CN105232474B - A kind of easy method for preparing uniform particle sizes' PLGA microballoons - Google Patents
A kind of easy method for preparing uniform particle sizes' PLGA microballoons Download PDFInfo
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- CN105232474B CN105232474B CN201510762108.9A CN201510762108A CN105232474B CN 105232474 B CN105232474 B CN 105232474B CN 201510762108 A CN201510762108 A CN 201510762108A CN 105232474 B CN105232474 B CN 105232474B
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Abstract
The invention provides the PLGA microballoons preparation that a kind of stirring and emulsifying method of improvement is used for uniform particle sizes.The microspherulite diameter narrow distribution prepared using this method, the PLGA microballoons of uniform particle sizes can be obtained with higher yield by simple centrifugal enrichment.Its preparation process is：PLGA is dissolved in dichloromethane as oil phase, using PVA solution as aqueous phase, oil phase is distributed in aqueous phase by a certain percentage, adds the bead co-emulsifier of several 2 8mm diameters, then the stirring and emulsifying under magnetic stirring apparatus；The PLGA microballoons of uniform particle sizes are obtained through volatile organic solvent, washing, differential centrifugation enrichment.
Description
Technical field
The present invention relates to the preparation technology of polymer microballoon, the more particularly to uniform PLGA microballoons of particle diameter distribution, belong to raw
Thing medical material tech field.
Background technology
Polylactic lactic acid (PLGA) is a kind of biodegradable high polymer material, and can finally degrade generation in vivo
Carbon dioxide and water, safe and non-toxic and good biocompatibility, it is considered as excellent medical material, and by U.S.'s food and medicine
Management board (FDA) ratifies to be used for clinic.Microsphere supported with the preparation of PLGA materials has important use in biomedicine field, by
To widely studied, including medicine delivery, Antibody preparation, vaccine adjuvant etc..At present, FDA has had been approved by a variety of micro- based on PLGA
The pharmaceutical preparation of ball enters clinical, such as LupronDeport.2009, China SFDA also have approved the micro- of 2 kinds of syringeabilities
Ball pharmaceutical preparation lists.
The particle diameter of PLGA microballoons is one of key factor for determining PLGA microballoon performances, and particle diameter is different, its purposes and biology
Learn effect significant difference.The control of particle size and uniformity directly influences the validity of PLGA microballoons application with repeating
Property.Based on this, how preparation technology is improved, size is controllable, PLGA microballoons of uniform particle sizes are this area all the time to prepare
One of emphasis of research.At present, the preparation method on PLGA microballoons mainly includes：1) stirring and emulsifying method；2) supersound method；
3) spray drying process；4) membrane emulsification.The more cheap simplicity of stirring and emulsifying method, it is big by mixing speed and time control particle diameter
It is small, but due in emulsion process liquid stress it is very uneven, the granular size of formation is very uneven.Although can by differential centrifugation
So that sizable microballoon obtains a certain degree of enrichment, but due to microspherulite diameter wider distribution, it is enriched with the microballoon production of acquisition
Rate is very low (＜ 30%).In addition, preparing small size microballoon using this method needs high rotating speed, such as obtaining 1-2 μm of microballoon needs
Nearly ten thousand revs/min of mixing speed is wanted, it is necessary to more professional equipment；Supersound method is generally used for preparing nanoscale microballoon, no
It is adapted to the preparation of micron order microballoon；Spray drying process not only needs special device, and prepares the lack of homogeneity of granular size；Film breast
Change method obtains the preferable but used professional equipment of PLGA particle uniformitys and consumables cost is higher.It is above-mentioned due to existing method
Limitation so that the quality and homogeneity of PLGA microballoons prepared by many researchs are bad, as a result poor repeatability；And homogeneity is preferable
PLGA microballoons can only be completed in more professional laboratory.Therefore, develop that a kind of particle uniformity is good, easy, replicability
Strong PLGA method for preparing microsphere is significant.
The content of the invention
, i.e. can be with higher using the agitator of routine it is an object of the invention to provide a kind of improved stirring and emulsifying method
Yield to prepare reduced size, the PLGA of uniform particle sizes microsphere supported, for drug delivery field.
The purpose of the present invention is achieved through the following technical solutions：
A kind of PLGA micro-sphere methods for preparing uniform particle sizes, comprise the following steps：
(1) PLGA is dissolved into dichloromethane organic solvent, obtains oil phase, PLGA concentration 6-20%；
(2) above-mentioned oil phase is distributed in polyvinyl alcohol aqueous phase, thereto the pearl of addition 2-8mm diameters, stirring and emulsifying,
Polyvinyl alcohol 1-4%, oil phase example 1: 10-1: 5 compared with water；
(3) pearl is taken out, dichloromethane organic solvent is fully volatilized；
(4) PLGA microballoons are collected by centrifugation, and use distillation water washing；
(5) PLGA microballoons are resuspended with distilled water, differential centrifugation more than 10 minutes, obtain PLGA microballoons.
