CN101816913A - Method and equipment for manufacturing microspheres - Google Patents
Method and equipment for manufacturing microspheres Download PDFInfo
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- CN101816913A CN101816913A CN201010177862A CN201010177862A CN101816913A CN 101816913 A CN101816913 A CN 101816913A CN 201010177862 A CN201010177862 A CN 201010177862A CN 201010177862 A CN201010177862 A CN 201010177862A CN 101816913 A CN101816913 A CN 101816913A
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Abstract
The invention provides a method and equipment for manufacturing microspheres. In the method for manufacturing the microspheres, the microspheres are produced by the equipment of the invention in a simple and continuous mode. In the method for producing the microspheres, raw materials in a liquid form are fed to the equipment and processed by the equipment to form droplets; the droplets move in the equipment and are cured gradually to form the microspheres; and the microsphere products are collected in an equipment collector in a mode of sweeping gas or liquid.
Description
Technical field:
The present invention relates to a kind of manufacture method and manufacturing equipment of microballoon.
Background technology:
A kind of small entity spheric granules, its particle size range is generally 1-250 μ m, is known as microballoon.Along with the development of pharmaceutical science, discovery can utilize some excellent characteristic of microballoon to reach the target of medicine or slowly-releasing, long-acting conveying effect.Microballoon promptly can be carried chemical small-molecule drug, can be used for carrying macromolecular drugs such as protein and polypeptide again.The microballoon of these pastilles is called as medicine microspheres.Medicine microspheres can oral administration, or muscle, hypodermic injection administration.
Prepare medicine microspheres, generally require the profile subglobular of medicine microspheres, carrying drug ratio is higher, and entrapment efficiency is higher, and particle diameter is controlled in certain scope, and it is concentrated to distribute.Also need to prevent prominent releasing for slowly-releasing or depot drug product microballoon, rate of release is controlled.
As operable pharmaceutical preparation, need to reduce the irrelevant residue that in preparation, brings, for example organic solvent residual as far as possible.For some sensitive drug, for example a lot of efficient and responsive polypeptide and pharmaceutical grade proteins also need use temperate condition to guarantee effectively stability and active of medicine in the preparation process of medicine microspheres as much as possible.
At present, it is few to be used for the simple and reliable method of large-scale production medicine microspheres.
Common have following preparation methods (" pharmacy " the 6th edition, People's Health Publisher, Cui Fude chief editor).
" solvent-nonsolvent method ", its preparation process is generally as follows: add a kind of solvent insoluble to material (non-solvent) in material solution, cause to be separated, and with the medicine parcel, make microballoon.Wherein need to use the solvent of a lot of toxicity, do not see this method in the industrial-scale production of medicine microspheres.
" intra-liquid desiccation method " generally removes the solvent flashing in the decentralized photo from emulsion, preparation pastille microballoon also is called " emulsification-solvent evaporation method ".Many use emulsifications and a large amount of organic solvents, difficulty is controlled in operation between batch, rare this method in the industrial-scale production of medicine microspheres.
" spray drying process " generally is that medicine is dispersed in the solution of material, and spray-on process by little nozzle, through spraying in the high temperature gas flow after the gases at high pressure shearing, obtains the pastille microballoon with this mixed liquor.This method needs high temperature, and the profile of particle and particle diameter distribute and be difficult to control, is limited to the special material preparation microballoon of minority.By the dried particle of spray that " spray drying process " obtains, profile is random mostly, therefore, can adopt the application of this method production microspheres product few.
The usage that also has some accommodations " spray drying process ", its preparation method is that emulsion is made with carrier material, medical surfaces activating agent, water, organic solvent etc. by elder generation, emulsion is sprayed in a large amount of ethanol ice by liquid nitrogen frozen again, organic liquor is removed in intensification, obtains medicine microspheres.Its preparation process is complicated, with high costs.
Present being seen said method generally needs to use exhibiting high surface activating agent or organic solvent, and perhaps the productive rate of product and envelop rate are lower, perhaps manufacturing condition complexity, industrial reliability and poor repeatability; With an organic solvent make the protein and peptide inactivation in the technology in a large number, and the difficult problems such as dissolvent residual toxicity of product industrial-scale production and wide application of medicine microspheres have been limited.At present, be not fit to carry out physical mechanical and the corresponding production method that medicine microspheres is produced on the commercial scale.
