CN102389756A - Method for preparing micro spheres by multiple emulsion process - Google Patents
Method for preparing micro spheres by multiple emulsion process Download PDFInfo
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- CN102389756A CN102389756A CN2011102300810A CN201110230081A CN102389756A CN 102389756 A CN102389756 A CN 102389756A CN 2011102300810 A CN2011102300810 A CN 2011102300810A CN 201110230081 A CN201110230081 A CN 201110230081A CN 102389756 A CN102389756 A CN 102389756A
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000004945 emulsification Methods 0.000 title claims abstract description 23
- 239000004005 microsphere Substances 0.000 title abstract description 9
- 239000000839 emulsion Substances 0.000 claims abstract description 111
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 25
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 15
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 11
- 239000008215 water for injection Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 8
- 229920002988 biodegradable polymer Polymers 0.000 claims description 8
- 239000004621 biodegradable polymer Substances 0.000 claims description 8
- 238000000265 homogenisation Methods 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 229920000954 Polyglycolide Polymers 0.000 claims description 4
- 230000001186 cumulative effect Effects 0.000 claims description 4
- 239000004633 polyglycolic acid Substances 0.000 claims description 4
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 229920002721 polycyanoacrylate Polymers 0.000 claims description 3
- 229920000570 polyether Polymers 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 17
- 239000002904 solvent Substances 0.000 abstract description 17
- 230000008569 process Effects 0.000 abstract description 7
- 210000003022 colostrum Anatomy 0.000 description 39
- 235000021277 colostrum Nutrition 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 28
- 239000003995 emulsifying agent Substances 0.000 description 15
- 238000005406 washing Methods 0.000 description 9
- 230000002572 peristaltic effect Effects 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 229910001220 stainless steel Inorganic materials 0.000 description 8
- 239000010935 stainless steel Substances 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 6
- 230000001804 emulsifying effect Effects 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 5
- 108010016076 Octreotide Proteins 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000011229 interlayer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229960001494 octreotide acetate Drugs 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007616 round robin method Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000008307 w/o/w-emulsion Substances 0.000 description 1
Landscapes
- Manufacturing Of Micro-Capsules (AREA)
- Medicinal Preparation (AREA)
- Colloid Chemistry (AREA)
Abstract
The invention discloses a method for preparing micro spheres by a multiple emulsion process. The method prepares multiple emulsion by a multiple emulsion process production technique adopting a multiple emulsion tank and a volatilization circulating process and comprises the following steps: preparing a first part of multiple emulsion, and subjecting two tanks to overall circulation to dilute the micro sphere concentration in the multiple emulsion tank; preparing a second part of multiple emulsion, subjecting the two tanks to overall circulating to dilute the micro sphere concentration in the multiple emulsion tank; and performing the following steps in the same way. After all multiple emulsion is prepared completely, all solution in the multiple emulsion tank is transferred to a volatilization tank to volatilize solvent. When the method is used, large batch of micro sphere products can be produced by using a smaller multiple emulsion tank, the productivity can be increased and the production cost of the micro spheres can be saved.
Description
Technical field
The present invention relates to the microsphere drug preparing technical field, especially multi-emulsion method prepares the method for microballoon.
Background technology
Solvent evaporated method is from emulsion, to remove the decentralized photo volatile solvent to prepare the method for microballoon.Technology comprises two basic processes: the solvent evaporation process between the gentle liquid phase of the extraction process between two liquid phases.This law is a very complicated process; Influence factor is more, method of phase solvent or the like like concentration, the theoretical medicine carrying amount of solidification temperature, time, pressure, vessel, alr mode, inside and outside decentralized photo solvent, emulsifying agent, inside and outside phase volume ratio, organic facies carrier material and in removing.The type of emulsion during by preparation, this preparation method can be divided into oil-in-water method (O/W method), oil bag oil process (O/O method), three types of multi-emulsion methods (being called W/O/W method or W/O/W method again).When the hydrophilic medicament of embedding polypeptide and protein, oil-in-water method commonly used and multi-emulsion method.
