CN102988301A - Preparation method of long-acting sustained-release microspheres containing bevacizumab - Google Patents
Preparation method of long-acting sustained-release microspheres containing bevacizumab Download PDFInfo
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Abstract
The invention discloses a preparation method of long-acting sustained-release microspheres containing bevacizumab, which is a preparation method of the sustained-release microspheres formed by encapsulating water-soluble drug protein bevacizumab in a degradable biomedical polymer material. The microspheres are prepared by a W/O/W (water-in-oil-in-water) solvent evaporation method, which comprises the steps of: dispersing bevacizumab and a solution thereof and alginate as inner water phases into a solution which uses the degradable biomedical polymer material as an oil phase to form colostrum; dispersing the colostrum into an outer water phase which is water liquid containing emulsifier to form multiple emulsion; and stirring, distilling in reduced pressure, centrifuging, washing and drying to obtain the bevacizumab sustained-release microspheres. According to the long-acting sustained-release microspheres containing bevacizumab prepared by the method, the encapsulation efficiency of the water-soluble protein drug can be effectively improved, the drug protein activity is not influenced, the releasing time of water-soluble protein can be effectively prolonged, and the sustained release period can be 2-3 months, even longer, so that the number of injection times can be reduced. The preparation method is convenient for clinical application.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of preparation method that contains the long-acting slow-release microsphere of bevacizumab.
Background technology
Bevacizumab is rhMAb VEGF, bevacizumab, Avastin is researched and developed by Roche Holding Ag, it is the full length monoclonal antibodies that suppresses VEGF VEGF, molecular weight is 149kDa, all hypotypes to people's VEGF all have the specificity affinity, can in conjunction with and the isomer of all VEGF of blocking-up, reach by suppressing VEGF the effect that new vessels generates that suppresses.U.S. FDA has obtained the approval of U.S. food and drug administration at the end of 2004 2 months, and goes on the market in the U.S. March in the same year, and commodity are called Bevacizumab, and this is a monoclonal antibody drug that is approved for the inhibition angiogenic growth that beats the world at present.Ratify first this medicine combined chemotherapy and be used for the first-line treatment colorectal cancer in late period.Bevacizumab has very considerable application prospect for the treatment of the diseases such as cornea, iris, choroid, amphiblestroid new vessels and age-related macular degeneration, macular edema in ophthalmology.
The intravitreous half-life of bevacizumab is about 3-5 days, and a lot of needs of patients repeat injection to reach therapeutic effect, and the interval that still repeats injection is still disputable.The RL Avery of California Retina Consultants equals 2006 and injects per month once at Ophthalmology 113 (3): 363-372 proposition initial treatment, need to continue 3 months, the RM RICH of University Hospital of Coimbra proposed to last till at Retina (Philadelphia, Pa.) that the OCT check result showed do not have the performance of macular edema just to stop in 2006.Majority studies show that, using the bevacizumab intravitreal is safer in a short time, and mostly maximum untoward reaction is that this has the wound operation to cause by intraocular injection.Therefore, if medicine can in initial quick release, be controlled release ideal subsequently.Polypeptide, pharmaceutical grade protein are owing to easily being hydrolyzed by ester, and biological half-life is short in vivo. and control release and be considered to the most promising route of administration of this type of medicine.
Summary of the invention
The object of the invention is to: for the deficiencies in the prior art, the invention provides a kind of initial controlled long-acting slow-release microsphere that contains bevacizumab that can discharge fast, discharge subsequently.