Summary of the invention:
The problem that quasi-solution of the present invention is determined
Under such situation, the purpose of this invention is to provide the method for producing microballoon.This method can be by simple plant equipment, but gives birth to microballoon with the mode of production of scale continuously.This method can also be suitable for some need avoid organic solvent and the surfactant microballoon preparation method of emulsification of going ahead of the rest, and is not suitable for and prepares microballoon by these solvents but also do not get rid of.Relatively low temperature conditions also can be provided and be fit to preparation the medicine microspheres of high temp. sensitive.Another object of the present invention provides the equipment of producing microballoon.
The mode of dealing with problems
According to the present invention, provide by simple plant equipment, can be continuously, the mode of production of scale produces medicine microspheres.
This mode according to plant equipment production microballoon provided by the invention can be described as, be dispersed into the mixed liquor of liquid raw material, be transported to by liquid feed device, the droplet generating means of equipment, behind the mixed liquor process droplet generating means, by with the form high degree of dispersion of droplet in main cavity, in the process that droplet moves in main cavity, remove gradually and desolvate or condensation cured forms the microballoon product; The microballoon product is collected device and collects.
According to the present invention, the production equipment of microballoon is provided, this equipment comprises:
Be used for the main case of microballoon preparation, the present invention is referred to as main cavity; The main cavity wall preferably contains the double-decker of thermal insulation layer.
Be used for mixed liquor is input to the liquid feed device of droplet generating means, this liquid feed device comprises at least one feed flow nozzle, can carry mixed liquor to the droplet generating means through nozzle;
Be used for mixed liquor is formed the device of droplet, this device comprises at least and is activated the video disc that can rotate at a high speed, and the power set that drive video disc, can be high-speed motor;
Be used for the air ring of entad blowing to the video disc planar central of at a high speed rotation;
Be used to form the airflow apparatus of tangential whirlwind;
Be used to collect the device of microballoon, this device is made up of sample divider and a plurality of fan trays.
The invention effect
As indicated above, according to the present invention, mixed liquor is infeeded the droplet generating means, and, form solid granulates gradually by the air-flow constrained operation in the main cavity, particle enters gathering-device with air-flow and forms the microballoon product.Thus, can effectively produce microballoon in simple mode.
The accompanying drawing summary
Fig. 1: the diagrammatic sketch of an embodiment of microballoon production equipment of the present invention.
Fig. 2: the annulus diagrammatic sketch that the airflow apparatus of the tangential whirlwind that an embodiment of microballoon production equipment of the present invention is used comprises.
Fig. 3: the diagrammatic sketch of the pallet that the used collection microballoon device of an embodiment of microballoon production equipment of the present invention is comprised.
Fig. 4: the displaing micro photo figure of the medicine microspheres that the embodiment of the invention 1 is produced.
Fig. 5: the displaing micro photo figure of the medicine microspheres that the embodiment of the invention 2 is produced.
Fig. 6: the displaing micro photo figure of the medicine microspheres that the embodiment of the invention 3 is produced.
Fig. 7: the displaing micro photo figure of the medicine microspheres that the embodiment of the invention 4 is produced.
Fig. 8: the displaing micro photo figure of the medicine microspheres that the embodiment of the invention 5 is produced.
Fig. 9: the displaing micro photo figure of the medicine microspheres that the embodiment of the invention 6 is produced.
Implement best mode of the present invention
According to the method for production microballoon of the present invention, the raw material mixed liquor of solution, microparticle suspending liquid, emulsion or fused solution form is infeeded the droplet generating means.
In preferred embodiment, mixed liquor comprises solvent, and the material of desire microballoonization is dissolved in wherein, and wherein solvent is a water.
In preferred embodiment, mixed liquor comprises solvent, and the material of desire microballoonization is dissolved in wherein, and wherein solvent can be organic solvent, for example ethanol.
In preferred embodiment, mixed liquor can also be an emulsion, and the material of desiring microballoonization is scattered in wherein, for example, polypeptide drugs is dissolved in the entry, mixes with the material liquid that is dissolved in carrene to form emulsion.
In preferred embodiment, mixed liquor can also be a microparticle suspending liquid, desires the material of microballoonization, can be dispersed in wherein, and the suspended particle particle diameter is preferably less than below 30 microns.For example, medicine is dispersed in the micro mist ethyl cellulose suspension.
In preferred embodiment, desire the material of microballoonization, can also be the liquid that melts shape, for example, drug powder is mixed in the wax oil of thawing, form and melt shape liquid.