Multi-emulsion method is the at present water-soluble polypeptide of preparation, the most frequently used method of protein medicine microsphere, has that the medicine carrying amount is high, protein stability is good, microballoon is porous surface, medicine is easy to advantages such as release.Through selecting different organic solvents, dispersive medium, type of polymer, emulsifying manner and regulating conditions such as each phase volume ratio, ionic strength, can prepare the microballoon of different-grain diameter, different shape.
The step that emulsion solvent evaporated method commonly used prepares microballoon comprises:
(a) with polypeptide drug dissolving or be dispersed in and form dispersion liquid or homogeneous solution, i.e. colostrum in the dichloromethane solution that contains dissolved polymers.
(b) colostrum is joined in the outer aqueous phase solution of effective dose, adopt the method for homogenate or high-speed stirred to prepare emulsion.
(c) solvent evaporation
After the emulsion preparation is accomplished solution (room temperature or preference temperature) under uniform temperature was stirred 3～6 hours, organic solvent volatilization, microballoon are solidified.
(d) washing, freeze-drying and packing.
In the above-mentioned preparation process (b), having now has two kinds of modes that prepare emulsion usually:
(1) disposable preparation: colostrum was generally 1: 10～1: 40 with the volume ratio of outer water, in container, directly carried out solvent evaporates after the emulsion preparation is accomplished.Like patent of invention 200610015923.X; That mentions in " organism degradable star-type structure poly (glycolide-lactide) medicine carrier microballoon and preparation method thereof " " under agitation is injected into outer aqueous phase with colostrum; colostrum is 4～10: 100 with the volume ratio of outer water; form the W/O/W emulsion through emulsification, be stirred to carrene and all volatilize, make the curing balling-up." patent of invention 00128884.9 and for example; mention in " making the method for slow release microballoon by multi-emulsion method " " 1 breast that will produce mutually or emulsion be dispersed in a kind of aqueous phase; And from the microballoon that is dispersed with medicine, remove organic solvent, make the stage of sealing like the particulate of medicine." United States Patent (USP) 7846479 and for example; mentioned in " composition of microballoon and preparation method " " emulsion of W/O/W is prepared by following step: water is mixed with water-in-oil emulsion mutually with the organic solvent that contains polymer, emulsion for preparing and the water that contains surfactant are mixed with water-in-oil-in-water compositions.”
(2) emulsion preparation is carried out respectively with solvent evaporates: colostrum and continuous media are mixed with emulsion, again emulsion are joined extraction organic solvent in the extraction medium of effective dose and form microballoon.Like patent of invention 200380103249.5; Mention in " pharmaceutical composition that comprises octreotide grains " " described dispersion liquid (being colostrum) is mixed with the continuous operation medium of effective dose to form emulsion, and this emulsion contains described working media and comprises the droplet that said octreotide acetate, said solvent and said linearity are gathered (lactide-glycolide); Form after the said emulsion immediately said emulsion all added in the extraction medium of effective dose and form described particulate from said droplet, to extract said solvent.Extract medium preferred 10 times or higher volume.”
When carrying out microballoon production, when adopting first kind of emulsion production method,, must be equipped with jumbo emulsion jar in order to satisfy the volume requirement of microballoon output and outer water.Microballoon is produced requirement to the emulsion jar than higher, must possess emulsification usually and stir and promptly stir (rotating speed is 500rpm～2000rpm, is used to prepare emulsion) and stirring (rotating speed is 200rpm～500rpm, is used for the solvent evaporates process) at a slow speed fast.For jumbo emulsion jar, be equipped with relatively difficulty of efficient, steady and high-quality quick mixing plant.And outer water volume is excessive, and it is proper that the balling-up property of microballoon also is difficult to control.When adopting second kind of emulsion production method, what the capacity of emulsion jar can be suitable dwindles, but often emulsifying effectiveness is not good in the production of microballoon in enormous quantities, when output is big, causes the adhesion of microballoon easily, influences the quality of final microballoon.And emulsion receives the restriction of emulsion tankage size, and the maximum output relative fixed can't further increase output.