In one embodiment, PLGA material molecule amounts can be 10-100kDa, and LA/GA can be 75: 25,50:
50,25: 75；
In another embodiment, bead diameter size can be 2-8mm, preferably 4-6mm.Other pearl can be appointed
The pearl of what appropriate materials, such as can be bead, copper bead, aluminium pill etc..
In another embodiment, rotating speed is no more than 1000rpm during emulsification.
In still another embodiment, medicine is added in step (1) to prepare drug bearing microsphere.Wherein described medicine can be with
It is dissolved in the medicine of dichloromethane, such as rifampin.
The beneficial effects of the invention are as follows under the emulsification aided in pearl, the low-speed agitator of routine, such as magnetic agitation are used
Device, you can reach good emulsion dispersion effect, with reference to simple differential centrifugation method, the PLGA that can obtain uniform particle sizes is micro-
Ball.In terms of existing technologies, this method equipment is simple, and cost is cheap, and stirring at low speed emulsification can obtain as low as 1 μm of diameter
PLGA microballoons, the microspherulite diameter obtained is evenly distributed, and enrichment yield is high.
Brief description of the drawings
Fig. 1 is that convention stir emulsification aids in stirring and emulsifying schematic diagram with bead.1a is that convention stir emulsifies schematic diagram；1b
Bead aids in stirring and emulsifying schematic diagram；
Fig. 2 is under different rotating speeds, and the PLGA microsphere opticals that convention stir emulsification obtains with bead auxiliary stirring and emulsifying shine
Piece.Wherein, Fig. 2 a are convention stir 3 hours under 400 revs/min of rotating speeds, and 2b is convention stir 3 hours, 2c under 800 revs/min of rotating speeds
For convention stir under 400 revs/min of rotating speeds 3 hours, 2d was bead auxiliary stirring 3 hours, 2e 800 under 400 revs/min of rotating speeds
Bead auxiliary stirring 3 hours under rev/min rotating speed, 2f are 3 hours (Bar=20 of bead auxiliary stirring under 1000 revs/min of rotating speeds
μm)；
Fig. 3 is the PLGA microballoons scanning electricity that convention stir emulsification obtains with bead auxiliary stirring and emulsifying under different rotating speeds
Mirror photo and particle diameter distribution.Wherein, Fig. 3 a are convention stir 3 hours under 400 revs/min of rotating speeds, and 3b is normal under 800 revs/min of rotating speeds
Rule stirring 3 hours, 3c are convention stir 3 hours under 1000 revs/min of rotating speeds, and 3d is bead auxiliary stirring under 400 revs/min of rotating speeds
3 hours, 3e was bead auxiliary stirring 3 hours under 800 revs/min of rotating speeds, and 3f is bead auxiliary stirring under 1000 revs/min of rotating speeds
3 hours (Bar=5 μm)；
Under Fig. 4 bead co-emulsifiers, the PLGA microballoon sizes of 1000 revs/min of emulsification 1h acquisitions；
The distribution of PLGA microspherulite diameters and scanning electron microscopic picture that differential centrifugation obtains under the conditions of Fig. 5 difference centrifugal force.Wherein,
Fig. 5 a are the particle diameter distribution that 50g centrifugal forces collect PLGA microballoons, and 5b is the grain that 200g centrifugal forces collect PLGA microballoons
Footpath is distributed, and 5c is the particle diameter distribution that 2000g centrifugal forces collect PLGA microballoons, and 5d is that 50g centrifugal forces collection PLGA is micro-
The scanning electron microscopic picture of ball, 5e are the scanning electron microscopic picture that 200g centrifugal forces collect PLGA microballoons, and 5f is 2000g centrifugal force
The scanning electron microscopic picture of PLGA microballoons is collected by centrifugation.
Slow releasing function of Fig. 6 .PLGA microballoons to rifampin.Wherein, Fig. 6 a are that the PLGA microballoons of parcel rifampin delay daily
Release rifampicin medicine amount；Fig. 6 b are the PLGA microballoons of parcel rifampin with the rifampicin medicine amount of time cumulative release.
Embodiment
The present invention is described in further detail below by following examples, so that those skilled in the art is further
Understand the present invention, but any restrictions are not formed to the present invention.