To achieve these goals, this utility model has adopted following technical scheme:
A kind of preparation method that contains the long-acting slow-release microsphere of bevacizumab is characterized in that comprising the following steps:
(1) compound concentration is the bevacizumab solution of 25-2500mg/ml;
(2) get the bevacizumab solution that makes in step (1), add sodium alginate, being mixed with sodium alginate concentration is the bevacizumab solution of 0-15mg/ml, as interior water; Compound concentration is the organic solvent solution of the degradable biological medical macromolecular material of 10-500mg/ml, as oil phase; Preparation contains the emulsifier aqueous solution of 1-1000mg/ml calcium ion, and the percentage composition of emulsifying agent is 0.25-15%, as outer water;
(3) preparation of W/O/W multi-emulsion method sustained-release micro-spheres
At first will be distributed to as the sodium alginate soln of interior water in the organic solvent solution as the degradable biological medical macromolecular material of oil phase, the volume ratio of interior water and oil phase is 1:3 ~ 1:20, and rate of dispersion is 8000-100000rpm, forms colostrum;
Colostrum is distributed in emulsifier aqueous solution as outer water, and wherein adding proportion is that 1:3 ~ 1:20 carries out according to the volume ratio of interior water and emulsifying agent oil phase, and rate of dispersion is 8000-50000rpm, forms emulsion;
With emulsion at 0-10 ℃ of lower reduction vaporization 1-4h, then at 30-40 ℃ of lower reduction vaporization 1-4 hour;
(4) emulsion is carried out centrifugal sucking filtration drying, obtain containing the long-acting slow-release microsphere of bevacizumab.
Calcium ion can generate calcium alginate with the sodium alginate reaction, and calcium alginate has special egg case structure, and during the preparation colostrum, rate of dispersion is 8000-100000rpm, and the envelop rate of colostrum and particle diameter are best, are conducive to the preparation of next step reagent.
In addition, the high low temperature reduction vaporization of segmentation can make the organic solvent fully volatilization at short notice in oil phase
As preferably, described degradable biological medical macromolecular material is one or more in polylactide, PGA, polylactide-co-glycolide, polycaprolactone, poly-river rising in Ningxia and flowing into central Shaanxi butanoic acid, poly-river rising in Ningxia and flowing into central Shaanxi valeric acid, cluster acid, poly-anhydride.After adopting above-mentioned preferred version, the biocompatibility of above-mentioned degradable biological medical macromolecular material is better, and problem hardly can cause inflammation because of problem of materials.
As preferably, described degradable biological medical macromolecular material is polylactide-co-glycolide, in described polylactide-co-glycolide, the polymerization ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25 or 50/50, and the molecular weight of described polylactide-co-glycolide is 30000-100000 dalton.
After adopting above-mentioned preferred version, Poly(D,L-lactide-co-glycolide is poly (lactic-co-glycolic acid, be abbreviated as PLGA, to be polymerized at random by two kinds of monomer lactic acid and hydroxyacetic acid, it is a kind of degradable macromolecule organic compound, at first be degraded in vivo hydroxyacetic acid and lactic acid, finally degradable is CO
2And H
2O excretes, and old friend's body is large to the toleration of this polymer, good biocompatibility.In addition, PLGA not only has good biocompatibility, nontoxic, good encystation and the performance of film forming, the more important thing is that the degradation rate of PLGA and the release of medicine can control by the ratio of polymeric physicochemical properties such as molecular weight, hydrophilic and lactide and glycolic, this biodegradation material is widely used in pharmacy and biomedical materials field.
And behind polymerization ratio preferred 75/25 or 50/50, the sustained-release micro-spheres of these two ratio preparations, the at first deenergized period of the adaptive medicine Avastin of energy on degradation property; Secondly they are higher to the envelop rate of this medicine.
As preferably, described organic solvent is one or more in dichloromethane, ethyl acetate or acetonitrile.After adopting above-mentioned preferred version, organic solvent concentration has direct impact to diameter and the sustained drug release effect of last microsphere particle, the appeal organic solvent is the biological medical polymer good solvent, and be easy to volatilization, adopt above-mentioned organic solvent can make last microsphere particle and medicine release slow and really reach best.
As preferably, the concentration of the degradable biological medical macromolecular material in the organic solvent solution of described degradable biological medical macromolecular material is 10-300mg/ml.After adopting above-mentioned preferred version, organic solvent concentration has direct impact to diameter and the sustained drug release effect of last microsphere particle, and after adopting above-mentioned preferred concentration, the diameter of microsphere particle and medicine are released the slow fruit can reach optimum.
