CN101402543A - Beta-elemi alkene bulk medicament and method of preparing its preparations - Google Patents
Beta-elemi alkene bulk medicament and method of preparing its preparations 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 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 distilled by molecular distillation method to remove compositions with high boiling points and non-volatile compositions; impurity compositions are removed by the ethanol extraction method and silver nitrate complex extraction method; 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, concise operating steps, mild operating conditions and improvement of the production efficiency of the beta elemene.
Description
Technical field:
The present invention relates to the preparation method of a kind of beta-elemene bulk drug and preparation thereof.
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.The patent No. is 200610129740.0 to adopt molecular distillation methods that Xishuangbanna pamorusa oil submember is extracted, though the content of beta-elemene reaches 85%～95%, and the less and requirement that do not reach the beta-elemene bulk drug of the probability that occurs.
Comprehensive various patent beta-elemene extracts the method for purifying, and major part is the difference according to boiling point, adopts rectifying column to separate separately, separation efficiency is low, and length consuming time, operational condition are very unstable, and isomers almost can not be realized separating fully, therefore is difficult to obtain highly purified beta-elemene.This patent contains the constructional feature of three terminal double links from beta-elemene, consider that it can carry out complexing with Silver Nitrate, and different according to double key number order and position, realize that beta-elemene separates from its isomers, thereby obtain highly purified 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, behind different methods extraction volatile oil, obtain content and be the beta-elemene raw material more than 1%, after the process molecular distillation is removed low-boiling monoterpene and sesquiterpenoids, the gained cut removed by the alcohol extraction method contain the oxygen terpene compound, 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 bulk drug source 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, simultaneously this method experimental design novelty from the angle of beta-elemene boiling point; Operation steps is succinct; The operational condition gentleness has improved beta-elemene production efficiency.
Technical solution of the present invention is: methods such as employing wet distillation are carried out the extraction of volatile oil from contain beta-elemene plant's root leaf flower seed; Gained volatile oil adds in the molecular distillation apparatus and carries out molecular distillation, collects beta-elemene content at 40.0%～70.0% cut; Then the gained cut is passed through 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 production efficiency obviously improves.
A kind of industrialized preparing process 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 being put into molecular distillation apparatus distills, control vacuum tightness is 1～50Pa, distillation temperature is 30 ℃～100 ℃, material flow is 1～3mL/min, the condensing surface temperature is 15～25 ℃, and the knifing rotating speed is 300～450rpm, 60～70 ℃ of circulating water temperatures, remove lower boiling terpene compound and high-boiling-point impurity composition, obtain the beta-elemene that content is 40.0%～70.0% (weight percent);
D. be 50%～80% aqueous ethanolic solution extraction three times with c step gained raw material with the above concentration of the long-pending amount of diploid, it is standby to collect upper oil phase;
E. with equal-volume concentration the aqueous solution extraction three times of 1.0～4.0mol/L Silver Nitrate with d 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, this goes on foot omnidistance nitrogen protection;
F.. be raw material with e step gained beta-elemene sample, carry out underpressure distillation or rectifying, control vacuum tightness is 133～1000Pa, and 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%.
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 is a molecular distillation apparatus; E is the alcohol extraction device; F is the Silver Nitrate extraction plant; G is the n-hexane extraction device; H is a vacuum rectifying apparatus; I is a vacuum distillation plant; J is high-purity finished product; K is the oil phase part that is dissolved in the ethanol; L reclaims the ethanol device; M is the upper oil phase part after the Silver Nitrate extraction; N 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) with (2) two kinds of parallel 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 molecular distillation apparatus distill, in vacuum tightness is 20Pa, tower still temperature is 60 ℃, material flow is 3mL/min, the condensing surface temperature is 15 ℃, the knifing rotating speed is 350rpm, and circulating water temperature is 60 ℃, and molecular distillation is removed low-boiling monoterpene and sesquiterpenoids; Heating up in a steamer that excess continues in vacuum tightness is 10Pa, and tower still temperature is 80 ℃, and material flow is 2mL/min, and the condensing surface temperature is 25 ℃, and the knifing rotating speed is 300rpm, and circulating water temperature is 60 ℃ of molecular distillations, and collecting overhead product, to obtain content be 45.6% beta-elemene.
