CN103611196A - PELA/BMP-2 microsphere and preparation method - Google Patents
PELA/BMP-2 microsphere and preparation method Download PDFInfo
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Abstract
The invention provides a PELA/BMP-2 microsphere in order to solve the problem of poor bone repairing ability of existing high molecular material/BMP-2 sustained release system and belongs to the technical field of preparation of bone repairing materials. The PELA/BMP-2 microsphere employs PELA as a carrier, thus the PELA/BMP-2 microsphere has good cell adsorption properties and stable medicine release properties, and therefore the absorptivity of the PELA/BMP-2 microsphere is raised, and the promotion function of the PELA/BMP-2 microsphere in the bone healing process is obviously raised. During the preparation process, a PELA emulsion is emulsified with span, the entrapment rate of the PELA/BMP-2 microsphere reaches 86%, the microsphere is a regular sphere and has a smooth surface, and therefore the fluidity of the PELA/BMP-2 microsphere is raised, which is beneficial for injection and absorption.
Description
Technical field
The present invention relates to a kind of PELA/ BMP-2 microsphere and preparation method thereof, belong to the preparing technical field of bone renovating material.
Background technology
BMP-2 (is bone morphogenetic protein-2, bone morphogenesis protein-2) there is the undifferentiated mescenchymal stem cell of induction to the ability of chondroblast and osteoblast directed differentiation and propagation, promote osteoblast differentiation ripe, participate in growth promoter and the process of reconstruction thereof of bone and cartilage, and then the damaged reparation of accelerated bone.But BMP-2 is a kind of water-fast acid noncollagen protein, easy loss of activity in vivo, growth that can not fine induced osteogenesis in part, its biological activity is difficult to be brought into play, and has greatly limited the application of BMP-2.
Drug sustained release system refers to is combined with macromolecular material medicine with physics or chemical method, make medicine can be in vivo by infiltration, the modes such as diffusion with low concentration sustained release out, to reach the object of giving full play to efficacy of drugs.Therefore, have in recent years researcher adopt to adopt macromolecular material as slow-released carrier to BMP-2 embedding, be prepared into macromolecular material/BMP-2 slow-released system and improve application clinically.
The material of slow-released carrier is the important component part of slow-released system, and desirable carrier material must possess good biocompatibility, biodegradability, and rational slow-release time and degradation speed, to key propertys such as human body have no side effect.Research discovery, the macromolecular material in existing macromolecular material/BMP-2 slow-released system is the lipotropy polymer material of synthetic; Its hydrophilic is poor, cell absorption affinity is weak, mechanical strength is not enough; Thereby the absorbance that causes existing macromolecular material/BMP-2 slow-released system is low, drug release is not steady; Finally cause the effect of macromolecular material/BMP-2 slow-released system in knitting process not obvious, a little less than bone repair ability.
Summary of the invention
The weak problem of bone repair ability existing in order to solve existing macromolecular material/BMP-2 slow-released system; The present invention adopts PELA triblock copolymer material as the slow-released carrier of embedding BMP-2, and a kind of PELA/ BMP-2 microsphere is provided.
PELA, i.e. polylactic acid-PVOH-polylactic acid (PLA-PEG-PLA), block three copolymers that formed by PLA, PEG, PLA, its constitutional repeating unit is [PLA-PEG-PLA-]; Possess the good cell tissue compatibility, biodegradability, and possess the parents characteristic of hydrophilic and close ester, can overcome the problem of PGLA and simple PLA strong-hydrophobicity.The present invention is by regulating the length of strand of PELA, the molecular weight of PEG, the content of PEG in PELA, thereby makes PELA meet the needs as BMP-2 slow-released carrier, and the bone repair ability of PELA/ BMP-2 microsphere is obviously improved.
The present invention also provides the preparation method of above-mentioned ELA/ BMP-2 microsphere.
Technical scheme of the present invention:
1. a PELA/ BMP-2 microsphere, according to the ratio of 1ug:66-176.7mg, adopts emulsion-solvent evaporation method to be prepared from by BMP-2 and PELA;
The molecular weight of described PELA is 20000-30000Da, viscosity IV (dl/g) scope: 0.20～0.4; The mass content of PEG is 10-20%, and the molecular weight of PEG is 4000-6500Da.
