CN101798308A - Preparation process and products of oridonin fine particles - Google Patents
Preparation process and products of oridonin fine particles Download PDFInfo
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- CN101798308A CN101798308A CN200810154555A CN200810154555A CN101798308A CN 101798308 A CN101798308 A CN 101798308A CN 200810154555 A CN200810154555 A CN 200810154555A CN 200810154555 A CN200810154555 A CN 200810154555A CN 101798308 A CN101798308 A CN 101798308A
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- oridonin
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- rubescensine
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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Abstract
A preparation process of oridonin fine particles is characterized by comprising the following steps: (1) preparing oridonin solution; (2) connecting the oridonin solution prepared in the step (1) with a solution pump; (3) charging carbon dioxide; (4) jetting the oridonin solution into a crystallization reactor by a nozzle in a supercritical fluid anti-solvent equipment system through the solution pump; and (5) separating out the oridonin crystals. The oridonin fine particles prepared by the process are characterized in that the particles are loose amorphous white superfine powder; and the particle size d (0.5) is 5.135um. The process is suitable for the superfine oridonin powder, improves the medicine dissolution and the curative effects and is used for preparing the oridonin fine particles by applying the supercritical fluid crystallization technology.
Description
(1) technical field:
The present invention relates to be the preparation oridonin fine particles technology, particularly be a kind of preparation process of oridonin fine particles and goods thereof.
(2) background technology:
With regard to medicine, the particulate size can directly have influence on the degree that is absorbed and the drug effect of medicine.In general, drug particles is more little, in the big more just easy more body fluid that is dissolved in human body of specific surface area, can more fully be absorbed by human body, thereby play better curative effect, the medicine of larger particles is then because dissolved speed is comparatively slow, is difficult to be absorbed fully and reaches the drug effect of expectation.
In the prior art, the refinement of drug particles adopts crushing method, ball milled, solution method, crystalization in supercritical fluid technology to realize usually.But the particle size distribution that preceding two kinds of methods obtain is broad usually, is difficult to satisfy the requirement of new and high technology now; Though solution method can obtain narrower particle size distribution, regular meeting remains in the particle and causes unnecessary side effect during used organic solvent; The crystalization in supercritical fluid technology is the novel method of preparation nano-micrometre medicine, and its principle is to utilize supercutical fluid such as carbonic acid gas etc. and drug solution to mix under supercritical state from the nozzle ejection, forms the nano-micrometre grade particulate in tens microseconds.By regulating parameters such as pressure, temperature, flow, concentration, the form that can control drug particle size, crystal formation even need from allotropic substance, select.The crystalization in supercritical fluid technology is compared with the ultrafine powder of conventional junction crystal method production, its crystallization ideal, smooth surface, epigranular, almost noresidue solvent.Novel method is to settle working system at one go, needn't drying and crushing etc. aftertreatment, none is useless for production process, is called as green technology.
The crystalization in supercritical fluid technology can also make medicine and high polymer adjuvant form composite particles, promptly makes full use of medicine and the auxiliary material unique novel drug delivery system of each function of characteristic system separately.Utilize micron order medicine that new technology produces can per os or nasal cavity directly send in the alveolar and play a role.Extremely unsettled macromole such as protein and peptide class also can obtain rock steady structure and produce longer curative effect.Some are difficult to absorb or the medicine of taste extreme difference then can utilize the coating parcel, reach functions such as quick-release, slowly-releasing, controlled release, taste masking.Therefore, the crystalization in supercritical fluid technology has become the technology platform of various chemicalses and the super new formulation of biochemical drug.
The rubescensine A chemical name is Kaur-16-en-15-one, 7, and 20-epoxy-1,6,14-tertrahydroxy-, (12,6b, 7a, 14R).Rubescensine A is a kind of colourless prism-shaped crystal, bitter, relative molecular mass 304.42.Rubescensine A is the tetracyclic diterpene compounds of kaurene skeleton, it is the most important antineoplastic component of plant Rabdosia rubescens, pharmacological testing proves that this composition anticancer spectrum is wider, can pass through the number of ways cancer cell specific induction of apoptosis, to the human hepatocellular carcinoma BEL-7402 cell, non-small cell lung cancerous tissue NCI-H520, NCI-H460, NCI-HI299, human leukemia HL-60 cell, esophageal carcinoma CaES-17 cell, colorectal carcinoma HCT8 cell and human melanoma cell etc. all have obvious cytotoxicity.Mainly adopt rubescensine A injection for treating primary hepatocarcinoma, the esophageal carcinoma clinically, and obtained certain curative effect.In addition, because this composition is insoluble in water, conventional injection relies on adding tensio-active agent or organic solvent to improve solvability more, and long-term intravenous drip easily causes side effects such as patient vessel's inflammation and pain.Therefore, how to increase solvability and target, and the body-internal-circulation time of prolong drug, be the key that improves its curative effect.