According to the present invention, mixed liquor is input to the droplet generating means by liquid feed device.Particularly, this liquid feed device comprises at least one feed flow nozzle, can carry mixed liquor revolving on the dish face under the droplet generating means through nozzle, and the diameter of preferred nozzle is below the 2mm; Nozzle does not contact with revolving the butterfly face, and preferred nozzle and video disc are closely below the 3mm.Mixed liquor adds to through nozzle and revolves on the dish face, preferably with the form of continuous drop.
According to the present invention, mixed liquor is handled through the droplet generating means and is formed droplet.This droplet generating means comprises circular video disc, and the CD-ROM drive motor that drives the video disc rotation.Particularly, mixed liquor is evenly added on the video disc of rotation, preferably the center of video disc, by the high speed rotating centrifugal effect of rotating compact disc, mixed liquor disperses and runs to the edge of video disc on video disc, be subjected to the effect of disc edge air-flow, form droplet, enter the main cavity operation.The speed of service of preferred video disc is more than 2000 rev/mins.
According to the present invention, entad the air ring device of Chui Qiing provides entad air-flow, preferred air ring identical with the residing horizontal plane of video disc or more than, preferred distance is to be lower than 10 centimetres rise; The temperature of air-flow and size can be controlled.Droplet is under the effect of air-flow entad, and droplet seldom flies on the main cavity wall, remains on operation in the main cavity.
According to the present invention, form the airflow apparatus of tangential whirlwind, the whirlwind that is subjected to size control is provided, the power of above-mentioned droplet at the main cavity continuous service can be provided.Tangential gas flow is not specifically limited at the inlet number of main cavity wall, and being preferably the inlet number is four.The entry position preferably at main cavity bottom position 5cm above water, is evenly arranged respectively.Under the tangent line air flow inlet, also comprise an annulus, can control the mainly upwards operation of local tangent line air-flow.Annulus can be that a plurality of fan-shaped circular ring plates are formed, its overall diameter should be near the main cavity internal diameter, the anchor ring width is unrestricted, is preferably 10 centimetres.Annulus 9 placement locations should be lower than the tangent line air flow inlet, and preferred difference in level should be less than 3 centimetres.
According to the present invention, preferably collect the microballoon product by three parts.
First comprises a plurality of fan trays compositions, preferably as shown in Figure 1 shown in position 12 and Fig. 1-2.The quantity of pallet is not specifically limited, but need surround a full circle.Pallet is positioned over the main cavity bottom, and the position 12 as shown in Figure 1, and each pallet is entad aimed at the passway 13 of main cavity bottom respectively, and the position 13 as shown in Figure 1.Each fan trays all has the purging mouth of a correspondence, and the position 11 as shown in Figure 1, can parallel holding tray surface purge gas entad; Perhaps can depict particular of the present invention as, this purging mouth can purge out liquid, for example liquid nitrogen, or other treat liquid as required.
Second portion is made up of first sample collection device.Preferred form comprises as shown in Figure 1 by gas channel 13, the sedimentation device 14 that circles round, and sample divider 15, and can be described to the liquid circulation channel outlet 22 that particular of the present invention is used, and backflow interface 23 is formed.
Third part is made up of the second sample divider device.Preferred form comprises the passage that links to each other by with 14 as shown in Figure 1, the sedimentation device 16 that circles round, and sample divider 17, and gas circulation adjuster 21 compositions.
According to method of the present invention, in the ordinary course of things, can produce with the microspheres with solid of particle diameter between 1-250 μ m.Contain at the raw material mixed liquor under the situation of medicine, can obtain solid-state medicine microspheres.Particular of the present invention can be depicted as, for example, microsphere suspension liquid can be obtained purging mouthful (diagram 1-1 position a 11) liquid purge or a liquid nitrogen.
Embodiment
An embodiment of microballoon production equipment of the present invention is described with reference to Fig. 1 below.
