CN105232474A - Simple method for preparing PLGA microspheres with uniform particle size - Google Patents
Simple method for preparing PLGA microspheres with uniform particle size Download PDFInfo
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Abstract
The invention provides an improved stirring emulsification method for preparing PLGA microspheres with the uniform particle size. The particle size distribution of the microspheres prepared through the method is narrower, and the PLGA microspheres with the uniform particle size can be obtained through simple centrifugation enriching at a higher yield. The preparation method comprises the steps that PLGA is dissolved in dichloromethane to serve as an oil phase, a PVA solution serves as a water phase, the oil phase is dispersed into the water phase according to a certain ratio, a plurality of glass balls with the diameter of 2-8 mm are added to assist in emulsification, and then stirring emulsification is performed with a magnetic stirrer; the PLGA microspheres with the uniform particle size are obtained through organic solvent volatilizing, washing and differential centrifugation enriching.
Description
Technical field
The present invention relates to the preparation technology of polymer microballoon, particularly the PLGA microsphere of even particle size distribution, belongs to biology medical material technical field.
Background technology
Polylactic lactic acid (PLGA) is a kind of biodegradable macromolecular material, finally can degrade in vivo and generate carbon dioxide and water, safety non-toxic and good biocompatibility, be regarded as excellent medical material, and be used for clinical by U.S. food and drug administration (FDA) approval.That prepares with PLGA material microsphere supportedly has important use at biomedicine field, is subject to extensive research, comprises drug delivery, antibody preparation, vaccine adjuvant etc.At present, FDA have approved the multiple pharmaceutical preparation based on PLGA microsphere and has entered clinical, as LupronDeport etc.2009, China SFDA also have approved the microsphere medicinal preparation listing of 2 kinds of syringeabilities.
The particle diameter of PLGA microsphere is one of key factor determining PLGA microsphere performance, and particle diameter is different, its purposes and biological effect significant difference.The control of size and uniformity directly has influence on effectiveness that PLGA microsphere applies with repeatable.Based on this, how to improve preparation technology, size is controlled to prepare, the PLGA microsphere of uniform particle sizes is one of emphasis of this area research all the time.At present, the preparation method about PLGA microsphere mainly comprises: 1) stirring and emulsifying method; 2) supersound method; 3) spray drying method; 4) film emulsion process.Stirring and emulsifying method is comparatively cheap easy, and it is by mixing speed and time controling size, but due to liquid in emulsion process stressed very uneven, the granular size of formation is very uneven.Although sizable microsphere can be made to obtain enrichment to a certain extent by differential centrifugation, due to microspherulite diameter wider distribution, the microsphere productive rate very low (< 30%) that enrichment obtains.In addition, utilizing the method to prepare small size microsphere needs high rotating speed, needs the mixing speed of nearly ten thousand revs/min as obtained 1-2 μm of microsphere, needs the equipment of comparatively specialty; Supersound method is generally used for prepares nanoscale microsphere, is not suitable for the preparation of micron order microsphere; Spray drying method not only needs special device, and the lack of homogeneity of preparation granular size; It is better that film emulsion process obtains PLGA particle uniformity, but professional equipment used and consumables cost higher.Due to existing methodical above-mentioned limitation, make the quality of the PLGA microsphere of many research preparations and homogeneity not good, result poor repeatability; And the good PLGA microsphere of homogeneity can only complete at comparatively professional laboratory.Therefore, the PLGA method for preparing microsphere that a kind of particle uniformity is good, easy, replicability is strong is developed significant.
Summary of the invention
The object of the present invention is to provide a kind of stirring and emulsifying method of improvement, utilize conventional agitator namely can prepare with higher productive rate reduced size, uniform particle sizes PLGA microsphere supported, for drug delivery field.
The object of the invention is to be achieved through the following technical solutions:
Prepare a PLGA micro-sphere method for uniform particle sizes, comprise the following steps:
(1) PLGA is dissolved in dichloromethane organic solvent, obtains oil phase, PLGA concentration 6-20%;
(2) above-mentioned oil phase is distributed in polyvinyl alcohol aqueous phase, adds the pearl of 2-8mm diameter wherein, stirring and emulsifying, polyvinyl alcohol 1-4%, oil phase and watr-proportion 1: 10-1: 5;
(3) take out pearl, dichloromethane organic solvent is fully volatilized;
(4) collected by centrifugation PLGA microsphere, and use distilled water wash;
(5) with the resuspended PLGA microsphere of distilled water, differential centrifugation more than 10 minutes, obtains PLGA microsphere.