As preferably, described emulsifying agent is one or more in polyvinyl alcohol, polyvinylpyrrolidone, poloxamer.After adopting above-mentioned preferred version, mentioned emulsifier is biocompatibility emulsifying agent preferably, and residual toxicity is less.
As preferably, the emulsifier concentration in described emulsifier aqueous solution is 0.25-10%.The concentration of emulsifying agent and emulsifying effectiveness are influential to envelop rate and particle diameter, and too large or too little equal emulsifying effectiveness is bad, does not reach requirement.After adopting above-mentioned preferred version, can make the envelop rate of releasing slow microsphere and the particle diameter that make reach optimum.
As preferably, organic solvent is removed in the 1-4h evaporation of reducing pressure under 0.0013MPa ~ 1.01325MPa, 0-4 ℃ of the emulsion in described step (3), then decompression 1-4h removes organic solvent under 0.0013MPa ~ 1.01325MPa, 30-37 ℃.After adopting above-mentioned preferred version, the volatilization better effects if of dividing high temperature section and low-temperature end solvent, the main purpose of low-temperature zone is to slow down the evaporation rate of the solvent of microsphere surface, in order to avoid after surface solidification, the internal layer solvent evaporates is incomplete, and low-temperature reduced-pressure is after evaporation a period of time, and the purpose of intensification is the volatilization that increases solvent on the one hand, accelerate on the other hand the solidification forming of microsphere surface, be convenient to the separation of lower step.
The long-acting slow-release microsphere that contains bevacizumab of the present invention will become the novel form for the treatment of disease related with intraocular neovascularization, can slowly discharge by single injection, reaches treatment concentration steady in a long-term.This
Due to most of degradable biological medical macromolecular materials lipotropy polymer material that is synthetic, exist certain limitation in application, lack specific combination with body cell, the burst effect of microsphere and nanoparticle is obvious, for water soluble drug or protein polypeptide entrapment efficiency low and drug release steadily the shortcoming of slow release also limited its some application.And the present invention to adopt sodium alginate be sodium alginate, be called for short SA, as the medicine sustained and controlled release carrier.Sodium alginate is by the natural polyanionic polysaccharide compound that extracts in Thallus Laminariae (Thallus Eckloniae), links by α (1-4) glycosidic bond the linear block copolymers that forms in 3 kinds of modes (MM section, GG section and MG section) by guluronic acid (G section) and 2 kinds of construction units of its stereoisomer mannuronic acid (M section).Sodium alginate is owing to containing more carboxylic acid ion, and hydrophilic has more by force biocompatibility, biodegradation, the advantage such as nontoxic, has become comparatively ideal medicine sustained and controlled release carrier.
the inventive method prepares in the process of bevacizumab sustained-release micro-spheres, by adjusting sodium alginate in the different addition of interior aqueous phase, increase the viscosity of interior water, the pharmaceutical protein molecule also enters into the organic solvent contact of the aquagel fibre network discord oil phase that forms after the sodium alginate suction simultaneously, farthest keep its biological activity, when forming emulsion, run into the calcium ion of outer aqueous phase, Sodium Alginate Hydrogel Films can form rapidly the egg case structure of calcium alginate, the loss of water in reducing, the degradable biological medical macromolecule of the curing in while and the oil phase pharmaceutical protein of internal aqueous phase together carries out double wrapped.Microsphere science and technology rule is without adhesion, and particle diameter is controlled, is generally less than 10 μ m, and drug loading and envelop rate are controlled, and drug loading is generally 0.5-30% and envelop rate generally can reach 60%, and slow-release period can reach more than 2 months, and dashing forward, it is lower to release rate.Prepared microsphere can be reprocessed into other dosage forms, can be applicable to local injection or intravenous injection; The bevacizumab sustained-release micro-spheres can be kept effective treatment concentration of medicine in 2-3 month, improve bioavailability, namely reduced patient's medication number of times, had also reduced Financial cost.
this patent is take calcium alginate and Bevacizumab as interior water, utilize the egg case structure of calcium alginate that pharmaceutical protein is carried out effectively wrapping carrying, do not affect simultaneously its biocompatibility and pharmaceutical protein structure, carry out the secondary parcel with the degradable biological medical macromolecular material again, the effective activity of protected protein, also can effectively improve envelop rate, the long-acting slow-release microsphere that contains bevacizumab by the preparation of W/O/W emulsion method, effectively improve the envelop rate of water-solubility protein class medicine, and do not affect the pharmaceutical protein activity, and can effectively extend water-solubility protein release time, slow-release period reach two to three month and more than, reduced frequency injection, convenient clinical use.
