three times.
G. be raw material with f step gained beta-elemene sample, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 4～5mm Hg, tower still temperature is 120 ℃～122 ℃, the collection temperature is 66 ℃～67 ℃ a cut, obtains the beta-elemene of content at 98.1% (weight percent).
Embodiment 5:
A, to get the bright leaf of natural phant Herba Solidaginis be raw material;
B, the Herba Solidaginis blade pass is crossed supercritical extraction obtain Herba Solidaginis volatile oil, wherein the content of beta-elemene is 14.3%;
C, the beta-elemene of b step gained 14.3% aqueous ethanolic solution with the long-pending amount 90% of diploid is diluted, be to carry out column chromatography on 20 times the macroporous adsorbent resin in weight, earlier with 50% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 65% aqueous ethanolic solution continuously towards two retention volume of post again, use 70% ethanol water towards two retention volume of post at last, the laggard liquid phase analysis of aqueous ethanolic solution concentrating under reduced pressure with 70%, the big composition of polarity still had not Ex-all of small amount of impurities before the result showed the beta-elemene retention time.
D, with c step gained oil phase with the ethanol water of quintuple 70% extraction three times, the laggard liquid phase analysis of gained upper oil phase concentrating under reduced pressure is found the basic Ex-all of the composition of retention time before beta-elemene.
F. be the aqueous solution extraction three times of 2.0mol/L Silver Nitrate with e step gained oil phase with equal-volume concentration, separatory takes off a layer water, continues with upper strata normal hexane concentrating under reduced pressure, to obtain the beta-elemene sample of colorless oil with isopyknic n-hexane extraction three times.
G. be raw material with f step gained beta-elemene sample, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 5～6mm Hg, tower still temperature is 124 ℃～125 ℃, the collection temperature is 68 ℃～69 ℃ a cut, obtains the beta-elemene of content at 98.4% (weight percent).
Embodiment 6:
A, to get natural plant curcuma zedoary stem tuber be raw material;
B, the medicinal material curcuma zedoary is obtained Rhizoma Curcumae volatile oil by organic solvent extraction, wherein the content of beta-elemene is 8.2%;
C, the beta-elemene of b step gained 8.2% aqueous ethanolic solution with the long-pending amount 95% of diploid is diluted, be to carry out column chromatography on 20 times the macroporous adsorbent resin in weight, earlier with 45% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 60% aqueous ethanolic solution continuously towards two retention volume of post again, use 75% ethanol water towards two retention volume of post at last, the laggard liquid phase analysis of aqueous ethanolic solution concentrating under reduced pressure with 75%, the big composition of polarity still had not Ex-all of small amount of impurities before the result showed the beta-elemene retention time.
D, with c step gained oil phase with six times of amount ethanol water of 72% extraction three times, the laggard liquid phase analysis of gained upper oil phase concentrating under reduced pressure is found the basic Ex-all of the composition of retention time before beta-elemene.
F. be the aqueous solution extraction three times of 1.5mol/L Silver Nitrate with e step gained oil phase with equal-volume concentration, separatory takes off a layer water, continues with upper strata normal hexane concentrating under reduced pressure, to obtain the beta-elemene sample of colorless oil with isopyknic n-hexane extraction three times.
G. be raw material with f step gained beta-elemene bar product, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 4～5mm Hg, tower still temperature is 122 ℃～123 ℃, the collection temperature is 68 ℃～69 ℃ a cut, obtains the beta-elemene of content at 96.5% (weight percent).
Embodiment 7:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carry out the beta-elemene liposome preparation: adopt alcohol injection to prepare liposome, (1) take by weighing cholesterol 2.0g, soybean lecithin 5.0g and beta-elemene bulk drug 0.75g back in small beaker adds an amount of absolute ethyl alcohol and stirring makes its dissolving form oil phase.(2) measure 100ml PBS damping fluid and place three-necked bottle,, with syringe oil phase is slowly injected aqueous phase under the rotating speed 30r/min magnetic agitation, vacuumize 10min then, promptly get the product of pastille 7.5mg/ml 50 ℃ of bath temperatures.Or (3) add 25% trehalose in above-mentioned beta-elemene liposome turbid liquor, promptly gets beta-elemene liposome powder through lyophilize, faces with preceding dilute with water and can dissolve rapidly.The liposome particle diameter that this preparation method obtains is about 100nm, can be used for oral or drug administration by injection.
