CN101392064B - Method for preparing monodisperse polylactic acid microsphere - Google Patents
Method for preparing monodisperse polylactic acid microsphere Download PDFInfo
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- CN101392064B CN101392064B CN2008102024240A CN200810202424A CN101392064B CN 101392064 B CN101392064 B CN 101392064B CN 2008102024240 A CN2008102024240 A CN 2008102024240A CN 200810202424 A CN200810202424 A CN 200810202424A CN 101392064 B CN101392064 B CN 101392064B
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Abstract
The invention relates to a preparation method of monodisperse polylactic acid (PLA) microballoon spheres, which includes: (1) the PLA is dissolved in methylene dichloride so as to be taken as a dispersed phase and polyvinyl alcohol is dissolved in water so as to be used as a continuous phase; (2) two solutions are respectively put into injectors and the injectors are arranged on two boost pumps and connected with a microchannel reactor, and then the flow velocities of the dispersed phase and the continuous phase are adjusted to ensure that liquid drops with uniform size are continuously generated at the joint of the two phases; (3) the generated liquid drops are collected in the aqueous solution of the polyvinyl alcohol and a variable frequency oscillator is adopted to assist the volatilization of a solvent so as to ensure that the liquid drops are solidified to spheres; and (4) the spheres are washed by ionized water for a plurality of times and arranged in an oven for drying to obtain the monodisperse PLA microballoon spheres. The monodisperse PLA microballoon spheres prepared by the invention have a smooth surface and a particle size ranging from 200 Mum to 1000 Mum; a reaction device has simple and easy preparation process and controllable dimension of microchannels. The size of the prepared microballoon spheres can be conveniently adjusted and controlled and the variable frequency oscillator is adopted for quickening the solidification process of the PLA microballoon spheres, with low cost and less time consumption.
Description
Technical field
The invention belongs to the preparation field of polylactic acid microsphere, particularly relate to a kind of preparation method of monodisperse polylactic acid microsphere.
Background technology
Poly(lactic acid) (PLA) is the polymer materials that second class can be used for human body through food and drug administration (FDA) approval after polyglycolic acid (PGA), have good biocompatibility, nontoxic, degradable, and degraded product can not assembled at vitals.Simultaneously, PLA and multipolymer thereof have good physics, chemical property, its intensity, mechanical property, degradation rate etc. can be regulated easily by the composition and the proportioning of control molecular weight, interpolymer, and therefore shape of products can be widely used in medicine and medical industry from microballoon, fiber to film, molding finished product etc.
But PLA microballoon, micro-capsule be embedding medicinal not only, is used for the sustained-release and controlled release system; The polyester biodegradable material that with PLA is representative also is one of timbering material of transplanted cells the most frequently used in the present Tissue Engineering Study, can be used as genophore, induces the gene of repairing infringement, thereby eradicates disease.Compare with protein-polysaccharide etc. with natural extracellular matrix such as collagen, the PLA material not only has good physical and mechanical properties, and adjusting that can be by molecular weight and molecular weight distribution is to adapt to different needs.But the polymerizing condition of PLA is very harsh, not only will be under vacuum condition, and to guarantee that reaction system is not moisture, can not adopt the method for limit polymerization limit balling-up to prepare PLA microballoon or micro-capsule usually.Therefore, be that the microballoon of raw material adopts emulsification-solidification method to prepare usually with natural polymers such as PLA, biodegradation high molecular, earlier it is prepared into O/W, W/O, W/O/W, O/W/O type emulsion, make drop be solidified into microballoon with removing the method for desolvating then.This emulsification-solidified method can make the PLA microballoon of different-grain diameter and size distribution according to its different emulsifying manner and emulsification condition, and I reaches tens nanometers, arrives tens of microns greatly.Park and Kim (J.Colloid Interf.Sci., 2004,271,336-341) prepared PLA and the PLA/PEG microcapsule that contain erythromycin with the emulsion solvent volatilization method, median size is respectively 40 μ m and 57 μ m.But adopt the emulsification solidification method when hundreds of microns microballoon is arrived in tens of microns of preparation, generally all adopt mechanical mixing method emulsification to make it form drop, and, therefore obtain the microballoon of size homogeneous than difficulty with the size droplet diameter wider distribution that this method forms.
Promptly by adopting coaxial microchannel reactor to prepare single dispersion PLA microballoon, cost is low in the present invention, and it is few to expend time in.Widened its application in biological medicine and field of tissue engineering technology.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of monodisperse polylactic acid microsphere, the surface smoothing of the monodisperse polylactic acid microsphere of the present invention's preparation, and particle size range is 200-1000 μ m; This reaction unit preparation process is simple, and the microchannel yardstick is controlled, and the size of microspheres prepared can be regulated and control easily, and by adopting variable frequency oscillator to accelerate the solidification process of polylactic acid microsphere, cost is low, and it is few to expend time in.