People extremely thirst for occurring a kind of particle superfining process that the rubescensine A medicine is made at present, find out suitable crystal formation and improve this medicine solubleness and curative effect, reduce the technology of use cost and toxic side effect; The formulation of Shi Yonging also has Foradil Aerolizer formoterol fumarate, aerosol, preparation capable of permeating skin and ointment etc. simultaneously.
(3) summary of the invention:
The objective of the invention is to invent a kind of preparation process of oridonin fine particles and goods thereof, it can overcome the deficiencies in the prior art, a kind of micropowders of suitable rubescensine A is provided, improve this medicine dissolution rate and curative effect, use the technology that the crystalization in supercritical fluid technology prepares oridonin fine particles.
Technical scheme of the present invention is: a kind of preparation process of oridonin fine particles is characterized in that it may further comprise the steps:
(1) configuration rubescensine A solution: according to organic solvent: rubescensine A is 200: 1-10: 1 ratio fully is dissolved in rubescensine A in the organic solvent, makes the concentration of rubescensine A be: 0.05-10%, and solvent temperature is controlled at 20-80 ℃;
(2) the rubescensine A solution with preparation in the step (1) links to each other with solution pump, and operating pressure is controlled to be 2-150MPa;
(3) feed carbon dioxide: with the CO in the steel cylinder
2By the anti-solvent equipment system of supercharging pump valve input supercutical fluid, enter crystallization kettle, flow control is controlled 20-80 ℃ of start-up temperature at 5-150ml/min; Pressure is 2-150MPa;
(4) the rubescensine A solution with configuration in the above-mentioned steps (1) sprays in the crystallization kettle rapidly by solution pump nozzle in the anti-solvent equipment system of supercutical fluid, and flow control is at 1-20ml/min; Entrainment agent is sprayed in the crystallization kettle by the entrainment agent solution pump, and flow control is 1-20ml/min; Operating time is 40 to 240min; Continue to feed CO2, the organic solvent that feeds in the step (1) is cleaned remaining solvent in the equipment pipeline;
(5) the rubescensine A crystallization is separated out: collect the rubescensine A crystallite attitude or the unformed shape subparticle of separating out in the crystallization kettle bottom from solvent, gains are oridonin fine particles.
Organic solvent in the above-mentioned said step (1) is at least a in methyl alcohol, ethanol, ether or the ethyl acetate.
Solution pump in the above-mentioned said step (2) is the high performance liquid chromatography solution pump.
Solution pump in the above-mentioned said step (4) is the high performance liquid chromatography solution pump.
Nozzle temperature is 20-100 ℃ in the above-mentioned said step (4), and its jet length is 1-50cm.
Entrainment agent in the above-mentioned said step (4) is dehydrated alcohol, 95% ethanol, methyl alcohol, ethyl acetate, acetone or chloroform.
The oridonin fine particles particle diameter that obtains in the above-mentioned said step (5) is d (0.5)=5.135um.
A kind of oridonin fine particles that makes according to above-mentioned technology is characterized in that it is the loose unformed fines of white, and its grain diameter is d (0.5)=5.135um.
Principle of the present invention and detection describe:
The present invention passes through nozzle 3 with rubescensine A in supercritical fluid solution, be sprayed onto rapidly in the surrounding environment of low pressure with supersonic speed by high pressure conditions.The supersaturation that reduces to make solution formation extreme rapidly of pressure, institute's dissolved solute is just separated out in the extremely short time.The particle that utilizes this technology to make is very little usually, can reach micron order, even nano level, and particle size distribution is very narrow, good dispersity.