Embodiment 8:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, and carry out the preparation of beta-elemene emulsion: (1) takes by weighing soybean oil 180g, egg phospholipids 15g, TPGS 35g, beta-elemene bulk drug 10g places the fusion of water-bath heated and stirred, keeps 70 ℃ of temperature, as oil phase; (2) take by weighing Poloxamer1883.0g and poly(oxyethylene glycol) 400 50g and join in an amount of water for injection, heated and stirred makes its dissolving, keeps 70 ℃ of temperature, as water.Under agitation water is splashed in the oil phase, continue to stir, form colostrum; (3) colostrum is spared 2 times through 700bar high pressure breast, and cooling curing can obtain the beta-elemene emulsion of 10mg/mL rapidly, and the granularity of this emulsion can be used for oral or drug administration by injection less than 100nm.
Embodiment 9:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carry out the preparation of injection beta-elemene microemulsion: (1) takes by weighing midchain oil (MCT) 100g, soybean phospholipid 15g, oleic acid 2.5g, beta-elemene bulk drug 8.5g places the fusion of water-bath heated and stirred, keep 75 ℃ of temperature, as oil phase; (2) take by weighing Poloxamer1883.0g, tween-80 2.0g and glycerine 85g join in an amount of water for injection, and heated and stirred makes its dissolving, keep 75 ℃ of temperature, as water.Under agitation water is splashed in the oil phase, continue to stir, promptly form the beta-elemene micro emulsion; Or (3) add 20% glucose in above-mentioned beta-elemene microemulsion, promptly gets injection beta-elemene micro emulsion pressed powder through lyophilize, faces with preceding dilute with water and can dissolve rapidly.
Embodiment 10:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carry out the preparation of beta-elemene nano-lipid carrier: (1) takes by weighing glyceryl monostearate 62.5g, soybean oil 25.5g, HS-1575g, oleic acid 1.0g, beta-elemene 5.0g places the fusion of water-bath heated and stirred, keeps 75 ℃ of temperature, as oil phase; (2) take by weighing poloxamer1885.0g and join in an amount of water for injection, heated and stirred makes its dissolving, keeps 75 ℃ of temperature, as water.Under agitation water is splashed in the oil phase, continue to stir, form colostrum; (3) colostrum is spared 6 times through 1200bar high pressure breast, and cooling curing can obtain beta-elemene nano-lipid carrier suspension rapidly; Or (4) add 15% N.F,USP MANNITOL in above-mentioned beta-elemene nano-lipid carrier suspension, and the spray-dried injection beta-elemene nano-lipid carrier pressed powder that promptly gets faces with preceding dilute with water and can dissolve rapidly.Spraying drying condition: 150 ℃ of temperature ins, 85 ℃ of temperature outs, air quantity 100%, flow velocity 0.01%, productive rate 37.8%.Said preparation can be used for oral or drug administration by injection, has certain slowly releasing effect.
Embodiment 11:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, and carry out the preparation of beta-elemene solid lipid nanoparticle: (1) takes by weighing stearic acid 95.0g, soybean phospholipid 25g, oleic acid 3.0g, beta-elemene bulk drug 7.5g places the fusion of water-bath heated and stirred, keep 85 ℃ of temperature, as oil phase; (2) take by weighing Poloxamer1885.0g, TPGS 18g joins in an amount of water for injection, and heated and stirred makes its dissolving, keeps 85 ℃ of temperature, as water.Under agitation water is splashed in the oil phase, continue to stir, form colostrum; (3) colostrum is spared 7 times through 800bar high pressure breast, and cooling curing can obtain beta-elemene solid lipid nanoparticle suspension rapidly; Or (4) add 15% sucrose in above-mentioned beta-elemene solid lipid nanoparticle suspension, promptly gets injection beta-elemene solid lipid nanoparticle pressed powder through vacuum lyophilization, faces with preceding dilute with water and can dissolve rapidly.Said preparation can be used for oral or drug administration by injection, has certain slowly releasing effect.
Embodiment 12:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carry out beta-elemene self-emulsifying soft capsule agent preparation: take by weighing beta-elemene bulk drug 10.0g and add propylene glycol 30.0g, 40 ℃ ultrasonic make its dissolving after, add ethyl oleate 25.0g, make soft capsule after tween 85 45.0g stirs.