Embodiment 1：It is prepared by the lower PLGA microballoons of bead auxiliary
(1) preparation of oil phase：PLGA 0.6g are weighed, are dissolved into 10mL dichloromethane, prepare 6% PLGA solution；
(2) preparation of the PVA aqueous solution：2.5g PVA solids are weighed, are added in 100mL distilled water, heating stirring is abundant
Dissolving, it is configured to the 2.5% PVA aqueous solution；
(3) bead co-emulsifier：In the appropriate vial of size, every bottle of addition 10mL 2.5% PVA solution, and
1mL 6% PLGA oil-phase solutions is scattered wherein, then add the glass of magnetic stirring apparatus rotor and several 4-6mm diameters
Pearl, stirring 3 hours is opened under 400 revs/min, 800 revs/min, 1000 revs/min of rotating speeds respectively；
(4) volatilization of organic solvent：After the completion of bead co-emulsifier, taking-up bead, stirring at low speed 12-24 hours,
Dichloromethane organic solvent is set fully to volatilize；
(5) collection of PLGA microballoons：2000g, which is centrifuged, collects PLGA microballoons for 20 minutes, and multiple using distillation water washing；
(6) observation by light microscope of PLGA microballoons：The PLGA microballoons of collection are resuspended with distilled water, are taken and one after another drop of are added to load
It is placed under inverted phase contrast microscope and is observed on slide, after standing and drying.If Fig. 2 a-f are respectively the routine under same rotating speed
PLGA microballoon light microscopic photos prepared by stirring and emulsifying and bead co-emulsifier；
(7) scanning electron microscopic observation and particle size determination of PLGA microballoons：PLGA microspheres solutions are evenly coated on masking foil, done
A clip wherein small pieces, are pasted onto on sample stage by conducting resinl after dry, and SEM is used for after metal spraying and is observed.With
Afterwards, on the stereoscan photograph of collection, the particle diameter of PLGA microballoons is measured by computer software, each sample measure
More than 500, analyze particle diameter distribution.If Fig. 3 a-f are the PLGA that conventional emulsion is prepared with bead co-emulsifier under different rotating speeds
Microballoon electromicroscopic photograph and particle diameter distribution situation.
Embodiment 2：The PLGA microballoons enrichment of uniform particle sizes
The present embodiment carries out uniform particle sizes' using the emulsified 1 hour PLGA microballoon prepared of 1000 revs/min of rotating speeds as sample
PLGA microballoons are enriched with, and main purpose prepares the microballoon of 2-3 μ m diameter sizes for enrichment.
(1) preparation of oil phase：PLGA 0.6g are weighed, are dissolved into 10mL dichloromethane, prepare 6% PLGA solution；
(2) preparation of the PVA aqueous solution：2.5g PVA solids are weighed, are added in 100mL distilled water, heating stirring is abundant
Dissolving, it is configured to the 2.5% PVA aqueous solution；
(3) bead co-emulsifier：In the appropriate vial of size, every bottle of addition 10mL 2.5% PVA solution, and
1mL 6% PLGA oil-phase solutions is scattered wherein, then add the glass of magnetic stirring apparatus rotor and several 4-6mm diameters
Pearl, stir 1 hour under the conditions of 1000 revs/min；
(4) volatilization of organic solvent：After the completion of bead co-emulsifier, taking-up bead, stirring at low speed 12-24 hours,
Dichloromethane organic solvent is set fully to volatilize；
(5) collection of PLGA microballoons：2000g centrifugal forces collect PLGA particles for 20 minutes, and use distillation water washing
Repeatedly；
(6) PLGA microsphere diameters determine：The PLGA microsphere diameters prepared using computer software measure.If Fig. 4 is 1000
Under rev/min rotating speed, the particle diameter distribution and electromicroscopic photograph of PLGA microballoons prepared by bead co-emulsifier 1h；
(7) the differential centrifugation enrichment of PLGA microballoons：The PLGA microballoons of acquisition are distributed in distilled water, stand 5- first
10min removes precipitation, is then centrifuged 15 minutes under the conditions of 50g, 200g, 2000g centrifugal force respectively, and collection centrifuges heavy every time
Starch, it is scanned observation or lyophilized preservation.It is enriched such as table 1 below, under the conditions of the present embodiment, the PLGA microballoon masters of preparation
~3 μm or so are distributed in, rate is closely~60%.Fig. 5 a-f are the PLGA microspherulite diameters distribution that different differential centrifugation conditions obtain
With stereoscan photograph.