In one embodiment, PLGA material molecule amount not can be 10-100kDa not etc., and LA/GA not can be 75: 25,50: 50,25: 75 not etc.;
In another embodiment, bead diameter size can be 2-8mm, preferred 4-6mm.Pearl can be the pearl of any appropriate materials in addition, such as, can be bead, copper pearl, aluminium pill etc.
In another one embodiment, during emulsifying, rotating speed is no more than 1000rpm.
In still another embodiment, in step (1), medicine is added to prepare medicine carrying microballoons.Wherein said medicine can be the medicine being dissolved in dichloromethane, such as rifampicin.
The invention has the beneficial effects as follows under the emulsifying that pearl is auxiliary, use conventional low-speed agitator, as magnetic stirring apparatus, good emulsion dispersion effect can be reached, in conjunction with simple differential centrifugation method, the PLGA microsphere of uniform particle sizes can be obtained.In terms of existing technologies, this method equipment is simple, with low cost, and stirring at low speed emulsifying can obtain the little PLGA microsphere to 1 μm of diameter, and the microspherulite diameter obtained is evenly distributed, and enrichment productive rate is high.
Accompanying drawing explanation
Fig. 1 is that convention stir emulsifying and bead assist stirring and emulsifying schematic diagram.1a is convention stir emulsifying schematic diagram; 1b bead assists stirring and emulsifying schematic diagram;
Fig. 2 is under different rotating speeds, the PLGA microsphere optical photo that convention stir emulsifying and bead assist stirring and emulsifying to obtain.Wherein, Fig. 2 a is convention stir 3 hours under 400 revs/min of rotating speeds, 2b is convention stir 3 hours under 800 revs/min of rotating speeds, 2c is convention stir 3 hours under 400 revs/min of rotating speeds, 2d is that 400 revs/min of rotating speed lower-glass pearls assist stirring 3 hours, 2e is that 800 revs/min of rotating speed lower-glass pearls assist stirring 3 hours, and 2f is that 1000 revs/min of rotating speed lower-glass pearls assist stirring 3 hours (Bar=20 μm);
Fig. 3 is under different rotating speeds, the PLGA microsphere stereoscan photograph that convention stir emulsifying and bead assist stirring and emulsifying to obtain and particle size distribution.Wherein, Fig. 3 a is convention stir 3 hours under 400 revs/min of rotating speeds, 3b is convention stir 3 hours under 800 revs/min of rotating speeds, 3c is convention stir 3 hours under 1000 revs/min of rotating speeds, 3d is that 400 revs/min of rotating speed lower-glass pearls assist stirring 3 hours, 3e is that 800 revs/min of rotating speed lower-glass pearls assist stirring 3 hours, and 3f is that 1000 revs/min of rotating speed lower-glass pearls assist stirring 3 hours (Bar=5 μm);
Under Fig. 4 bead co-emulsifier, the PLGA microsphere size that 1000 revs/min of emulsifying 1h obtain;
The PLGA microspherulite diameter distribution that under the different centrifugal force condition of Fig. 5, differential centrifugation obtains and scanning electron microscopic picture.Wherein, Fig. 5 a is the particle size distribution that 50g centrifugal force collects PLGA microsphere, 5b is the particle size distribution that 200g centrifugal force collects PLGA microsphere, 5c is the particle size distribution that 2000g centrifugal force collects PLGA microsphere, 5d is the scanning electron microscopic picture that 50g centrifugal force collects PLGA microsphere, 5e is the scanning electron microscopic picture that 200g centrifugal force collects PLGA microsphere, and 5f is the scanning electron microscopic picture that 2000g centrifugal force collects PLGA microsphere.
Fig. 6 .PLGA microsphere is to the slow releasing function of rifampicin.Wherein, Fig. 6 a is the PLGA microsphere slow release every day rifampicin medicine amount of parcel rifampicin; Fig. 6 b is the rifampicin medicine amount of the PLGA microsphere cumulative release in time of parcel rifampicin.
Detailed description of the invention
Below by following examples, the present invention is described in further detail, so that those skilled in the art understands the present invention further, but any restriction is not formed to the present invention.