Embodiment 13:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carry out the preparation of beta-elemene transdermal patch: take by weighing beta-elemene 5.0g, compound infiltration accelerating agent azone 15g, mentha camphor 30g, propylene glycol 50g after the grinding evenly, adds acrylate copolymer to 100% as latent solvent, be coated on the thick PVC film of 80 μ m after grinding evenly, 70 ℃ of dry backs become transparent solid to disperse thin slice.
Embodiment 14:
The beta-elemene that makes with the foregoing description 1～6 is a raw material; carry out beta-elemene liposome spraying agent preparation: take by weighing soybean lecithin 37.5g; cholesterol 2.5g; oleic acid 0.3g; azone 0.01g; vitamin-E 0.03g; spearmint oil 0.3g; beta-elemene 8.0g adds 40mL ethanol; heated and stirred adds the ethanol drug solution in the 160mL water of high-speed stirring (3000r/min) to dissolving fully, after continuing to stir 30min under the condition of nitrogen protection; spare matter 5 times through 700bar high pressure dispersing emulsification machine, promptly obtain the beta-elemene liposome solutions.Filter with exsiccant G6 sintered glass filter, divide to be filled in the aerosol container, promptly get beta-elemene liposome spraying agent.
Embodiment 15:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carries out the preparation of beta-elemene suppository: take by weighing stearic acid 18g and semi-synthetic fatty acid ester 25g, heat fused in 65 ℃ of water-baths.Take by weighing beta-elemene 9.5g and divide in the matrix that adds fusing for three times, constantly stir and make the medicine homodisperse, when treating that this mixture is the thickness state, pour in the model that scribbles lubricant, overflow part on the die orifice of pruning after the cooled and solidified, the demoulding, promptly.
Embodiment 16:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carry out beta-elemene Nano microsphere preparation: take by weighing beta-elemene 5.0g and join in the dichloromethane solution that concentration is 7% poly(lactic acid) or poly lactic coglycolic acid, ultra-sonic dispersion is made suspension, then suspension slowly is added drop-wise to concentration and is in 2.5% the polyoxyethylene glycol aqueous solution, 2h makes the methylene dichloride volatilization fully under the room temperature, collect microballoon by vacuum filtration, distilled water wash 5 times, behind vacuum-drying 48h under the room temperature, promptly get beta-elemene microballoon work in-process, and promptly can be made into injection or implant behind other solvent complexes.
Embodiment 17:
The beta-elemene that makes with the foregoing description 1～6 is a raw material, carry out the preparation of beta-elemene nanometer liposome nasal drop: take by weighing soybean lecithin 2.0g, cholesterol 1.0g, Sodium cholic acid 0.01g and beta-elemene 0.85g are dissolved in the 40mL chloroformic solution, 65 ℃ of reduction vaporizations form lipoid film, the phosphoric acid buffer concussion dissolving that adds 40mL, regulating the pH value is 6.0, add the 0.1g Stearyl Amine, 0.05g tween-80 obtains the beta-elemene Liposomal dispersion, after the even matter of 800bar high pressure dispersing emulsification machine 7 times, obtain the liposome turbid liquor of particle diameter, after wherein adding the 0.8g phosphatidyl glycerol, promptly obtain nasal cavity administrated preparation less than 100nm.
Claims (10)
1, a kind of industrialized preparing process of high-purity beta-Elemene bulk drug, it is characterized in that to contain beta-elemene natural phant rhizome leaf flower seed and carry out the extraction of volatile oil, through obtaining the beta-elemene of higher degree after the rectification under vacuum, then adopt macroporous adsorbent resin partition method or macroporous adsorbent resin successively in conjunction with the alcohol extraction method, the Silver Nitrate complexing abstraction is removed other impurity, finally by obtaining content after underpressure distillation or the rectifying at 95.0%～99.9% beta-elemene bulk drug.