D. be 70% aqueous ethanolic solution extraction three times with the beta-elemene sample of c step gained 45.6% with the long-pending amount of pentaploid concentration, it is standby to collect upper oil phase.
E. be the aqueous solution extraction three times of 1.0mol/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 399～533Pa, tower still temperature is 111 ℃～112 ℃, 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 molecular distillation apparatus distill, in vacuum tightness is 30Pa, tower still temperature is 70 ℃, material flow is 3mL/min, the condensing surface temperature is 15 ℃, the knifing rotating speed is 400rpm, and circulating water temperature is 65 ℃, and molecular distillation is removed low-boiling monoterpene and sesquiterpenoids; Heating up in a steamer the excess continuation is 10Pa in vacuum tightness, and tower still temperature is 85 ℃, and material flow is 2mL/min, the condensing surface temperature is 25 ℃, the knifing rotating speed is 350rpm, carries out molecular distillation when circulating water temperature is 65 ℃, and collecting overhead product, to obtain content be 48.6% beta-elemene.
D. be 74% aqueous ethanolic solution extraction three times with the beta-elemene sample of c step gained 48.6% with the long-pending amount of pentaploid concentration, it is standby to collect upper oil phase.
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 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 665～798Pa, tower still temperature is 120 ℃～121 ℃, the collection temperature is 72 ℃～73 ℃ a cut, obtains the beta-elemene of content at 97.2% (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 16.0%;
C, the raw material of b gained is put into molecular distillation apparatus distill, in vacuum tightness is 30Pa, tower still temperature is 70 ℃, material flow is 3mL/min, the condensing surface temperature is 15 ℃, the knifing rotating speed is 450rpm, and circulating water temperature is 65 ℃, and molecular distillation is removed low-boiling monoterpene and sesquiterpenoids; Heating up in a steamer the excess continuation is 10Pa in vacuum tightness, and tower still temperature is 90 ℃, and material flow is 3mL/min, the condensing surface temperature is 15 ℃, the knifing rotating speed is 400rpm, carries out molecular distillation when circulating water temperature is 65 ℃, and collecting overhead product, to obtain content be 70.0% beta-elemene.
D. be 70% aqueous ethanolic solution extraction three times with the beta-elemene sample of c step gained 70.0% with the long-pending amount of pentaploid concentration, it is standby to collect upper oil phase.
E. be the aqueous solution extraction three times of 2.5mol/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 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 266～399Pa, tower still temperature is 121 ℃～122 ℃, the collection temperature is 63 ℃～64 ℃ a cut, obtains the beta-elemene of content at 99.9% (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 molecular distillation apparatus distill, in vacuum tightness is 40Pa, tower still temperature is 90 ℃, material flow is 3mL/min, the condensing surface temperature is 15 ℃, the knifing rotating speed is 350rpm, and circulating water temperature is 70 ℃, and molecular distillation is removed low-boiling monoterpene and sesquiterpenoids; Heating up in a steamer the excess continuation is 20Pa in vacuum tightness, and tower still temperature is 80 ℃, and material flow is 1mL/min, the condensing surface temperature is 15 ℃, the knifing rotating speed is 300rpm, carries out molecular distillation when circulating water temperature is 70 ℃, and collecting overhead product, to obtain content be 60.0% beta-elemene.
D. be 70% aqueous ethanolic solution extraction three times with the beta-elemene sample of c step gained 60.0% with the long-pending amount of pentaploid concentration, it is standby to collect upper oil phase.
E. be the aqueous solution extraction three times of 3.5mol/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 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 532～665Pa, tower still temperature is 120 ℃～122 ℃, the collection temperature is 66 ℃～67 ℃ a cut, obtains the beta-elemene of content at 97.5% (weight percent).