Summary of the invention
The present invention is directed to deficiency, propose the method that a kind of multi-emulsion method prepares microballoon, can adopt the emulsion jar of low capacity to realize the production of microballoon in enormous quantities.
In order to realize the foregoing invention purpose, the present invention provides following technical scheme: a kind of multi-emulsion method prepares the method for microballoon, may further comprise the steps:
1., medicine is dissolved in the water for injection;
2., the biodegradable polymer material is dissolved in the organic solvent;
3., with step 1. the aqueous solution add in the step organic solution 2. high-speed homogenization;
4., step 3. in the homogenate of 1/2～1/10 volume add and to be equipped with in the emulsion device of 0.5～2.0wt% polyvinyl alcohol water solution, the volume ratio of homogenate and polyvinyl alcohol water solution is 1: 1～1: 25, emulsion is carried out in stirring;
5., with step 4. in the emulsion device emulsion of 1/2～3/4 volume change in the volatilizer, 0.5～2.0wt% polyvinyl alcohol water solution is housed in the said volatilizer, volume is 5～200 times of homogenate; Simultaneously polyvinyl alcohol water solution equal-volume in the volatilizer is changed in the emulsion device;
6., repeating step 4. with step 5., to the whole emulsions of homogenate, emulsion in the emulsion device is all changed in the volatilizer, stirring at room 3～6 hours, organic solvent volatilization, microballoon.
Preferably, step 2. the biodegradable polymer material be PLA, polyglycolic acid, pla-pcl, Merlon, polycyanoacrylate or polyether ester.
Preferably, step 2. biodegradable polymer material is that mol ratio is 1: 1 the lactic acid and the copolymer of glycolic acid, and mean molecule quantity is 5000～70000 dalton, and inherent viscosity is 0.1～0.6dl/g.
Preferably, step 2. organic solvent be carrene or ethyl acetate.
Preferably, step 3. high-speed homogenization is 6500rpm～19500rpm, 3min～10min, 5～20 ℃.
Preferably, 4. to add the homogenate in the emulsion device be 1/4～1/8 of cumulative volume to step.
Preferably, 5. to change the emulsion volume in the volatilizer over to be 1/2～2/3 of cumulative volume to step.
Compared with prior art, the present invention adopts the emulsion production technology of emulsion jar and volatilization jar two jars of round-robin methods, the preparation emulsion; The emulsion of i.e. preparation earlier first carries out whole circular with two jars then, makes the microballoon concentration in the emulsion jar be able to dilution; The emulsion for preparing second portion again; And then carry out whole circular with two jars, make the microballoon concentration in the emulsion jar be able to dilution, by that analogy.After the preparation of whole emulsion is accomplished the solution in the emulsion jar all transferred in the volatilization jar and carry out solvent evaporates.Can use less emulsion jar to produce large batch of microspheres product, enlarge output, practice thrift the production cost of microballoon.
The specific embodiment
Emulsionization prepares the production technology of microballoon, may further comprise the steps:
(1) water in the preparation
Medicine is dissolved in the proper amount of water for injection; Whole course of dissolution is in the stainless steel syringe of relative closure, to carry out; Scavenge port connects the air filter of 0.22 μ m, and the syringe propulsion system is sped structure, adopts the stainless steel syringe needle that interior water is injected the colostrum retort.
(2) oil phase in the preparation
The biodegradable polymer material is dissolved in the organic solvent; In oil phase, said biodegradable polymer material is selected from PLA (PLA), lactic-co-glycolic acid (PLGA), polyglycolic acid (PGA), pla-pcl, Merlon, polycyanoacrylate, polyether ester etc.Wherein the ratio of the lactic acid of PLGA (LA) and glycolic acid (GA) is 1: 1, and mean molecule quantity is 5000～70000 dalton, and inherent viscosity is 0.1～0.6dl/g; Said organic solvent is selected from carrene or ethyl acetate.Whole course of dissolution is in the middle oil phase preparing tank of relative closure, to carry out, its with the colostrum retort between adopt silica gel hose to be connected, the middle oil phase employing peristaltic pump that preparation is accomplished pumps in the colostrum retort.