2, preparation method according to claim 1 is characterized in that implementation method comprises following steps:
A. be raw material to contain beta-elemene natural phant rhizome leaf flower seed, it mainly comprises stem tuber or piece root, the bright leaf of Herba Cymbopogonis Citrari and root, stem, leaf, flower and the seed of Herba Solidaginis of curcuma zedoary;
B. the privileged site of above natural phant is adopted wet distillation, solvent extraction, methods such as supersound extraction or supercritical extraction are extracted, and obtain containing beta-elemene volatile oil raw material of (weight percent) more than 1.0%;
C. the raw material of b gained is put into precision fractional distillation Tata still and carried out rectifying, control vacuum tightness is 1～7mm Hg, and the temperature of tower still is 110 ℃～124 ℃, is 1: 1 o'clock in reflux ratio, removes temperature at the impurity cut below 75 ℃; The control reflux ratio is between 1: 1～5: 1, collects temperature at 77 ℃～82 ℃ cut, obtains the beta-elemene that content is 16.0%～60.0% (weight percent);
D. the aqueous ethanolic solution of c gained cut with the long-pending amount 80%～95% of diploid diluted, be to carry out column chromatography on 20 times the macroporous adsorbent resin in weight, earlier with 30%～65% aqueous ethanolic solution continuously towards four on post more than the retention volume, use 70%～80% ethanol water towards two retention volume of post again, gained oil phase behind the aqueous ethanolic solution concentrating under reduced pressure of 70%-80% is standby;
E. d step gained oil phase is passed through liquid-phase chromatographic analysis, if the big basic Ex-all of composition of polarity before the beta-elemene retention time, then d step gained oil phase carries out next step operation; If the big composition of polarity does not have Ex-all in addition on a small quantity, then d step gained oil phase is passed through the further Ex-all of part that its Semi-polarity is big of alcohol extraction method, be 50%～80% aqueous ethanolic solution extraction three times with the above concentration of the long-pending amount of diploid, the collection upper oil phase;
F. with equal-volume concentration the aqueous solution extraction three times of 1.0～4.0mol/L Silver Nitrate with e step gained oil phase, separatory takes off a layer water, continues with isopyknic n-hexane extraction three times, with upper strata normal hexane concentrating under reduced pressure, obtain colourless oil liquid, the omnidistance nitrogen protection of this extraction process;
G.. be raw material with f step gained beta-elemene sample, adopt the condition of high vacuum degree oil pump to carry out underpressure distillation or rectifying, control vacuum tightness is 1～7mm Hg, tower still temperature is 115 ℃～126 ℃, the collection temperature is 63 ℃～80 ℃ a cut, obtains the beta-elemene of content at 95.0%～99.9% (weight percent).
3, preparation method according to claim 2 is characterized in that containing stem tuber or piece root, the blade of Herba Cymbopogonis Citrari and root, stem, leaf, flower and the seed of Herba Solidaginis that beta-elemene natural phant rhizome leaf flower seed raw material comprises curcuma zedoary; Vacuum tightness in rectifying and the underpressure distillation operation is 1～7mmHg.
4, preparation method according to claim 2 is characterized in that:
Step b adopts content that different essential oil extraction methods obtain beta-elemene more than 1.0%, and promptly all content all can adopt this method to obtain high-purity beta-elemene product at the sample of the beta-elemene more than 1%;
Rectifying tower is a filler with 3 * 3mm stainless steel net volume among the step c; Control of reflux ratio was at 1: 1～5: 1; The temperature range of tower still is 110 ℃～124 ℃; The temperature that cut is collected in rectifying is 77 ℃～82 ℃; The resulting beta-elemene content of rectifying is between 16.0%～60.0%.
5, preparation method according to claim 2 is characterized in that:
The used method of extraction is the macroporous adsorbent resin partition method in the steps d; The model of big pore adsorption resin is: CAD series of Lewapol G-7318, the SP-1/2 of Czech of Duolite PSP, the Duolite S-30 of the Diaion HP series of Mitsubishi chemistry, the Amberlite XAD series of U.S.'s ROHM AND HAAS, U.S. DiamondAlkali company, Germany, the GDX series of Chinese Tianjin reagent two factories and Shandong Lukang Record Pharmaceuticals Co., Ltd. and DM series etc.; Adopt the macroporous adsorbent resin of 20 times of oil phase weight to load during the dress post; Adopt the ethanol water of the long-pending amount 80%～95% of diploid that oil phase is diluted before the last sample; The ethanol that removes the big impurity component employing 30%～65% of depolarization is towards four retention volume of post; The gained oil phase both gets towards two retention volume of post are concentrated with 70%～80% ethanol water;
The chromatographic condition of high performance liquid phase among the step e:
Chromatographic column: Kromasil C18 5um 200 * 4.6um
Moving phase: acetonitrile: water: Glacial acetic acid=82: 18: 0.01
Flow velocity: 1.0ml/min
Detect wavelength: 210nm
Column temperature: 30 ℃.