Description of drawings
Fig. 1 is the structural representation that the present invention contains the long-acting slow-release microsphere of bevacizumab;
Fig. 2 be the present invention's long-acting slow-release microsphere of containing bevacizumab embodiment 15 amplify 000 stereoscan photograph;
Fig. 3 is the particle size distribution picture of the embodiment 5 of the present invention's long-acting slow-release microsphere of containing bevacizumab;
Fig. 4 is that the present invention contains bevacizumab sustained-release micro-spheres embodiment 1 ~ 5 Chinese medicine albumen stripping rear electrophoresis testing result figure;
Fig. 5 is that the present invention contains tablets in vitro curve chart in bevacizumab sustained-release micro-spheres embodiment 1 ~ 5;
Fig. 6 is the egg case structural representation that the present invention contains the long-acting slow-release microsphere of bevacizumab.
The specific embodiment
The structure of the long-acting slow-release microsphere that contains bevacizumab that the present invention makes as shown in Figure 1, wherein, a is pharmaceutical protein, b is the egg case structure of calcium alginate, c is PLGA, Fig. 6 is the egg case structure of the calcium alginate of the long-acting slow-release microsphere that contains bevacizumab of the present invention.
Embodiment 1
Contain the preparation method of the long-acting slow-release microsphere of bevacizumab, comprise the following steps:
(1) configuration concentration is the bevacizumab solution of 200mg/ml;
(2) get the bevacizumab solution that makes in step (1), add sodium alginate, being mixed with sodium alginate concentration is the bevacizumab solution of 15mg/ml, as interior water; Compound concentration is the dichloromethane solution of the PLGA of 150mg/ml, and as oil phase, wherein, the polymerization ratio of PLGA is 75/25,3W; Preparation contains the polyvinyl alcohol water solution of 1000mg/ml calcium ion, and the percentage composition of polyvinyl alcohol is 0.25%, as outer water;
(3) preparation of W/O/W multi-emulsion method sustained-release micro-spheres
At first will be distributed to as the sodium alginate soln of interior water in the organic solvent solution as the degradable biological medical macromolecular material of oil phase, the volume ratio of interior water and oil phase is 1:3, and rate of dispersion is 100000rpm, forms colostrum;
Colostrum is distributed to as outer water, and the volume ratio of the cumulative volume of interior water and oil phase and outer water volume is 1:20, polyvinyl alcohol water solution in, rate of dispersion is, 50000rpm forms emulsion;
With emulsion reduction vaporization 3h under 4 ℃, 0.0020MPa, reduction vaporization 1 hour under 35 ℃, 1.0MPa then;
(4) emulsion is carried out centrifugal, the washing, at lyophilization 36h, obtain containing the long-acting slow-release microsphere of bevacizumab.
The long-acting slow-release microsphere that contains bevacizumab that embodiment 1 is prepared carries out electron microscope experiment, obtains experiment Electronic Speculum figure, and as shown in Figure 2, balling-up is more smooth without adhesion, and particle diameter is at 10 μ m.It is phosphate buffer that the bevacizumab sustained-release micro-spheres is added pH=7.4, after one day, adopts SDS-PAGE electrophoretic determination protein relative molecular mass, result compares with the bevacizumab injection as shown in Figure 3, sees Fig. 4, band is identical, because stripping quantity is different, so the intensity of band is not high.The external release conditions of bevacizumab sustained-release micro-spheres as shown in Figure 4, be about 10 days the release time of embodiment 1 gained sample.