Embodiment 5:
The beta-elemene that makes with the foregoing description 1～5 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 6:
The beta-elemene that makes with the foregoing description 1～5 is a raw material, and carry out the emulsion preparation: (1) takes by weighing soybean oil 180g, egg phospholipids 15g, and 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 Poloxamer188 3.0g 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 7:
The beta-elemene that makes with the foregoing description 1～5 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 Poloxamer188 3.0g, 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 8:
The beta-elemene that makes with the foregoing description 1～5 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 9:
The beta-elemene that makes with the foregoing description 1～5 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 10:
The beta-elemene that makes with the foregoing description 1～5 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 11:
The beta-elemene that makes with the foregoing description 1～5 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 12:
The beta-elemene that makes with the foregoing description 1～5 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 13:
The beta-elemene that makes with the foregoing description 1～5 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 14:
The beta-elemene that makes with the foregoing description 1～5 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 15:
The beta-elemene that makes with the foregoing description 1～5 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, the preparation method of a kind of beta-elemene bulk drug and preparation thereof, it is characterized in that to contain beta-elemene natural phant rhizome leaf flower seed and carry out the preliminary extraction of volatile oil, then through obtaining the beta-elemene of higher degree behind the molecular distillation, then adopt the alcohol extraction method successively, 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 being put into molecular distillation apparatus distills, control vacuum tightness is 1～50Pa, distillation temperature is 30 ℃～100 ℃, material flow is 1～3mL/min, the condensing surface temperature is 15～25 ℃, and the knifing rotating speed is 300～450rpm, 60～70 ℃ of circulating water temperatures, remove lower boiling terpene compound and high-boiling-point impurity composition, obtain the beta-elemene that content is 40.0%～70.0% (weight percent);
D. be 50%～80% aqueous ethanolic solution extraction three times with c step gained raw material with the above concentration of the long-pending amount of diploid, it is standby to collect upper oil phase;
E. with equal-volume concentration the aqueous solution extraction three times of 1.0～4.0mol/L Silver Nitrate with d 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, this goes on foot omnidistance nitrogen protection;
F.. be raw material with e step gained beta-elemene sample, carry out underpressure distillation or rectifying, control vacuum tightness is 133～1000Pa, and 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.
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 beta-elemene sample more than 1%;
The molecular distillation condition is among the step c: vacuum tightness is 1～50Pa, and distillation temperature is 30 ℃～100 ℃, and material flow is 1～3mL/min, and the condensing surface temperature is 15～25 ℃, and the knifing rotating speed is 300～450rpm, 60～70 ℃ of circulating water temperatures; The purpose of this step molecular distillation is to remove lower boiling terpene compound and high-boiling-point impurity composition.
5, preparation method according to claim 2 is characterized in that:
The used concentration of ethanol of extraction is 50%～80% in the steps d, and the volume of the used ethanol water of alcohol extraction is more than two times or two times of oil phase.
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 e; The concentration that extracts used Silver Nitrate is 1.0～4.0mol/L, and omnidistance nitrogen protection.
7, preparation method according to claim 2 is characterized in that:
Step f is on step e gained sample basis, comes purifying through underpressure distillation or distillation operation; Vacuum tightness is: 133～1000Pa; The temperature range of distillation tower or rectifying Tata still is 115 ℃～126 ℃; The temperature range 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 and e step can be inverted, and is final under the processing of f 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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| US20120322892A1 (en) * | 2010-02-25 | 2012-12-20 | Tian XIE | Oral microemulsion of elemene |
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| CN102992940A (en) * | 2012-12-19 | 2013-03-27 | 石药集团远大(大连)制药有限公司 | Method for extracting delta-elemene |
| CN104403799A (en) * | 2014-11-22 | 2015-03-11 | 河南恒瑞源实业有限公司 | Comprehensive utilizing method of eucommia ulmoides |
| CN104403799B (en) * | 2014-11-22 | 2020-12-22 | 河南恒瑞源实业有限公司 | Comprehensive utilization method of eucommia ulmoides |
| CN108042758A (en) * | 2017-12-22 | 2018-05-18 | 无锡济民可信山禾药业股份有限公司 | A kind of method that volatile oil in curcuma zedoary medicinal material is separated based on postcritical preparative |
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| CN111135143A (en) * | 2020-01-19 | 2020-05-12 | 齐鲁工业大学 | β -elemene self-microemulsion and preparation method thereof |
| CN111135143B (en) * | 2020-01-19 | 2021-12-14 | 齐鲁工业大学 | Beta-elemene self-microemulsion and preparation method thereof |
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