(3) preparation colostrum
Adopt the mode of screw propulsion that interior water adding has been had in the colostrum retort of middle oil phase, adopt the mode of high-speed homogenization to prepare colostrum.The colostrum emulsifying rate is 6500rpm～19500rpm, and emulsification times is 3min～10min.Feed cool brine in the colostrum tank wall interlayer with the control emulsion temperature, temperature range is 5～20 ℃.
(4) preparation emulsion
The mode that adopts peristaltic pump to pump into colostrum directly joins the shaft core position in the emulsion retort, and adding speed is 10ml/min～100ml/min, and the emulsifying agent that uses is the PVA aqueous solution.The ratio of emulsifying agent is 1: 1～1: 25 in colostrum and the emulsion jar, and the ratio of emulsifying agent is 1: 5～1: 200 in colostrum and the volatilization jar.
Adopt mode intermittently to prepare emulsion; The emulsion that promptly prepares a part earlier; (soon the solution of 1/2 volume in the emulsion jar or more volumes imports in the volatilization jar to carry out whole circular with two jars then; Adopt identical speed that the emulsifying agent in the volatilization jar of equivalent is imported in the emulsion jar simultaneously), make the microballoon concentration in the emulsion jar be able to dilution.The emulsion of preparation second portion in the emulsion jar then, and then carry out whole circular with two jars, make the microballoon concentration in the emulsion jar be able to dilution, by that analogy.
A collection of microballoon production can be divided into 2～10 parts with the emulsion preparation, and promptly the preparation amount of each part is 1/2～1/10 of a total amount.Adopt the two pot type circulatory systems that the microballoon output is enlarged on the basis of existing maximum output again, as adopt a volatilization jar can make 10 times of maximum output enlarged proximal, be preferably 4～8 times of expansions.
(5) solvent evaporates
After the preparation of whole emulsion is accomplished the solution in the emulsion jar all transferred in the volatilization jar and carry out solvent evaporates.Stirring at room 3～6 hours is solidified organic solvent volatilization, microballoon, needs to feed aseptic compressed air in the volatilization process.
(6) washing and packing
Adopt the microballoon collecting tank of relative closure to carry out microballoon collection and washing, slurry is a water for injection, and microballoon packing after freeze drying gets product.
Describe the present invention below in conjunction with specific embodiment, the description of this part only is exemplary and explanatory, should any restriction not arranged to protection scope of the present invention.
Embodiment 1
Emulsionization prepares the production technology of microballoon, may further comprise the steps:
Step 1: octreotide acetate freeze-dried powder 11g is dissolved in the 10ml water for injection, and container is the stainless steel syringe.
Step 2: 250g PLGA is dissolved in the 1000m1 carrene, after the dissolving fully solution is pumped in the colostrum retort with peristaltic pump, flow velocity is 100ml/min.
Step 3: adopt the mode of screw propulsion will be contained in the interior aqueous phase solution adding colostrum retort in the stainless steel syringe; Adopt the mode of high-speed homogenization to prepare colostrum from beginning to add; The colostrum emulsifying rate is 13500rpm, and emulsification times is that interior water all adds continued emulsification 3min.Colostrum jar interlayer temperature is controlled at 10 ℃.
Step 4: the mode that adopts peristaltic pump to pump into colostrum directly joins the shaft core position in the emulsion retort, and adding speed is 50ml/min.Adopt the mode of 5 two jars of circulating emulsions to carry out the emulsion preparation, the emulsifying agent volume is 2L in the emulsion jar, and the emulsifying agent of use is 1.0% the PVA aqueous solution.
Step 5: after emulsion prepares completion, the solution in the emulsion jar is all transferred in the volatilization jar, emulsifier concentration is 1.0% the PVA aqueous solution in the volatilization jar, and volume is 20L, and the solvent evaporates time is stirring at room 4 hours.
Step 6: adopt the microballoon collecting tank of relative closure to carry out microballoon collection and washing, slurry is a water for injection, adopts 10 μ m sieve and 180 μ m sieve to carry out microballoon during washing and collects, and microballoon packing after freeze drying gets product.