Embodiment 2
Contain the preparation method of the long-acting slow-release microsphere of bevacizumab, comprise the following steps:
(1) obtain the bevacizumab solution that concentration is 50mg/ml with commercially available bevacizumab injection is concentrated;
(2) get the bevacizumab solution that makes in step (1), add sodium alginate, being mixed with sodium alginate concentration is the bevacizumab solution of 10mg/ml, as interior water; Compound concentration is the dichloromethane solution of the PLGA of 300mg/ml, and as oil phase, wherein, the polymerization ratio of PLGA is 50/50,10W;
Preparation contains the polyvinyl alcohol water solution of 1000mg/ml calcium ion, and the percentage composition of polyvinyl alcohol is 2%, as outer water;
(3) preparation of W/O/W multi-emulsion method sustained-release micro-spheres
At first will be distributed to as the sodium alginate soln of interior water in the organic solvent solution as the degradable biological medical macromolecular material of oil phase, the volume ratio of interior water and oil phase is 1:20, and rate of dispersion is 8000rpm, forms colostrum;
Colostrum is distributed in polyvinyl alcohol water solution as outer water, and the cumulative volume of interior water and oil phase and the volume ratio of outer water are 1:3, and rate of dispersion is 8000rpm, form emulsion, form emulsion;
Emulsion is put into Rotary Evaporators, reduction vaporization 3h under 4 ℃, 0.053MPa, then reduction vaporization 1 hour under 35 ℃, 0.0620MPa;
(4) emulsion is carried out centrifugal, washing, vacuum drying 72h at normal temperatures, obtain containing the long-acting slow-release microsphere of bevacizumab.
Embodiment 3
Contain the preparation method of the long-acting slow-release microsphere of bevacizumab, comprise the following steps:
(1) obtain the bevacizumab solution that concentration is 500mg/ml with commercially available bevacizumab injection is concentrated;
(2) get the bevacizumab solution that makes in step (1), add sodium alginate, being mixed with sodium alginate concentration is the bevacizumab solution of 5mg/ml, as interior water; Compound concentration is the dichloromethane solution of the PLGA of 10mg/ml, as oil phase,
Preparation contains the polyvinyl alcohol water solution of 1000mg/ml calcium ion, and the percentage composition of polyvinyl alcohol is 15%, as outer water;
(3) preparation of W/O/W multi-emulsion method sustained-release micro-spheres
At first will be distributed to as the sodium alginate soln of interior water in the organic solvent solution as the degradable biological medical macromolecular material of oil phase, the volume ratio of interior water and oil phase is 1:10, and rate of dispersion is 30000rpm, forms colostrum;
Colostrum is distributed in polyvinyl alcohol water solution as outer water, and the cumulative volume of interior water and oil phase and the volume ratio of outer water are 1:5, and rate of dispersion is 14500rpm, form emulsion, form emulsion;
Emulsion is put into Rotary Evaporators, reduction vaporization 3h under 0 ℃, 1.0025MPa, then reduction vaporization 1 hour under 40 ℃, 0.0245MPa;
(4) emulsion is carried out centrifugal, the washing, at lyophilization 36h, obtain containing the long-acting slow-release microsphere of bevacizumab.
It is phosphate buffer that the bevacizumab sustained-release micro-spheres is added PBS, after one day, adopts SDS-PAGE electrophoretic determination protein relative molecular mass, result compares with the bevacizumab injection as shown in Figure 4, and band is identical, because stripping quantity is different, so the intensity of band is not high.Be that 70 days Cumulative release amounts are 75.04 ± 8.63% the release time of embodiment 3 gained samples, as shown in Figure 5.