Described emulsion-solvent evaporation method, is about to after BMP-2 water and PELA organic facies mixing and emulsifying and PVA water mixing and emulsifying again; Evaporate again the method for organic solvent.
2. above-mentioned PELA/ BMP-2 microsphere, the molecular weight of described PELA is preferably 30000Da; The mass content of PEG is preferably 20%; The molecular weight of PEG be 6000Da.
3. above-mentioned PELA/ BMP-2 microsphere, the ratio of described BMP-2 and PELA is preferably 1ug:106-110mg.
4. above-mentioned PELA/ BMP-2 microsphere, preferably adopts following method to be prepared from:
A. the BMP-2-deionized water solution of 15-25ug/ml is mixed with the PELA-dichloromethane emulsion of 82.5-132.5mg/ml, ultrasonic emulsification, obtains colostric fluid; Then adding mass concentration is 1.0-3.0%PVA aqueous solution ultrasonic emulsification again, obtains emulsion;
B. stirring and emulsifying liquid makes organic solvent evaporation, obtains PELA/ BMP-2 microsphere;
The ratio of described colostric fluid and PVA aqueous solution is 83-134mg:1ml.
5. above-mentioned PELA/ BMP-2 microsphere, the PELA-dichloromethane emulsion that adopted in the preparation preferably adopts span to carry out emulsifying, and the quality of span is-0.5-3.0% of dichloromethane emulsion.
6. above-mentioned PELA/ BMP-2 microsphere, preferred in the preparation, and in step a, ultrasound condition is for the first time: power is 100W, time 10-20min; Ultrasound condition is for the second time: power is 100W, time 20-30min; In step b, to emulsion preferably with the rotating speed electromagnetic agitation 30-60 min of 800-1200 r/min.
7. a preparation method for above-mentioned PELA/ BMP-2 microsphere, comprises the steps:
A. in PELA-dichloromethane emulsion, add span, ultrasonic dissolution obtains PELA emulsion; The quality of span is the 0.5-3.0% of PELA solution;
B. the BMP-2-deionized water solution of 15-25ug/ml is mixed with the PELA-dichloromethane emulsion of 82.5-132.5mg/ml, ultrasonic emulsification, obtains colostric fluid; Then adding mass concentration is 1.0-3.0%PVA aqueous solution ultrasonic emulsification again, obtains emulsion;
C. stirring and emulsifying liquid makes organic solvent evaporation, obtains PELA/ BMP-2 microsphere;
The ratio of described colostric fluid and PVA aqueous solution is 83-134mg:1ml.
8. the preparation method of above-mentioned PELA/ BMP-2 microsphere, described BMP-2 deionized water solution is that BMP-2 is dissolved in the deionized water that contains guanidine hydrochloride and is prepared from; In the described deionized water that contains guanidine hydrochloride, the concentration of guanidine hydrochloride is 0.4mol/L.
9. the preparation method of above-mentioned PELA/ BMP-2 microsphere, preferred, in step a, ultrasound condition is for the first time: power is 100W, time 10-20min; Ultrasound condition is for the second time: power is 100W, time 20-30min; In step b, to emulsion preferably with the rotating speed electromagnetic agitation 30-60 min of 800-1200 r/min.
10. the preparation method of above-mentioned PELA/ BMP-2 microsphere, preferred, also comprises steps d: by distilled water wash 3 times of PELA/ BMP-2 microsphere; Then lyophilization under-55 ~-60 ℃, the condition of 10-20Pa.
Beneficial effect
1. the prepared PELA/ BMP-2 microsphere of the present invention, adopts PELA as carrier; Make PELA/ BMP-2 microsphere possess good cell absorption property and medicine-releasing performance stably; Thereby improved the absorbance of PELA/ BMP-2 microsphere; The facilitation of PELA/ BMP-2 microsphere in knitting process significantly improved;
2. in preparation process, adopt span to carry out emulsifying to PELA emulsion; Thereby make the envelop rate of prepared PELA/ BMP-2 microsphere reach 86%, and make microsphere be the spherical of rule, smooth surface; Thereby improved the mobility of PELA/ BMP-2 microsphere, be conducive to injection and absorb.