Above-mentioned output need adopt the emulsion jar (perhaps the emulsion jar is bigger, but can hold 20L liquid) of 1 20L as if being 1: 20 according to colostrum and emulsion ratio by existing microballoon production method.Present embodiment has only adopted the emulsion jar of 1 5L and the volatilization jar of 1 50L.
Embodiment 2
Emulsionization prepares the production technology of microballoon, may further comprise the steps:
A), octreotide acetate freeze-dried powder 36g is dissolved in the 30ml water for injection, container is the stainless steel syringe.
B), 500g PLGA is dissolved in the 2L carrene, after the dissolving fully solution is pumped in the colostrum retort with peristaltic pump, flow velocity is 100ml/min.
C), adopt the mode of screw propulsion will be contained in the interior aqueous phase solution adding colostrum retort in the stainless steel syringe; Adopt the mode of high-speed homogenization to prepare colostrum from beginning to add; The colostrum emulsifying rate is 13500rpm, and emulsification times is that interior water all adds continued emulsification 3min.Colostrum jar interlayer temperature is controlled at 10 ℃.
D), the mode that adopts peristaltic pump to pump into colostrum directly joins the shaft core position in the emulsion retort, adding speed is 50ml/min.Adopt the mode of 5 emulsifications to carry out the emulsion preparation, the emulsifying agent volume is 4L in the emulsion jar, and the emulsifying agent of use is 1.0% the PVA aqueous solution.
E), after emulsion preparation accomplishes, the solution in the emulsion jar is all transferred in the volatilization jar, emulsifier concentration is 1.0% the PVA aqueous solution in the volatilization jar, and volume is 40L, and the solvent evaporates time is stirring at room 4 hours.
F), adopt the microballoon collecting tank of relative closure to carry out that microballoon is collected and washing, slurry is a water for injection, adopts 10 μ m sieve and 180 μ m sieve to carry out the microballoon collection during washing, microballoon packing after freeze drying gets product.
Above-mentioned output need adopt the emulsion jar (perhaps the emulsion jar is bigger, but can hold 40L liquid) of 1 40L as if being 1: 20 according to colostrum and emulsion ratio by existing microballoon production method.Present embodiment has only adopted the emulsion jar of 1 5L and the volatilization jar of 1 50L.
Embodiment 3
Emulsionization prepares the production technology of microballoon, may further comprise the steps:
A), octreotide acetate freeze-dried powder 72g is dissolved in the 60ml water for injection, container is the stainless steel syringe.
B), 1000g PLGA is dissolved in the 4L carrene, after the dissolving fully solution is pumped in the colostrum retort with peristaltic pump, flow velocity is 100ml/min.
C), adopt the mode of screw propulsion will be contained in the interior aqueous phase solution adding colostrum retort in the stainless steel syringe; Adopt the mode of high-speed homogenization to prepare colostrum from beginning to add; The colostrum emulsifying rate is 13500rpm, and emulsification times is that interior water all adds continued emulsification 3min.Colostrum jar interlayer temperature is controlled at 10 ℃.
D), the mode that adopts peristaltic pump to pump into colostrum directly joins the shaft core position in the emulsion retort, adding speed is 50ml/min.Adopt emulsion jar and 2 volatilization jars to carry out the preparation of emulsion, 2 volatilization jars are used alternatingly, and each volatilization jar respectively carries out the mode of 4 emulsifications and carries out the emulsion preparation, and the emulsifying agent volume is 4L in the emulsion jar, and the emulsifying agent of use is 1.0% the PVA aqueous solution.
E), after emulsion preparation accomplishes, the solution equivalent in the emulsion jar is all transferred in 2 volatilizations jar, emulsifier concentration is 1.0% the PVA aqueous solution in the volatilization jar, and every jar of emulsifying agent volume is 40L, and the solvent evaporates time is stirring at room 4 hours.
F), adopt the microballoon collecting tank of relative closure to carry out that microballoon is collected and washing, slurry is a water for injection, adopts 10 μ m sieve and 180 μ m sieve to carry out the microballoon collection during washing, microballoon packing after freeze drying gets product.