Embodiment 1: the auxiliary lower PLGA microsphere preparation of bead
(1) preparation of oil phase: take PLGA0.6g, is dissolved in 10mL dichloromethane, the PLGA solution of preparation 6%;
(2) preparation of PVA aqueous solution: take 2.5gPVA solid, join in 100mL distilled water, heated and stirred is fully dissolved, and is mixed with the PVA aqueous solution of 2.5%;
(3) bead co-emulsifier: in the vial that size is suitable, every bottle of PVA solution adding 10mL2.5%, and by the dispersion of the PLGA oil-phase solution of 1mL6% wherein, add the bead of magnetic stirring apparatus rotor and several 4-6mm diameter subsequently, under 400 revs/min, 800 revs/min, 1000 revs/min rotating speeds, open stirring 3 hours respectively;
(4) volatilization of organic solvent: after bead co-emulsifier completes, take out bead, stirring at low speed 12-24 hour, makes dichloromethane organic solvent fully volatilize;
(5) collection of PLGA microsphere: 2000g collects PLGA microsphere in centrifugal 20 minutes, and uses distilled water wash repeatedly;
(6) observation by light microscope of PLGA microsphere: the PLGA microsphere of collection is resuspended with distilled water, get and be one after another drop ofly added on microscope slide, standing and drying is observed under being placed on inverted phase contrast microscope.As Fig. 2 a-f is respectively PLGA microsphere light microscopic photo prepared by convention stir emulsifying and bead co-emulsifier under same rotating speed;
(7) scanning electron microscopic observation of PLGA microsphere and particle size determination: be evenly coated on masking foil by PLGA microspheres solution, clip wherein small pieces after dry, are pasted onto on sample stage, for sem observation after metal spraying by conducting resinl.Subsequently, in the stereoscan photograph gathered, measured by the particle diameter of computer software to PLGA microsphere, each sample determination more than 500, analyze particle size distribution.If Fig. 3 a-f is the PLGA microsphere electromicroscopic photograph and particle size distribution situation that prepared by conventional emulsion and bead co-emulsifier under different rotating speeds.
Embodiment 2: the PLGA microsphere enrichment of uniform particle sizes
The present embodiment is with the PLGA microsphere of 1000 revs/min of rotating speeds preparation in emulsified 1 hour for sample, and carry out the PLGA microsphere enrichment of uniform particle sizes, main purpose is the microsphere that 2-3 μm of diameter is prepared in enrichment.
(1) preparation of oil phase: take PLGA0.6g, is dissolved in 10mL dichloromethane, the PLGA solution of preparation 6%;
(2) preparation of PVA aqueous solution: take 2.5gPVA solid, join in 100mL distilled water, heated and stirred is fully dissolved, and is mixed with the PVA aqueous solution of 2.5%;
(3) bead co-emulsifier: in the vial that size is suitable, every bottle of PVA solution adding 10mL2.5%, and by the dispersion of the PLGA oil-phase solution of 1mL6% wherein, add the bead of magnetic stirring apparatus rotor and several 4-6mm diameter subsequently, stir 1 hour under 1000 revs/min of conditions;
(4) volatilization of organic solvent: after bead co-emulsifier completes, take out bead, stirring at low speed 12-24 hour, makes dichloromethane organic solvent fully volatilize;
(5) collection of PLGA microsphere: 2000g centrifugal force collects PLGA granule in 20 minutes, and uses distilled water wash repeatedly;
(6) PLGA microsphere diameter measures: utilize computer software to measure the PLGA microsphere diameter of preparation.Under Fig. 4 is 1000 revs/min of rotating speeds, the particle size distribution of PLGA microsphere prepared by bead co-emulsifier 1h and electromicroscopic photograph;
(7) the differential centrifugation enrichment of PLGA microsphere: the PLGA microsphere of acquisition is distributed in distilled water, first leave standstill 5-10min and remove precipitation, respectively under 50g, 200g, 2000g centrifugal force condition centrifugal 15 minutes subsequently, collect at every turn centrifugal precipitate, carry out scanning or lyophilizing preservation.As following table 1, through enrichment, under the present embodiment condition, the PLGA microsphere of preparation is mainly distributed in ~ about 3 μm, and rate is near ~ and 60%.Fig. 5 a-f is that the PLGA microspherulite diameter that different differential centrifugation condition obtains distributes and stereoscan photograph.