Accompanying drawing explanation
Fig. 1 is the electron-microscope scanning figure of the mixture of the prepared PELA/BMP-2 of embodiment 1-9;
Fig. 2 is the electron-microscope scanning figure of the PELA/BMP-2 microsphere of embodiment 2 preparation:
Fig. 3 is the electron-microscope scanning figure of the PELA/BMP-2 microsphere of embodiment 1 preparation.
The specific embodiment
For a better understanding of the present invention, below in conjunction with specific embodiment, be described further.
Embodiment 1
The PELA that takes 330mg is dissolved in 4ml dichloromethane, and stirring and emulsifying obtains the PELA-dichloromethane emulsion of 82.5mg/ml; The molecular weight of PELA is 30000Da, the mass content 20% of PEG; The molecular weight of PEG is 6000Da;
The BMP-2 deionized water solution of getting 200ul, 15ug/ml is mixed homogeneously with PELA-dichloromethane emulsion, stirring and emulsifying, and then add 40mlPVA aqueous solution (mass concentration is 1.0%), continue stirring and emulsifying; And then with rotating speed electromagnetic agitation 30 min of 800 r/min, make organic solvent evaporation, obtain PELA/ BMP-2 microsphere.
Embodiment 2
The PELA that takes 330mg is dissolved in 4ml dichloromethane, and stirring and emulsifying obtains the PELA-dichloromethane emulsion of 82.5mg/ml; The molecular weight of PELA is 20000Da, the mass content 10% of PEG; The molecular weight of PEG is 4000Da;
The BMP-2 deionized water solution of getting 200ul, 15ug/ml is mixed homogeneously with PELA-dichloromethane emulsion, stirring and emulsifying, and then add 40mlPVA aqueous solution (mass concentration is 1.0%), continue stirring and emulsifying; And then with rotating speed electromagnetic agitation 30 min of 800 r/min, make organic solvent evaporation, obtain PELA/ BMP-2 microsphere.
Embodiment 3
The PELA that takes 330mg is dissolved in 4ml dichloromethane, and stirring and emulsifying obtains the PELA-dichloromethane emulsion of 82.5mg/ml; The molecular weight of PELA is 320000Da, the mass content 20% of PEG; The molecular weight of PEG is 6500Da;
The BMP-2 deionized water solution of getting 200ul, 15ug/ml is mixed homogeneously with PELA-dichloromethane emulsion, stirring and emulsifying, and then add 40mlPVA aqueous solution (mass concentration is 1.0%), continue stirring and emulsifying; And then with rotating speed electromagnetic agitation 30 min of 800 r/min, make organic solvent evaporation, obtain PELA/ BMP-2 microsphere.
Embodiment 4
The PELA that takes 330mg is dissolved in 4ml dichloromethane, and stirring and emulsifying obtains the PELA-dichloromethane emulsion of 82.5mg/ml; The molecular weight of PELA is 30000Da, the mass content 20% of PEG; The molecular weight of PEG is 6000Da;
The BMP-2 deionized water solution of getting 200ul, 25ug/ml is mixed homogeneously with PELA-dichloromethane emulsion, stirring and emulsifying, and then add 40mlPVA aqueous solution (mass concentration is 1.0%), continue stirring and emulsifying; And then with rotating speed electromagnetic agitation 30 min of 800 r/min, make organic solvent evaporation, obtain PELA/ BMP-2 microsphere.
Embodiment 5
The PELA that takes 530mg is dissolved in 4ml dichloromethane, and stirring and emulsifying obtains the PELA-dichloromethane emulsion of 82.5mg/ml; The molecular weight of PELA is 30000Da, the mass content 20% of PEG; The molecular weight of PEG is 6000Da;
The BMP-2 deionized water solution of getting 200ul, 15ug/ml is mixed homogeneously with PELA-dichloromethane emulsion, stirring and emulsifying, and then add 40mlPVA aqueous solution (mass concentration is 1.0%), continue stirring and emulsifying; And then with rotating speed electromagnetic agitation 30 min of 800 r/min, be organic solvent evaporation, obtain PELA/ BMP-2 microsphere.