6, preparation method according to claim 2 is characterized in that:
The extraction method therefor is that silver nitrate aqueous solution complexometric extraction and normal hexane reextraction method combine among the step f; The concentration that extracts used Silver Nitrate is 1.0～4.0mol/L, and the omnidistance nitrogen protection of extraction process.Here used normal hexane can change the little solvent of sherwood oil isopolarity into.
7, preparation method according to claim 2 is characterized in that:
Step g is on f step gained sample basis, comes purifying through underpressure distillation or distillation operation; The temperature of distillation tower or rectifying tower is 115 ℃～126 ℃; The temperature of collecting cut is 63 ℃～80 ℃.
8, preparation method according to claim 2 is characterized in that all adopting three times in each step extracting process
Extraction process; The content of final preparation gained beta-elemene is 95.0%～99.9%.
9, preparation method according to claim 2 is characterized in that the operation of c step can be saved, and the working order of d, e and f step can be inverted, and is final under the processing of g step, can obtain 95.0%～99.9% beta-elemene product equally.
10, according to Claim 8 or 9 described preparation methods, the raw material that makes can be made oral administration conventional and slow, controlled release preparation, the conventional or slow controlled release of parenteral administration, targeting preparation with acceptable auxiliary material pharmaceutically.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010091629A1 (en) * | 2009-02-16 | 2010-08-19 | 吕青松 | Chemical complexing directional separation and purification method for preparing high-purity beta-elemene raw material medicament |
| CN102432419A (en) * | 2011-12-31 | 2012-05-02 | 攀枝花学院 | Method for extracting and separating beta-elemene from Eupatorium adenophorum |
| CN101756900B (en) * | 2010-02-25 | 2012-05-30 | 谢恬 | Elemene micro-emulsion |
| CN101624325B (en) * | 2009-07-23 | 2013-06-05 | 北京联合大学 | Extracting agent for separating beta-elemene, extracting method and extracting device thereof |
| CN103182056A (en) * | 2011-12-31 | 2013-07-03 | 新昌县冠阳技术开发有限公司 | Preparation method of zedoary oil |
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| WO2010091629A1 (en) * | 2009-02-16 | 2010-08-19 | 吕青松 | Chemical complexing directional separation and purification method for preparing high-purity beta-elemene raw material medicament |
| CN101624325B (en) * | 2009-07-23 | 2013-06-05 | 北京联合大学 | Extracting agent for separating beta-elemene, extracting method and extracting device thereof |
| CN101756900B (en) * | 2010-02-25 | 2012-05-30 | 谢恬 | Elemene micro-emulsion |
| CN102432419A (en) * | 2011-12-31 | 2012-05-02 | 攀枝花学院 | Method for extracting and separating beta-elemene from Eupatorium adenophorum |
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| CN102432419B (en) * | 2011-12-31 | 2014-05-14 | 攀枝花学院 | Method for extracting and separating beta-elemene from Eupatorium adenophorum |
| CN105967967A (en) * | 2016-05-13 | 2016-09-28 | 大连德泽药业有限公司 | Energy-saving and consumption-reducing elemene extraction system |
| CN105967967B (en) * | 2016-05-13 | 2018-07-27 | 大连德泽药业有限公司 | Energy-saving elemene extraction system |
| CN112213400A (en) * | 2019-07-09 | 2021-01-12 | 成都康弘药业集团股份有限公司 | Method for detecting beta-elemene and related substances thereof |
| CN115260001A (en) * | 2022-08-15 | 2022-11-01 | 山东第一医科大学附属眼科研究所(山东省眼科研究所 山东第一医科大学附属青岛眼科医院) | Process for preparing (1S, 2S, 4R) -dipentene-1, 2-diol |
| CN115260001B (en) * | 2022-08-15 | 2024-04-12 | 山东第一医科大学附属眼科研究所(山东省眼科研究所山东第一医科大学附属青岛眼科医院) | Preparation method of (1S, 2S, 4R) -dipentene-1, 2-diol |
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