Embodiment 4
Contain the preparation method of the long-acting slow-release microsphere of bevacizumab, comprise the following steps:
(1) obtain the bevacizumab solution that concentration is 1000mg/ml with commercially available bevacizumab injection is concentrated;
(2) get the bevacizumab solution that makes in step (1), add sodium alginate, being mixed with sodium alginate concentration is the bevacizumab solution of 2.5mg/ml, as interior water; Compound concentration is the dichloromethane solution of the polylactide of 300mg/ml, as oil phase,
Preparation contains the polyvinyl alcohol water solution of 5mg/ml calcium ion, and the percentage composition of polyvinyl alcohol is 2%, as outer water;
(3) preparation of W/O/W multi-emulsion method sustained-release micro-spheres
At first will be distributed to as the sodium alginate soln of interior water in the organic solvent solution as the degradable biological medical macromolecular material of oil phase, the volume ratio of interior water and oil phase is 1:3, and rate of dispersion is 20500rpm, forms colostrum;
Colostrum is distributed to as outer aqueous phase, and the cumulative volume of interior water and oil phase and the volume ratio of outer water are that the 1:3 rate of dispersion is 9500rpm, form emulsion;
With emulsion reduction vaporization 3h under 4 ℃, 0.7834MPa, reduction vaporization 1 hour under 35 ℃, 0.4512MPa then;
(4) emulsion is carried out centrifugal, the washing, at lyophilization 36h, obtain containing the long-acting slow-release microsphere of bevacizumab.
The bevacizumab sustained-release micro-spheres is added PBS, after one day, adopt SDS-PAGE electrophoretic determination protein relative molecular mass, compare with the bevacizumab injection, band is identical, because stripping quantity is different, so the intensity of band is not high.The external release conditions of bevacizumab sustained-release micro-spheres.
Embodiment 5
Contain the preparation method of the long-acting slow-release microsphere of bevacizumab, comprise the following steps:
(1) obtain the bevacizumab solution that concentration is 25mg/ml with commercially available bevacizumab injection is concentrated;
(2) get the bevacizumab solution that makes in step (1), as interior water, be mixed with the polyvinyl alcohol water solution that concentration is 500mg/ml, as interior water; Compound concentration is the dichloromethane solution of the PLGA of 500mg/ml, and as oil phase, wherein, the polymerization ratio of PLGA is 50/50,7.5W;
Preparation contains the polyvinyl alcohol water solution of 1000mg/ml calcium ion, and the percentage composition of polyvinyl alcohol is 10%, as outer water;
(3) preparation of W/O/W multi-emulsion method sustained-release micro-spheres
At first will be distributed to as the polyvinyl alcohol water solution of interior water in the organic solvent solution as the degradable biological medical macromolecular material of oil phase, the volume ratio of interior water and oil phase is 1:3, and rate of dispersion is 30000rpm, forms colostrum;
Colostrum is distributed in polyvinyl alcohol water solution as outer water, and the cumulative volume of interior water and oil phase and the volume ratio of outer water are 1:3, and rate of dispersion is 14500rpm, form emulsion;
With emulsion reduction vaporization 3h under 4 ℃, 0.1354MPa, reduction vaporization 1 hour under 35 ℃, 0.3412MPa then;
(4) emulsion is carried out centrifugal, the washing, at normal temperature drying 72h, obtain containing the long-acting slow-release microsphere of bevacizumab.
The bevacizumab sustained-release micro-spheres is added PBS, after one day, adopt SDS-PAGE electrophoretic determination protein relative molecular mass, compare with the bevacizumab injection, band is identical, because stripping quantity is different, so the intensity of band is not high.The release time of embodiment 3 gained samples is the shortest, is about 7 days, sees Fig. 5.
Claims (8)
1. preparation method that contains the long-acting slow-release microsphere of bevacizumab is characterized in that comprising the following steps:
(1) compound concentration is the bevacizumab solution of 25-2500mg/ml;
(2) get the bevacizumab solution that makes in step (1), add sodium alginate, being mixed with sodium alginate concentration is the bevacizumab solution of 0-15mg/ml, as interior water; Compound concentration is the organic solvent solution of the degradable biological medical macromolecular material of 10-500mg/ml, as oil phase; Preparation contains the emulsifier aqueous solution of 1-1000mg/ml calcium ion, and the percentage composition of emulsifying agent is 0.25-15%, as outer water;
(3) preparation of W/O/W multi-emulsion method sustained-release micro-spheres
At first will be distributed to as the sodium alginate soln of interior water in the organic solvent solution as the degradable biological medical macromolecular material of oil phase, the volume ratio of interior water and oil phase is 1:3 ~ 1:20, and rate of dispersion is 8000-100000rpm, forms colostrum;
Colostrum is distributed in emulsifier aqueous solution as outer water, and wherein adding proportion is that 1:3 ~ 1:20 carries out according to the volume ratio of interior water and emulsifying agent oil phase, and rate of dispersion is 8000-50000rpm, forms emulsion;
With emulsion at 0-10 ℃ of lower reduction vaporization 1-4h, then at 30-40 ℃ of lower reduction vaporization 1-4 hour;
(4) emulsion is carried out centrifugal sucking filtration drying, obtain containing the long-acting slow-release microsphere of bevacizumab.