This equipment has and is used for to equipment body chamber 1, introduces the nozzle 3 of raw material mixed liquor and the raw material mixed liquor is become the high speed that the droplet generating means of droplet 20 comprised to revolve dish 4; The air ring device 5 that is used for entad blowing, this device can provide air-flow to the plate-spinning of rotation at a high speed, retrains the scope of droplet operation, and the gas of uniform temperature is provided as required, and the contained solvent of droplet is evaporated, and plays the preliminary effect that concentrates; Tangent line airflow apparatus 8 is used for producing along main cavity inwall swirling eddy, can prolong the range ability of droplet in cavity that concentrates through preliminary, further removes the contained solvent of droplet, makes droplet be cured as the microballoon object of solid shape; Be used for the fan trays device 12 of auxiliary microballoon product collection and the purging mouth 11 that is parallel to each holding tray surface purge gas is provided, the microspheres with solid product that this device promotes part to fall to pallet is entad concentrated; The microballoon product enters first sample collection device 15 through passway 13.
Type to nozzle 3 is not specifically limited, as long as this nozzle can add to mixed liquor homogeneous and controllable ground the center that rotates dish at a high speed, preferred diameter is the atomizer below the 2mm.
At the droplet generating means, by the dish 4 that revolves that rotates at a high speed the raw material mixed liquor is disperseed, form the operation in the main cavity that enters of droplet.The rotating speed of plate-spinning without limits, preferred plate-spinning rotating speed be 2000 change more than, generally being no more than 15000 changes, but does not limit this rotating speed upper limit.This device comprises, the raw material mixed liquor is separated into the plate-spinning 4 of droplet, for rotating disk provides the motor 6 of rotary power, and is used for air-breathing device 7.Getter device is used to remove plate-spinning 4 issuable a small amount of leakage or irregular materials 19, and its bore does not limit, and preferably is not more than to revolve 2 centimetres of dish diameters, and the air entry height and position is adjustable, and preferably its position plane is lower than and revolves dish but be no more than 5 centimetres.
Through the droplet that the droplet generating means produces, enter the main cavity operation, the entad air-flow effect that the air ring device 5 that is subjected to entad blowing produces.Device 5 can entad provide air-flow to rotation dish plane, and the scope of constraint droplet operation is evaporated the contained solvent of droplet, plays the preliminary effect that concentrates.Droplet is under the effect of air-flow entad, and droplet seldom flies on the main cavity wall, remains on operation in the main cavity.This air ring setting position, preferably with revolve the residing horizontal plane of dish identical or more than, preferably exceed and highly be no more than 10 centimetres; Air ring is connected with other external device, and this external device provides the air-flow of temperature and size-controlled system.
Droplet is operation downwards gradually in main cavity, is subjected to the effect of the swirling eddy of main cavity internal tangent air-stream generating device 8 generations, and range ability prolongs, and the contained solvent of droplet is removed, and forms solid shape microballoon.Be used to produce the tangent line air-stream generating device 8 along the tangential swirling eddy of main cavity, this device air flow inlet quantity is unrestricted, and preferred four inlets are evenly distributed on same horizontal plane.The air flow direction of four inlets should be consistent, and preferably the direction of rotation with plate-spinning 4 is consistent.The tangent line air-stream generating device also comprises an annulus 9 (diagrammatic sketch 1-2), also can be that a plurality of fan-shaped circular ring plates are formed, and its overall diameter should be near the main cavity internal diameter, and the anchor ring width is unrestricted, is preferably 10 centimetres.Annulus 9 placement locations should be lower than the tangent line air flow inlet, and preferred difference in level should be less than 3 centimetres.
The solid shape microballoon that forms to the operation of the bottom of main cavity, through passage 13, enters first sample collection device 14 gradually, and most of microballoon falls to sample divider 15.
In the equipment of the present embodiment, mainly be the collection efficiency that improves microballoon as the second sample divider device 16, link to each other with 14 by passage, collecting the 15 part microballoons that do not have to collect can obtain in sample divider 17.Wherein gas can be by exhaust dispensing device 21, and the distribution of control air-flow is for example got rid of 50% of tolerance and turned back to purge gas passway 10 by adjusting device.
In the equipment of the present embodiment,, can accept the part microballoon that is deposited in the main cavity bottom as the fan trays 12 of auxiliary gathering-device.When each fan trays all has a nozzle or liquid inlet 11, the pallet highest point preferably should be less than 5 millimeters under the horizontal plane of annulus 9.
Can be described as the specific implementations of the present embodiment, when taking the gas purging mode, pump into gas by 21 devices, enter the mouth 11 for gas nozzle this moment, and each pallet has the purge gas purge pallet that is pumped into by passage 21, and this moment is by 22,23,24 fluid paths that connect are in closed condition.