Above-mentioned output need adopt the emulsion jar (perhaps the emulsion jar is bigger, but can hold 80L liquid) of 1 80L as if being 1: 20 according to colostrum and emulsion ratio by existing microballoon production method.Present embodiment has only adopted the emulsion jar of 1 5L and the volatilization jar of 2 50L.
It below only is preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (7)
1. a multi-emulsion method prepares the method for microballoon, may further comprise the steps:
1., medicine is dissolved in the water for injection;
2., the biodegradable polymer material is dissolved in the organic solvent;
3., with step 1. the aqueous solution add in the step organic solution 2. high-speed homogenization;
4., step 3. in the homogenate of 1/2～1/10 volume add and to be equipped with in the emulsion device of 0.5～2.0wt% polyvinyl alcohol water solution, the volume ratio of homogenate and polyvinyl alcohol water solution is 1: 1～1: 25, emulsion is carried out in stirring;
5., with step 4. in the emulsion device emulsion of 1/2～3/4 volume change in the volatilizer, 0.5～2.0wt% polyvinyl alcohol water solution is housed in the said volatilizer, volume is 5～200 times of homogenate; Simultaneously polyvinyl alcohol water solution equal-volume in the volatilizer is changed in the emulsion device;
6., repeating step 4. with step 5., to the whole emulsions of homogenate, emulsion in the emulsion device is all changed in the volatilizer, stirring at room 3～6 hours, organic solvent volatilization, microballoon.
2. the method for claim 1, it is characterized in that: step 2. biodegradable polymer material is PLA, polyglycolic acid, pla-pcl, Merlon, polycyanoacrylate or polyether ester.
3. the method for claim 1, it is characterized in that: step 2. biodegradable polymer material is that mol ratio is 1: 1 the lactic acid and the copolymer of glycolic acid, and mean molecule quantity is 5000～70000 dalton, and inherent viscosity is 0.1～0.6dl/g.
4. like claim 1,2 or 3 described methods, it is characterized in that: step 2. organic solvent is carrene or ethyl acetate.
5. the method for claim 1, it is characterized in that: step 3. high-speed homogenization is 6500rpm～19500rpm, 3min～10min, 5～20 ℃.
6. the method for claim 1, it is characterized in that: the homogenate that 4. step adds in the emulsion device is 1/4～1/8 of a cumulative volume.
7. the method for claim 1, it is characterized in that: the emulsion volume that 5. step changes in the volatilizer is 1/2～2/3 of a cumulative volume.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN113616524A (en) * | 2021-06-07 | 2021-11-09 | 浙江圣兆药物科技股份有限公司 | Device and process for preparing reservoir foamed liposome |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102755323A (en) * | 2012-07-03 | 2012-10-31 | 中国人民解放军第三军医大学第三附属医院 | Medicinal composition for treating periodontitis and method for preparing sustained-release microsphere by using same |
| CN102755323B (en) * | 2012-07-03 | 2014-09-10 | 中国人民解放军第三军医大学第三附属医院 | Medicinal composition for treating periodontitis and method for preparing sustained-release microsphere by using same |
| FR3031914A1 (en) * | 2015-01-27 | 2016-07-29 | Jerome Bibette | ENCAPSULATION METHOD |
| WO2016120308A1 (en) * | 2015-01-27 | 2016-08-04 | Jérome Bibette | Encapsulation method |
| US10786798B2 (en) | 2015-01-27 | 2020-09-29 | Calyxia | Encapsulation method |
| CN106834204A (en) * | 2017-01-16 | 2017-06-13 | 西北民族大学 | A kind of cell culture SFL microcarriers and its preparation method and application |
| CN106834204B (en) * | 2017-01-16 | 2020-10-02 | 西北民族大学 | SFL microcarrier for cell culture and preparation method and application thereof |
| CN113616524A (en) * | 2021-06-07 | 2021-11-09 | 浙江圣兆药物科技股份有限公司 | Device and process for preparing reservoir foamed liposome |
| CN113616524B (en) * | 2021-06-07 | 2024-05-14 | 浙江圣兆药物科技股份有限公司 | Device and process for preparing reservoir foam liposome |
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