The preparation method of a kind of monodisperse polylactic acid microsphere of the present invention comprises:
(1) configuration of disperse phase and continuous phase solution: poly(lactic acid) is dissolved in the methylene dichloride, and compound concentration is the disperse phase solution of 0.01-0.1g/mL, and wherein the molecular weight of poly(lactic acid) is 20000-100000; An amount of polyvinyl alcohol 124 is added in the deionized water, and magneton stirs and slowly is heated to 90 ℃ and makes its dissolving, and the preparation percentage concentration is the continuous phase solution of 1%-5%;
(2) formation of poly(lactic acid) drop: above-mentioned two kinds of solution are respectively charged in the glass syringe of 10mL, place on two boost pumps, after connecting micro passage reaction, control disperse phase flow rates is 5-50 μ L/min, the external phase flow rates is 200-1600 μ L/min, make two-phase in the thicker microtubule of internal diameter, meet, and constantly generate the drop of size homogeneous;
(3) drop solidifies balling-up: collect the drop that generates in the beaker of polyvinyl alcohol solution that concentration is 1%-2% is housed, again beaker placed on the variable frequency oscillator concussion 2-4 hour, treat that solvent volatilizees fully after, drop can be solidified into microballoon;
(4) washing and drying of microballoon: behind deionized water wash 3-5 time, place 50-90 ℃ baking oven 1-2 hour, promptly get monodisperse polylactic acid microsphere.
Micro passage reaction in the described step (2) can be by adjusting disperse phase and the flow velocity of external phase and the monodispersed polylactic acid microsphere that concentration makes different-grain diameter;
The particle size range of the monodisperse polylactic acid microsphere in the described step (4) is 200-1000 μ m.
The present invention has adopted coaxial canaliculus reactor made monodisperse polylactic acid microsphere, in this reactor, the mobile laminar flow that belongs to of liquid can not produce disorder, chance is provided for the surface reaction of polymkeric substance; There is surface tension between two kinds of laminar flow fluidic interfaces, in a biphase current system, the balance of surface tension and the viscous force of fluid own has determined the fluidic structure, change with the system parameter, liquid fails to be convened for lack of a quorum and changes drop into, it occurs in fluid with respect under the unsettled situation of surrounding environment, is fractured into drop and obtains stability to reduce surface-area.Therefore, the character of convection cell or flow velocity are done little change, just can produce the drop of different size, and the size droplet diameter homogeneous that forms.
Beneficial effect
(1) surface smoothing of the monodisperse polylactic acid microsphere of the present invention's preparation, particle size range is 200-1000 μ m;
(2) this reaction unit preparation process is simple, and the microchannel yardstick is controlled, and the size of microspheres prepared can be regulated and control easily, and by adopting variable frequency oscillator to accelerate the solidification process of polylactic acid microsphere, cost is low, and it is few to expend time in.
Description of drawings
Fig. 1 is the opticmicroscope picture of the PLA microballoon of embodiment 1 preparation, and scale is 500 μ m;
Fig. 2 is the opticmicroscope picture of the PLA microballoon of embodiment 2 preparations, and scale is 500 μ m;
Fig. 3 is the opticmicroscope picture of the PLA microballoon of embodiment 3 preparations, and scale is 500 μ m;
Fig. 4 is the opticmicroscope picture of the PLA microballoon of embodiment 4 preparations, and scale is 500 μ m.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
With the 0.3827g molecular weight is that 75000 PLA is dissolved in the 5mL methylene dichloride and obtains disperse phase solution, takes by weighing 1.5g polyvinyl alcohol 124 and pours in the flask that contains 100mL water, and magneton stirs and slowly is heated to 90 ℃ and makes its dissolving, obtains continuous phase solution.Two kinds of solution are respectively charged in the glass syringe of 10mL, after placing on two boost pumps, link to each other with micro passage reaction, it is 10 μ L/min that the disperse phase flow velocity is set, the external phase flow velocity is 500 μ L/min, two-phase is met in the thicker microtubule of internal diameter, constantly generate the drop of size homogeneous at the two-phase place of meeting.The drop that collect to generate is in being equipped with the beaker of polyvinyl alcohol solution that concentration is 2% (g/g), again beaker is placed on the variable frequency oscillator and shook 2 hours, treat that solvent volatilizees fully, after drop is solidified into microballoon, with deionized water wash 3 times, place 60 ℃ of baking ovens 2 hours, and can obtain monodispersed PLA microballoon.
Fig. 1 is the opticmicroscope picture of the microballoon that makes, and the microspherulite diameter homogeneous has monodispersity as can be seen, and particle diameter is about 680 μ m.
Embodiment 2
With the 0.1626g molecular weight is that 75000 PLA is dissolved in the 5mL methylene dichloride and obtains disperse phase solution, takes by weighing 1.5g polyvinyl alcohol 124 and pours in the flask that contains 100mL water, and magneton stirs and slowly is heated to 90 ℃ and makes its dissolving, obtains continuous phase solution.Two kinds of solution are respectively charged in the glass syringe of 10mL, after placing on two boost pumps, link to each other with micro passage reaction, it is 10 μ L/min that the disperse phase flow velocity is set, the external phase flow velocity is 500 μ L/min, two-phase is met in the thicker microtubule of internal diameter, constantly generate the drop of size homogeneous at the two-phase place of meeting.The drop that collect to generate is in being equipped with the beaker of polyvinyl alcohol solution that concentration is 2% (g/g), again beaker is placed on the variable frequency oscillator and shook 2 hours, treat that solvent volatilizees fully, after drop is solidified into microballoon, with deionized water wash 3 times, place 50 ℃ of baking ovens 2 hours, and can obtain monodispersed PLA microballoon.