Embodiment 3：Wrap up rifampicin medicine, prepared by the PLGA drug bearing microspheres of 2-3 μm of particle diameter
(1) preparation of oil phase；Weigh 0.6g PLGA, 0.05g rifampicin medicines, co-dissolve into 10mL dichloromethane,
Prepare the solution containing 6%PLGA, 0.5% rifampin；
(2) preparation of the PVA aqueous solution：2.5g PVA solids are weighed, are added in 100mL distilled water, heating stirring is abundant
Dissolving, it is configured to the 2.5% PVA aqueous solution；
(3) bead co-emulsifier：In the appropriate vial of size, every bottle of addition 10mL2.5% PVA solution, and
1mL 6% PLGA oil-phase solutions is scattered wherein, then add the glass of magnetic stirring apparatus rotor and several 5-6mm diameters
Pearl, stir 1 hour under the conditions of 1000 revs/min；
(4) volatilization of organic solvent：After the completion of bead co-emulsifier, taking-up bead, stirring at low speed 12-24 hours,
Dichloromethane organic solvent is set fully to volatilize；
(5) collection of rifampin-PLGA drug bearing microspheres：2000g centrifugal forces collect complex microsphere in 20 minutes, and use
It is multiple to distill water washing；
(6) collection of rifampin-PLGA drug bearing microspheres：The above-mentioned PLGA microballoons aqueous solution is first stood 5-10min and removed and is sunk
Form sediment, then centrifugal enrichment 15 minutes under 50g centrifugal force, collect precipitation, freeze standby.
(7) the drugloading rate measure of drug bearing microsphere：Rifampin is dissolved using DMSO, prepares the rifampin solution of various concentrations,
The light absorption value of rifampin solution under various concentrations is determined under the conditions of 475nm, draws standard curve；10mg rifampins-PLGA is taken to carry
Medicine microballoon, 1mL DMSO are dissolved in, determine its light absorption value, its drugloading rate is calculated according to standard curve.Measured by the above method
Rifampin drugloading rate is 20 ± 0.12 μ g/mg.
(8) the drug slow release function measure of drug bearing microsphere：Rifampin is dissolved in DMSO, then passes through NaH2PO4-
Na2HPO4 buffer solutions (PH7.4) dilution prepares the standard liquid of various concentrations, 475nm measure light absorption values, draws standard curve；
Weigh 5mg and carry medicine PLGA microballoons (containing rifampin~100 μ g), be scattered in 1mL NaH2PO4-Na2HPO4Buffer solution (PH7.4), puts
It is incubated in 37 DEG C of incubators, collects supernatant daily, and supplements the fresh buffer solutions of 1mL, it is continuous to collect 4 weeks, determine 475nm extinctions
Value, rifampicin medicine burst size is calculated according to standard curve, draw release profiles, Fig. 6 a are that rifampin-PLGA drug bearing microspheres are every
The rifampin metering of its release, Fig. 6 b are the rifampin dosage that rifampin-PLGA drug bearing microspheres discharge with time cumulation.
Claims (7)
1. a kind of easy method for preparing uniform particle sizes' PLGA microballoons, comprises the following steps：
(1) PLGA is dissolved into dichloromethane organic solvent, obtains oil phase, PLGA concentration 6-20%；
(2) above-mentioned oil phase is distributed in polyvinyl alcohol aqueous phase, thereto add 2-8mm diameters pearl, no more than
Stirring and emulsifying under 1000rpm rotating speeds, polyvinyl alcohol concentration 1-4%, oil phase example 1 compared with water:10-1:5；
(3) pearl is taken out, dichloromethane organic solvent is fully volatilized；
(4) PLGA microballoons are collected by centrifugation, and use distillation water washing；
(5) PLGA microballoons are resuspended with distilled water, differential centrifugation more than 10 minutes, obtain PLGA microballoons.
2. according to the method for claim 1, wherein the pearl can be the pearl of any appropriate materials.
3. according to the method for claim 2, wherein the pearl is bead, copper bead or aluminium pill.
4. according to the method for claim 1, wherein the bead diameter is 2-8mm.
5. according to the method described in claim any one of 1-4, wherein it is micro- to prepare load medicine to be additionally added medicine in step (1)
Ball.
6. according to the method for claim 5, wherein the medicine can be dissolved in the medicine of dichloromethane.
7. according to the method for claim 6, wherein the medicine is rifampin.
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| CN1437933A (en) * | 2003-03-28 | 2003-08-27 | 中国科学院长春应用化学研究所 | Method for preparing Rifampiciu microballs covered by degradable high-molecular material |
| WO2006002365A2 (en) * | 2004-06-24 | 2006-01-05 | Angiotech International Ag | Microparticles with high loadings of a bioactive agent |
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