Concerning drug crystallization and particle engineering, the importantly high and control easily of the compressibility of supercutical fluid, near stagnation point, the minor alteration of temperature and pressure can make the density, spread coefficient, viscosity, surface tension, solubleness of solvent etc. produce obvious variation.Current application supercutical fluid the most widely is a carbonic acid gas, purity is high by 99.999%, critical temperature and emergent pressure are lower (Tc=37.3 ℃, Pc=7.15MPa) odorless nontoxic pollution-free, unreactiveness does not have corrosion, and is not easy to blast safe in utilization, recovery cheap and easy to get is convenient, the quality product height, with short production cycle, and be widely used in removing the separation and the purification of aspects such as caffeine and food flavoring, healthcare products.In recent years, be subjected to paying attention to widely both at home and abroad and studying on each in particulate systems such as medicine, polymkeric substance and catalyzer.
Superiority of the present invention is: 1, technology of the present invention is fit to the rubescensine A raw material, can make the super-refinement subparticle, is beneficial to absorption of human body, can improve rubescensine A solubleness and curative effect, reduces use cost and toxic side effect; 2, rubescensine A ultrafine particle through the present invention's preparation, possesses special advantages clinical, this medicine advantage is as follows: a, because rubescensine A is widely distributed in vivo, shortage is to the pathoklisis of tumor locus, and biological half-life is short in the body, often needing to strengthen dosage just can make medicine produce a higher concentration at target site, to improve result of treatment, yet the increase of dosage can cause patient's conformability to reduce, and the initiation toxic side effects, the micropowders of the rubescensine A that the present invention makes is fit to lung's inhalation, medication is convenient, and directly targeting is in lung tumors; B, since this composition be insoluble in water, conventional injection relies on adding tensio-active agent or organic solvent to improve solvability more, long-term intravenous drip easily causes side effects such as patient vessel's inflammation and pain, therefore, what the present invention solved is the solvability that increases rubescensine A, by the inhalation of powder inhalation or aerosol, directly enters blood circulation via alveolar, easy to use, patient's conformability improves; C, micropowders are fit to make dry powder formulations, owing to do not adopt fluoroalkane hydro carbons propellent (CFCs), belong to Green Product; The dissolvent residual of d, micropowders is lower than 2005 editions requirements of Chinese Pharmacopoeia; F, dynamic size distribution reach 2005 editions powder inhalation requirements of Chinese Pharmacopoeia, can be widely used for the exploitation of several formulations.
(4) description of drawings:
The anti-solvent equipment of supercutical fluid connects and schematic flow sheet in the related a kind of preparation process of oridonin fine particles of accompanying drawing the present invention.
Wherein, 1 is rubescensine A solution, and 2 is solution pump, and 3 is nozzle, and 4 is crystallization kettle, and 5 for the gas-liquid separation still, and 6 is gas discharge outlet, and 7 is collector at residual night, and 8 is topping-up pump, and 9 is CO
2, 10 is the entrainment agent solution pump, and P1 is an equipment system pressure, and P2 is the crystallization kettle operating pressure.
(5) embodiment:
Embodiment: a kind of preparation process of oridonin fine particles is characterized in that it may further comprise the steps:
(1) configuration rubescensine A solution: according to organic solvent: rubescensine A is that 100: 2 ratio fully is dissolved in rubescensine A in the organic solvent, makes the concentration of rubescensine A be: 2.0%, and solvent temperature is controlled at 40 ℃;
(2) the rubescensine A solution 1 with preparation in the step (1) links to each other with solution pump 2, and operating pressure is controlled to be 15MPa;
(3) feed carbon dioxide: with the CO in the steel cylinder
29 by the anti-solvent equipment system of supercharging pump valve 8 input supercutical fluids, enters crystallization kettle 4, and flow control is controlled 45 ℃ of start-up temperature at 10ml/min; Pressure is 15MPa;
(4) the rubescensine A solution with configuration in the above-mentioned steps (1) sprays in the crystallization kettle 4 rapidly by solution pump 2 nozzle 3 in the anti-solvent equipment system of supercutical fluid, injects the solution of 300ml rubescensine A, and flow control is at 1.5ml/min; Entrainment agent is sprayed in the crystallization kettle 4 by entrainment agent solution pump 10, and flow control is 1.5ml/min; Operating time is 100min; Continue to feed CO2, the organic solvent that feeds in the step (1) is cleaned remaining solvent in the equipment pipeline;
(5) the rubescensine A crystallization is separated out: collect the rubescensine A crystallite attitude or the unformed shape subparticle of separating out from solvent in crystallization kettle 4 bottoms, gains are oridonin fine particles;
(6) residue is handled through gas-liquid separation still 5, and gas is discharged by gas discharge outlet 6, and raffinate flows into raffinate collector 7.