2. the preparation method that contains the long-acting slow-release microsphere of bevacizumab according to claim 1 is characterized in that: described degradable biological medical macromolecular material is one or more in polylactide, PGA, polylactide-co-glycolide, polycaprolactone, poly-river rising in Ningxia and flowing into central Shaanxi butanoic acid, poly-river rising in Ningxia and flowing into central Shaanxi valeric acid, cluster acid, poly-anhydride.
3. the preparation method that contains the long-acting slow-release microsphere of bevacizumab according to claim 2, it is characterized in that: described degradable biological medical macromolecular material is polylactide-co-glycolide, in described polylactide-co-glycolide, the polymerization ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25 or 50/50, and the molecular weight of described polylactide-co-glycolide is 30000-100000 dalton.
4. the preparation method that contains the long-acting slow-release microsphere of bevacizumab according to claim 1, it is characterized in that: described organic solvent is one or more in dichloromethane, ethyl acetate or acetonitrile.
5. the preparation method that contains the long-acting slow-release microsphere of bevacizumab according to claim 1, it is characterized in that: the concentration of the degradable biological medical macromolecular material in the organic solvent solution of described degradable biological medical macromolecular material is 10-300mg/ml.
6. the preparation method that contains the long-acting slow-release microsphere of bevacizumab according to claim 1, it is characterized in that: described emulsifying agent is one or more in polyvinyl alcohol, polyvinylpyrrolidone, poloxamer.
7. according to claim 1 or 6 described preparation methoies that contain the long-acting slow-release microsphere of bevacizumab, it is characterized in that: the emulsifier concentration in described emulsifier aqueous solution is 0.25-10%.
8. the preparation method that contains the long-acting slow-release microsphere of bevacizumab according to claim 1, it is characterized in that: organic solvent is removed in reduce pressure under 0.0013MPa ~ 1.01325MPa, 0-4 ℃ 1-4h evaporation of the emulsion in described step (3), then decompression 1-4h removes organic solvent under 0.0013MPa ~ 1.01325MPa, 30-37 ℃.
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| CN104117056A (en) * | 2013-04-28 | 2014-10-29 | 上海现代药物制剂工程研究中心有限公司 | Placental growth factor loaded nano-particle, as well as preparation method and application thereof |
| CN106924184A (en) * | 2017-03-29 | 2017-07-07 | 烟台大学 | A kind of eye intravitreal injection multivesicular liposome and preparation method thereof |
| CN111249255A (en) * | 2020-03-04 | 2020-06-09 | 烟台大学 | Novel microsphere composite preparation for carrying drug by temperature-sensitive hydrogel and preparation method thereof |
| CN115252799A (en) * | 2022-07-27 | 2022-11-01 | 中国药科大学 | Ultrahigh drug-loading compound prepared based on phase transfer inhibition principle and method thereof |
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| CN103405766B (en) * | 2013-08-06 | 2016-01-06 | 温州医学院眼视光研究院 | A kind of bevacizumab eye drop and preparation method thereof |
| CN106924184A (en) * | 2017-03-29 | 2017-07-07 | 烟台大学 | A kind of eye intravitreal injection multivesicular liposome and preparation method thereof |
| CN106924184B (en) * | 2017-03-29 | 2020-07-17 | 烟台大学 | Multivesicular liposome for ocular vitreous injection and preparation method thereof |
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