Can be described as another specific implementations of the present embodiment, when needs are taked liquid wash or are handled the microballoon product, liquid inlet 24 by each pallet, with each pallet of liquid wash, and interface channel mouth 22 and EGR 23 can return the sample divider supernatant, and circulation flushing is when the input starting liq, can not limit by the input of 22 or 23 access ports.When adopting liquid wash, the gas regulation of passage 21 does not pump into gas.
When first, second sample divider device 16 provides enough microballoon collecting effect, needn't provide more gathering-device.In order further to improve the collecting effect of microballoon, can link together with second gathering-device a plurality of.
To describe the equipment that uses above-mentioned embodiment below, carry out the embodiment that microballoon is produced.
Embodiment 1
150 gram gelatin are dissolved in 1000 ml waters of about 60 degree of temperature, add 10 gram Doxycycline Hyclates in the stirring, to dissolving fully.This pastille mixed liquor is prepared the Doxycycline Hyclate medicine microspheres according to embodiment.Wherein in auxiliary pallet operation of collecting, adopt the gas purging method.Collect microballoon at gatherer 15 and 17 places, produce the medicine microspheres of embodiment 1 thus.
100 gram ethyl celluloses are dissolved in 1000 milliliter 82% the ethanol, add paracetamol 15 grams.This pastille mixed liquor is prepared the paracetamol medicine microspheres according to embodiment.Wherein in auxiliary pallet operation of collecting, adopt the gas purging method.Collect microballoon at gatherer 15 and 17 places, produce the medicine microspheres of embodiment 2 thus.
40 gram dextrans are dissolved in 250 ml waters, add thymopeptide-5 1 gram in the gentle agitation, this aqueous solution under minutes 400 mixing speeds of changeing, evenly is added in 300 milliliter 10% the dichloromethane solution of polylactic acid-glycolic guanidine-acetic acid, forms milky white shape emulsion.This pastille emulsion is prepared the thymopeptide-5 medicine microspheres according to embodiment.Wherein in auxiliary pallet operation of collecting, adopt the gas purging method.Collect microballoon at gatherer 15 and 17 places, produce the medicine microspheres of embodiment 3 thus.
Embodiment 4
With 120 gram micro mist ethyl celluloses (particle diameter is distributed in below 30 microns), be dispersed in 300 milliliter 5% the HPMC, again metoprolol tartrate medicine 20 grams are dissolved in wherein, stir, obtain pastille suspension.This pastille emulsion is prepared the metoprolol tartrate medicine microspheres according to embodiment.Wherein in auxiliary pallet operation of collecting, adopt the gas purging method.Collect microballoon at gatherer 15 and 17 places, produce the medicine microspheres of embodiment 4 thus.
Embodiment 5
Get 100 gram cetanols, heating and melting adds 5 gram Risperidones in this wax oil, stir, and the pastille that obtains Risperidone melts shape liquid.This pastille is melted shape liquid prepare the Risperidone medicine microspheres according to embodiment.Wherein in auxiliary pallet operation of collecting, adopt the gas purging method.Collect microballoon at gatherer 15 and 17 places, produce the medicine microspheres of embodiment 5 thus.
12 gram sodium alginates are dissolved in 200 ml waters, add interferon 0.3 gram again, stir gently and form the interferon sodium alginate soln.Other prepares 2000 milliliters of 3% calcium dihydrogen phosphate aqueous solution, as the liquid handling flushing liquor.Wherein in auxiliary pallet operation of collecting, adopt the liquid wash method.Collect microsphere suspension liquid at gatherer 15 places, centrifugal back produces the gel medicine microspheres of embodiment 6.
Test implementation example 1
1. the microballoon sample outward appearance of embodiment 1-6 is carried out microscopic observation and taken pictures, (LeicaDM5000B Germany), adopts the interference light source to take pictures as come card microscope to use instrument.Fig. 4-9 shows.
Picture shows employing equipment provided by the invention and implementation method, and the sphericity of Zhi Bei medicine microspheres sample is good in a continuous manner, and is dispersed good.
2. the microballoon sample to embodiment 1-6 carries out the particle diameter distributional analysis, and instrument is MASTERSIZER 2000 (MALVERNINSTRUMENT).
Wherein, adopt dry method to measure to embodiment 1-5 sample; Adopt wet method to measure to embodiment 6 samples, medium is the phosphate buffer of PH 5.0.
The particle diameter testing result sees Table 1.The result shows, adopts equipment provided by the invention and implementation method, the centralized particle diameter of Zhi Bei medicine microspheres sample in a continuous manner, and uniformity is good.