Organic solvent in the above-mentioned said step (1) is an ethyl acetate.
Solution pump in the above-mentioned said step (2) is the high performance liquid chromatography solution pump.
Solution pump in the above-mentioned said step (4) is the high performance liquid chromatography solution pump.
Nozzle temperature is 45 ℃ in the above-mentioned said step (4), and its jet length is 5cm.
Entrainment agent in the above-mentioned said step (4) is a dehydrated alcohol.
The oridonin fine particles particle diameter that obtains in the above-mentioned said step (5) is d (0.5)=5.135um.
A kind of oridonin fine particles that makes according to above-mentioned technology is characterized in that it is the loose unformed fines of white, and its grain diameter is d (0.5)=5.135um.
To detection method and result with the oridonin fine particles size distribution of prepared of the present invention:
With the dynamic laser light scattering experimental particle size analyzer to after the crystalization in supercritical fluid technology preparation particle diameter and distribution thereof measure.Condition determination is: sample thief adopts the dry method test, and measuring temperature is 25 ℃, and effective size of grain is 10um, and measurement result is as follows:
Sample particle size determination result before and after the preparation
X ray polycrystalline diffraction analysis method:
Carry out sample pre-treatments and become homodisperse pressed powder, sample test.Testing conditions: graphite monochromator monochromatization CuK α radiation; Manage electric 40kV; Pipe stream 70mA, 4 ℃/min of sweep velocity, 5 ° ~ 50 ° of sweep limits (2 θ).
Unprocessed sample X-ray diffractogram shows that rubescensine A has close and thin peak crystallization between 10 ° ~ 30 °, shows that rubescensine A exists with stable crystal formation.
5 ° ~ 50 ° diffraction peaks that do not have feature, be unformed feature through the rubescensine A collection of illustrative plates of crystalization in supercritical fluid preparation.
Content assaying method:
Instrument Waters company high performance liquid chromatograph, Waters2487 Ultraviolet Detector, 515HPLC pump.
Rubescensine A is an amount of to getting this product, and accurate the title decides, and puts in the 100ml measuring bottle, moving phase is that methyl alcohol one water (50: 50) adds the moving phase solvent soln, and shake up: precision is measured 5ml, puts in the 25ml measuring bottle, be diluted to scale with moving phase, shake up, make the need testing solution that contains 0.20mg among every 1ml.Other gets the rubescensine A reference substance, and accurate the title decides, and puts in the 100ml measuring bottle, adds the moving phase dissolving and is diluted to scale, shakes up; Precision is measured 5ml, puts in the 25ml measuring bottle, adds moving phase and is diluted to scale, shakes up, and makes to contain the 0.2mg reference substance solution among every 1ml.Precision is measured reference substance solution and each 10ul of need testing solution, injects liquid chromatograph, and the record color atlas is pressed external standard method with calculated by peak area, promptly.
All in the 95.0-105.0% of labelled amount scope, determination data sees the following form preparation front and back its content of two batch samples after tested:
Samples contg measurement result before and after the preparation
This product contains the 95.0-105.0% that rubescensine A C20H2806 should be labelled amount, meets drug standard.
Claims (8)
1. preparation process of oridonin fine particles is characterized in that it may further comprise the steps:
(1) configuration rubescensine A solution: according to organic solvent: rubescensine A is 200: 1-10: 1 ratio fully is dissolved in rubescensine A in the organic solvent, makes the concentration of rubescensine A be: 0.05-10%, and solvent temperature is controlled at 20-80 ℃;
(2) the rubescensine A solution with preparation in the step (1) links to each other with solution pump, and operating pressure is controlled to be 2-150MPa;
(3) feed carbon dioxide: with the CO in the steel cylinder
2By the anti-solvent equipment system of supercharging pump valve input supercutical fluid, enter crystallization kettle, flow control is controlled 20-80 ℃ of start-up temperature at 5-150ml/min; Pressure is 2-150MPa;
(4) the rubescensine A solution with configuration in the above-mentioned steps (1) sprays in the crystallization kettle rapidly by solution pump nozzle in the anti-solvent equipment system of supercutical fluid, and flow control is at 1-20ml/min; Entrainment agent is sprayed in the crystallization kettle by the entrainment agent solution pump, and flow control is 1-20ml/min; Operating time is 40 to 240min; Continue to feed CO2, the organic solvent that feeds in the step (1) is cleaned remaining solvent in the equipment pipeline;
(5) the rubescensine A crystallization is separated out: collect the rubescensine A crystallite attitude or the unformed shape subparticle of separating out in the crystallization kettle bottom from solvent, gains are oridonin fine particles.