Embodiment 6
The PELA that takes 330mg is dissolved in 4ml dichloromethane, and stirring and emulsifying obtains the PELA-dichloromethane emulsion of 82.5mg/ml; The molecular weight of PELA is 30000Da, the mass content 20% of PEG; The molecular weight of PEG is 6000Da;
The BMP-2 deionized water solution of getting 200ul, 15ug/ml is mixed homogeneously with PELA-dichloromethane emulsion, stirring and emulsifying, and then add 40mlPVA aqueous solution (mass concentration is 3.0%), continue stirring and emulsifying; And then with rotating speed electromagnetic agitation 30 min of 800 r/min, make organic solvent evaporation, obtain PELA/ BMP-2 microsphere.
Embodiment 7
A. the BMP-2 of 3 ug is dissolved in guanidine hydrochloride-distilled water that 200ul concentration is 0.4mol/L;
B. the molecular weight that takes the PELA(PELA of 330mg is 30000Da, the mass content 20% of PEG; The molecular weight of PEG is 4000Da) be dissolved in 4ml dichloromethane;
C. in above-mentioned b step, add the span of 1.675mg; Then under 100W ultrasound condition, carry out ultrasonic dissolution 10min;
D. above-mentioned a is mixed with the solution in c step, ultrasonic (100W) 20 minutes, fully emulsified after, add 40mlPVA aqueous solution (mass concentration is 1.0%), carry out ultrasonic (100W) emulsifying for the second time; Obtain emulsion;
E. rotating speed electromagnetic agitation 30 min with 800 r/min by the emulsion of d step, then evaporate organic solvent, obtain microgranule;
F. by distilled water wash 3 times, centrifugalize, the collection microgranule for microgranule of e step ,-10 ℃ of lyophilizations, obtain microsphere, put into refrigerator, standby.
Embodiment 8
A. in guanidine hydrochloride-distilled water that the BMP-2 of 5 ug to be dissolved in to 200ul, concentration be 0.4mol/L;
B. (molecular weight of PELA is 30000Da, the mass content 20% of PEG to take the PELA material of 530mg; The molecular weight of PEG is 4000Da) be dissolved in 4ml dichloromethane;
C. in above-mentioned b step, add the span of 1.6mg, then under 100W ultrasound condition, carry out ultrasonic dissolution 20min;
D. above-mentioned a is mixed with the solution in c step, ultrasonic (100W) 30 minutes, fully emulsified after, add respectively the PVA solution of 40ml3.0%, carry out ultrasonic (100W) emulsifying for the second time; Obtain emulsion;
E. rotating speed electromagnetic agitation 60 min with 1200 r/min by the emulsion of d step, then evaporate organic solvent, obtain microgranule;
F. by distilled water wash 3 times for the microgranule of e step, centrifugal collection microgranule ,-20 ℃ of lyophilizations, obtain microsphere, put into refrigerator, standby.
Embodiment 9
A. in guanidine hydrochloride-distilled water that the BMP-2 of 4 ug to be dissolved in to 200ul, concentration be 0.4mol/L;
B. (molecular weight of PELA is 30000Da, the mass content 20% of PEG to take the PELA material of 430mg; The molecular weight of PEG is 4000Da) be dissolved in 4ml dichloromethane;
C. in above-mentioned b step, add 2.0% span, then under 100W ultrasound condition, carry out ultrasonic dissolution 20min;
D. above-mentioned a is mixed with the solution in c step, ultrasonic (100W) 20 minutes, fully emulsified after, add respectively the PVA solution of 40ml2.0%, carry out ultrasonic (100W) emulsifying for the second time; Obtain emulsion;
E. rotating speed difference electromagnetic agitation 45 min with 1000 r/min by the emulsion of d step, then evaporate organic solvent, obtain microgranule;
F. by distilled water wash 3 times for the microgranule of e step, centrifugal collection microgranule ,-20 ℃ of lyophilizations, obtain microsphere, put into refrigerator, standby.