Embodiment 3: the PLGA medicine carrying microballoons preparation of parcel rifampicin medicine, 2-3 μm particle diameter
(1) preparation of oil phase; Take 0.6gPLGA, 0.05g rifampicin medicine, be jointly dissolved in 10mL dichloromethane, preparation is containing the solution of 6%PLGA, 0.5% rifampicin;
(2) preparation of PVA aqueous solution: take 2.5gPVA solid, join in 100mL distilled water, heated and stirred is fully dissolved, and is mixed with the PVA aqueous solution of 2.5%;
(3) bead co-emulsifier: in the vial that size is suitable, every bottle of PVA solution adding 10mL2.5%, and by the dispersion of the PLGA oil-phase solution of 1mL6% wherein, add the bead of magnetic stirring apparatus rotor and several 5-6mm diameter subsequently, stir 1 hour under 1000 revs/min of conditions;
(4) volatilization of organic solvent: after bead co-emulsifier completes, take out bead, stirring at low speed 12-24 hour, makes dichloromethane organic solvent fully volatilize;
(5) collection of rifampicin-PLGA medicine carrying microballoons: 2000g centrifugal force collects complex microsphere in 20 minutes, and uses distilled water wash repeatedly;
(6) collection of rifampicin-PLGA medicine carrying microballoons: above-mentioned PLGA microsphere aqueous solution is first left standstill 5-10min and remove precipitation, centrifugal enrichment 15 minutes under 50g centrifugal force subsequently, collecting precipitation, lyophilizing is for subsequent use.
(7) drug loading of medicine carrying microballoons measures: use DMSO to dissolve rifampicin, and the rifampicin solution of preparation variable concentrations, measures the light absorption value of rifampicin solution under variable concentrations, drawing standard curve under 475nm condition; Get 10mg rifampicin-PLGA medicine carrying microballoons, be dissolved in 1mLDMSO, measure its light absorption value, calculate its drug loading according to standard curve.Recording rifampicin drug loading by said method is 20 ± 0.12 μ g/mg.
(8) drug slow release function of medicine carrying microballoons measures: be dissolved in by rifampicin in DMSO, the standard solution of variable concentrations is prepared subsequently by NaH2PO4-Na2HPO4 buffer (PH7.4) dilution, 475nm measures light absorption value, drawing standard curve; Take 5mg medicine carrying PLGA microsphere (containing rifampicin ~ 100 μ g), be scattered in 1mLNaH
2pO
4-Na
2hPO
4buffer (PH7.4), be placed in 37 DEG C of incubators to hatch, every day collects supernatant, and supplement the fresh buffer of 1mL, collect 4 weeks continuously, measure 475nm light absorption value, rifampicin medicine burst size is calculated according to standard curve, draw release profiles, Fig. 6 a is the rifampicin metering of rifampicin-PLGA medicine carrying microballoons release every day, and Fig. 6 b is the rifampicin dosage of rifampicin-PLGA medicine carrying microballoons accumulative release in time.
Claims (8)
1. prepare a method for uniform particle sizes PLGA microsphere easily, comprise the following steps:
(1) PLGA is dissolved in dichloromethane organic solvent, obtains oil phase, PLGA concentration 6-20%;
(2) above-mentioned oil phase is distributed in polyvinyl alcohol aqueous phase, adds the pearl of 2-8mm diameter wherein, stirring and emulsifying, polyvinyl alcohol concentration 1-4%, oil phase and watr-proportion 1: 10-1: 5;
(3) take out pearl, dichloromethane organic solvent is fully volatilized;
(4) collected by centrifugation PLGA microsphere, and use distilled water wash;
(5) with the resuspended PLGA microsphere of distilled water, differential centrifugation more than 10 minutes, obtains PLGA microsphere.
2. method according to claim 1, wherein said pearl can be the pearl of any appropriate materials.
3. method according to claim 2, wherein said pearl is bead, copper pearl or aluminium pill.
4. method according to claim 1, wherein said bead diameter is 2-8mm.
5. the method according to claim 1-4, wherein to be no more than 1000rpm rotating speed emulsified.
6. the method according to claim 1-4, wherein also adds medicine to prepare medicine carrying microballoons in step (1).
7. method according to claim 6, wherein said medicine can be the medicine being dissolved in dichloromethane.
8. method according to claim 7, wherein said medicine is rifampicin.
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