2. according to the said a kind of preparation process of oridonin fine particles of claim 1, it is characterized in that organic solvent in the said step (1) is at least a in methyl alcohol, ethanol, ether or the ethyl acetate.
3. according to the said a kind of preparation process of oridonin fine particles of claim 1, it is characterized in that the solution pump in the said step (2) is the high performance liquid chromatography solution pump.
4. according to the said a kind of preparation process of oridonin fine particles of claim 1, it is characterized in that the solution pump in the said step (4) is the high performance liquid chromatography solution pump.
5. according to the said a kind of preparation process of oridonin fine particles of claim 1, it is characterized in that nozzle temperature is 20-100 ℃ in the said step (4), its jet length is 1-50cm.
6. according to the said a kind of preparation process of oridonin fine particles of claim 1, it is characterized in that the entrainment agent in the said step (4) is dehydrated alcohol, 95% ethanol, methyl alcohol, ethyl acetate, acetone or chloroform.
7. according to the said a kind of preparation process of oridonin fine particles of claim 1, it is characterized in that the oridonin fine particles particle diameter that obtains in the said step (5) is d (0.5)=5.135um.
8. an oridonin fine particles that makes according to above-mentioned technology is characterized in that it is the loose unformed fines of white, and its grain diameter is d (0.5)=5.135um.
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| CN200810154555A CN101798308A (en) | 2008-12-25 | 2008-12-25 | Preparation process and products of oridonin fine particles |
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| CN200810154555A CN101798308A (en) | 2008-12-25 | 2008-12-25 | Preparation process and products of oridonin fine particles |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058566A (en) * | 2010-12-24 | 2011-05-18 | 中国药科大学 | Dry powder inhaler with constituent rubescensin A as well as preparation method and application thereof |
| CN102106823A (en) * | 2010-12-24 | 2011-06-29 | 国家纳米技术与工程研究院 | Resveratrol composite fine particle preparation process applying supercritical fluid crystallization technology |
| CN104224717A (en) * | 2014-04-25 | 2014-12-24 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Application of oridonin powder aerosol in treatment of acute lung injury |
| CN108159020A (en) * | 2018-01-24 | 2018-06-15 | 广州中医药大学(广州中医药研究院) | Super-critical anti-solvent fluidized coating nano particle and preparation method thereof |
| CN108159064A (en) * | 2018-01-24 | 2018-06-15 | 广州中医药大学(广州中医药研究院) | Super-critical anti-solvent Breviscapinun nano particle and preparation method thereof and Breviscapinun capsule and tablet |
-
2008
- 2008-12-25 CN CN200810154555A patent/CN101798308A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058566A (en) * | 2010-12-24 | 2011-05-18 | 中国药科大学 | Dry powder inhaler with constituent rubescensin A as well as preparation method and application thereof |
| CN102106823A (en) * | 2010-12-24 | 2011-06-29 | 国家纳米技术与工程研究院 | Resveratrol composite fine particle preparation process applying supercritical fluid crystallization technology |
| CN104224717A (en) * | 2014-04-25 | 2014-12-24 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Application of oridonin powder aerosol in treatment of acute lung injury |
| CN108159020A (en) * | 2018-01-24 | 2018-06-15 | 广州中医药大学(广州中医药研究院) | Super-critical anti-solvent fluidized coating nano particle and preparation method thereof |
| CN108159064A (en) * | 2018-01-24 | 2018-06-15 | 广州中医药大学(广州中医药研究院) | Super-critical anti-solvent Breviscapinun nano particle and preparation method thereof and Breviscapinun capsule and tablet |
| CN108159020B (en) * | 2018-01-24 | 2020-06-30 | 广州中医药大学(广州中医药研究院) | Supercritical anti-solvent fluidized coated nano-particles and preparation method thereof |
| CN108159064B (en) * | 2018-01-24 | 2020-09-04 | 广州中医药大学(广州中医药研究院) | Supercritical anti-solvent breviscapine nano-particles and preparation method thereof, and breviscapine capsule and tablet |
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Open date: 20100811 |