Claims (10)
1. a PELA/ BMP-2 microsphere, is characterized in that, by BMP-2 and PELA, according to the ratio of 1ug:66-176.7mg, adopts emulsion-solvent evaporation method to be prepared from;
The molecular weight of described PELA is 20000-30000Da, viscosity IV (dl/g) scope: 0.20～0.4; The mass content of PEG is 10-20%, and the molecular weight of PEG is 4000-6500Da.
2. PELA/ BMP-2 microsphere according to claim 1, is characterized in that, the molecular weight of described PELA is 30000Da; The mass content of PEG is 20%; The molecular weight of PEG is 6000Da.
3. PELA/ BMP-2 microsphere according to claim 1, is characterized in that, the ratio of described BMP-2 and PELA is 1ug:106-110mg.
4. according to the PELA/ BMP-2 microsphere described in claim 1,2 or 3, it is characterized in that, adopt following method to be prepared from:
The BMP-2-deionized water solution of 15-25ug/ml is mixed with the PELA-dichloromethane emulsion of 82.5-132.5mg/ml, and ultrasonic emulsification, obtains colostric fluid; Then adding mass concentration is 1.0-3.0%PVA aqueous solution ultrasonic emulsification again, obtains emulsion;
Stirring and emulsifying liquid makes organic solvent evaporation, obtains PELA/ BMP-2 microsphere;
The ratio of described colostric fluid and PVA aqueous solution is 83-134mg:1ml.
5. PELA/ BMP-2 microsphere according to claim 4, is characterized in that, the PELA-dichloromethane emulsion that adopted in the preparation adopts span to carry out emulsifying, the quality of span is-and the 0.5-3.0% of dichloromethane emulsion.
6. PELA/ BMP-2 microsphere according to claim 4, is characterized in that, in the preparation, in step a, ultrasound condition is for the first time: power is 100W, time 10-20min; Ultrasound condition is for the second time: power is 100W, time 20-30min; In step b, the rotating speed electromagnetic agitation 30-60 min to emulsion with 800-1200 r/min.
7. a preparation method for the PELA/ BMP-2 microsphere described in claim 1～6, is characterized in that, comprises the steps:
A. in PELA-dichloromethane emulsion, add span, ultrasonic dissolution obtains PELA emulsion; The quality of span is the 0.5-3.0% of PELA solution;
B. the BMP-2-deionized water solution of 15-25ug/ml is mixed with the PELA-dichloromethane emulsion of 82.5-132.5mg/ml, ultrasonic emulsification, obtains colostric fluid; Then adding mass concentration is 1.0-3.0%PVA aqueous solution ultrasonic emulsification again, obtains emulsion;
C. stirring and emulsifying liquid makes organic solvent evaporation, obtains PELA/ BMP-2 microsphere;
The ratio of described colostric fluid and PVA aqueous solution is 83-134mg:1ml.
8. the preparation method of PELA/ BMP-2 microsphere according to claim 7, is characterized in that, described BMP-2 deionized water solution is that BMP-2 is dissolved in the deionized water that contains guanidine hydrochloride and is prepared from; In the described deionized water that contains guanidine hydrochloride, the concentration of guanidine hydrochloride is 0.4mol/L.
9. the preparation method of PELA/ BMP-2 microsphere according to claim 7, is characterized in that, in step a, ultrasound condition is for the first time: power is 100W, time 10-20min; Ultrasound condition is for the second time: power is 100W, time 20-30min; In step b, the rotating speed electromagnetic agitation 30-60 min to emulsion with 800-1200 r/min.
10. the preparation method of PELA/ BMP-2 microsphere according to claim 7, is characterized in that, also comprises steps d: by distilled water wash 3 times of PELA/ BMP-2 microsphere; Then lyophilization under-55 ~-60 ℃, the condition of 10-20Pa.
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| CN106620654A (en) * | 2017-01-25 | 2017-05-10 | 山东大学 | BMP-2/PPLA (bone morphogenetic protein-2/polylactic acid and polyethylene glycol block copolymer) microspheres and preparation method thereof |
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