Table 1
3. the microballoon sample to embodiment 1-6 carries out medicine assay.The results are shown in Table 2.
Entrapment efficiency (%)=mensuration microsphere drug content/medicine drops into content * 100%
The result shows that adopt equipment provided by the invention and implementation method, the envelop rate of Zhi Bei medicine microspheres sample is all more than 95% in a continuous manner.
Analytical method to each embodiment microballoon sample medicament contg is described below respectively:
Embodiment 1 sample is with reference to " 2010 editions two ones of Chinese pharmacopoeia, Doxycycline Hyclate sheet contain quantifier below method and measure.
Embodiment 4 samples are with reference to " 2010 editions two ones of Chinese pharmacopoeia, tartaric acid acid metoprolol sheet contain quantifier below method and measure.
Embodiment 5 samples, with reference to " national drug standards " WS1-(X-056)-2003Z, Risperidone sheet assay item is measured down.
Table 2
Claims (8)
1. produce the method for microballoon, it is characterized in that this method comprises that the raw material mixed liquor with solution, microparticle suspending liquid, emulsion or fused solution form infeeds the droplet generating means; By the droplet generating means raw material mixed liquor is scattered in main cavity with the form of droplet; The operation of droplet in main cavity is subjected to the constraint of air-flow, removes gradually and desolvates or condensation cured formation microballoon product; The microballoon product is collected device and collects.
2. according to the method for the production microballoon of claim 1, the raw material of wherein treating microballoonization is the form of liquid.
3. according to the method for the production microballoon of claim 1, by containing the droplet that the droplet generating means that revolves dish at a high speed forms the raw material mixed liquor high degree of dispersion.
4. according to the method for the production microballoon of claim 1, droplet is subjected to the entad constrained operation of air-flow and tangent line swirling eddy in main cavity.
5. according to the method for the production microballoon of claim 1, the microballoon product is collected device and collects.
6. produce the equipment of microballoon, it is characterized in that this equipment comprises:
The main case that is used for the microballoon preparation contains the double-decker of thermal insulation layer;
Be used for mixed liquor is input to the feed flow nozzle of droplet generating means, the raw material mixed liquor be transported to the droplet generating means through nozzle;
Be used for the raw material mixed liquor is formed the device of droplet, this device comprises at least and is activated the video disc that can rotate at a high speed, and the power set of driving video disc, can be high-speed motor;
Be used for the air ring of entad blowing to the video disc planar central of at a high speed rotation;
Be used to form the airflow apparatus of tangential whirlwind;
Be used to collect the device of microballoon.
7. according to the equipment of the production microballoon of claim 6, be used to form the airflow apparatus of tangential whirlwind, comprise the inlet that tangential gas flow is provided, and can control the mainly annulus of operation upwards of local tangent line air-flow under the tangent line air flow inlet.
8. according to the equipment of the production microballoon of claim 6, its device of collecting the microballoon product comprises,
First, the purging mouth of a plurality of fan trays and each fan trays correspondence, purge mouthful can parallel holding tray surface purge gas entad; Perhaps liquid purge.
Second portion, first sample collection device, this installs by gas channel, the sedimentation device that circles round, sample divider.Also comprise liquid to be circulated to and be back to the lane device that purges mouth.
Third part, the second sample divider device, this installs by the passage that links to each other with first sample, the sedimentation device that circles round, sample divider, and can be with gas circulation to the adjuster device that purges mouth.
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| CN201010177862.3A CN101816913B (en) | 2010-05-20 | 2010-05-20 | A kind of Microsphere manufacture method and manufacturing equipment |
| PCT/CN2011/070790 WO2011143953A1 (en) | 2010-05-20 | 2011-01-29 | Method and apparatus for manufacturing microspheres |
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| CN201010177862.3A CN101816913B (en) | 2010-05-20 | 2010-05-20 | A kind of Microsphere manufacture method and manufacturing equipment |
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| CN101816913B CN101816913B (en) | 2015-10-21 |
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| CN102579365A (en) * | 2012-03-22 | 2012-07-18 | 中山大学 | Risperidone microsphere preparation and preparation method thereof |
| CN102579365B (en) * | 2012-03-22 | 2014-06-11 | 中山大学 | Risperidone microsphere preparation and preparation method thereof |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2011143953A1 (en) | 2011-11-24 |
| CN101816913B (en) | 2015-10-21 |
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