Fig. 2 is the opticmicroscope picture of the microballoon that makes, and the microspherulite diameter homogeneous has monodispersity as can be seen, and particle diameter is about 480 μ m.
Embodiment 3
With the 0.4g molecular weight is that 55000 PLA is dissolved in the 10mL methylene dichloride and obtains disperse phase solution, takes by weighing 3g polyvinyl alcohol 124 and pours in the flask that contains 100mL water, and magneton stirs and slowly is heated to 90 ℃ and makes its dissolving, obtains continuous phase solution.Two kinds of solution are respectively charged in the glass syringe of 10mL, place on two boost pumps, link to each other with micro passage reaction, it is 20 μ L/min that the disperse phase flow velocity is set, the external phase flow velocity is 300 μ L/min, two-phase is met in the thicker microtubule of internal diameter, constantly generate the drop of size homogeneous at the two-phase place of meeting.The drop that collect to generate is in being equipped with the beaker of polyvinyl alcohol solution that concentration is 1.5% (g/g), again beaker is placed on the variable frequency oscillator and shook 3 hours, treat that solvent volatilizees fully, after drop is solidified into microballoon, with deionized water wash 4 times, place 80 ℃ of baking ovens 1 hour, and can obtain monodispersed PLA microballoon.
Fig. 3 is the opticmicroscope picture of the microballoon that makes, and the microspherulite diameter homogeneous has monodispersity as can be seen, and particle diameter is about 500 μ m.
Embodiment 4
With the 0.4g molecular weight is that 55000 PLA is dissolved in the 10mL methylene dichloride and obtains disperse phase solution, takes by weighing 5g polyvinyl alcohol 124 and pours in the flask that contains 100mL water, and magneton stirs and slowly is heated to 90 ℃ and makes its dissolving, obtains continuous phase solution.Two kinds of solution are respectively charged in the glass syringe of 10mL, place on two boost pumps, link to each other with micro passage reaction, it is 20 μ L/min that the disperse phase flow velocity is set, the external phase flow velocity is 300 μ L/min, two-phase is met in the thicker microtubule of internal diameter, constantly generate the drop of size homogeneous at the two-phase place of meeting.The drop that collect to generate is in being equipped with the beaker of polyvinyl alcohol solution that concentration is 1.5% (g/g), again beaker is placed on the variable frequency oscillator and shook 3 hours, treat that solvent volatilizees fully, after drop is solidified into microballoon, with deionized water wash 4 times, place 90 ℃ of baking ovens 1 hour, and can obtain monodispersed PLA microballoon.
Fig. 4 is the opticmicroscope picture of the microballoon that makes, and the microspherulite diameter homogeneous has monodispersity as can be seen, and particle diameter is about 450 μ m.
Claims (3)
1. the preparation method of a monodisperse polylactic acid microsphere comprises:
(1) configuration of disperse phase and continuous phase solution: poly(lactic acid) is dissolved in the methylene dichloride, and compound concentration is the disperse phase solution of 0.01-0.1g/mL, and wherein the molecular weight of poly(lactic acid) is 20000-100000; Polyvinyl alcohol 124 is added in the deionized water, and magneton stirs and slowly is heated to 90 ℃ and makes its dissolving, and the preparation percentage concentration is the continuous phase solution of 1%-5%;
(2) formation of poly(lactic acid) drop: above-mentioned two kinds of solution are respectively charged in the glass syringe of 10mL, place on two boost pumps, after connecting micro passage reaction, control disperse phase flow rates is 5-50 μ L/min, the external phase flow rates is 200-1600 μ L/min, make two-phase in the thicker microtubule of internal diameter, meet, and constantly generate the drop of size homogeneous;
(3) drop solidifies balling-up: collect the drop that generates in the beaker of polyvinyl alcohol solution that concentration is 1%-2% is housed, again beaker placed on the variable frequency oscillator concussion 2-4 hour, treat that solvent volatilizees fully after, drop can be solidified into microballoon;
(4) washing and drying of microballoon: behind deionized water wash 3-5 time, place 50-90 ℃ baking oven 1-2 hour, promptly get monodisperse polylactic acid microsphere.
2. the preparation method of a kind of monodisperse polylactic acid microsphere according to claim 1, it is characterized in that: the micro passage reaction in the described step (2) is by adjusting disperse phase and the flow velocity of external phase and the monodispersed polylactic acid microsphere that concentration makes different-grain diameter.
3. the preparation method of a kind of monodisperse polylactic acid microsphere according to claim 1, it is characterized in that: the particle size range of the monodisperse polylactic acid microsphere in the described step (4) is 200-1000 μ m.
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| CN1415295A (en) * | 2002-08-08 | 2003-05-07 | 广东药学院 | Method for preparing cyproxacin polylactic acid microsphere of ciprofloxacin |
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