CN114099448A - Preparation method of uniform polymer microspheres - Google Patents
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- CN114099448A CN114099448A CN202111492047.0A CN202111492047A CN114099448A CN 114099448 A CN114099448 A CN 114099448A CN 202111492047 A CN202111492047 A CN 202111492047A CN 114099448 A CN114099448 A CN 114099448A
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- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention relates to a preparation method of uniform polymer microspheres, belongs to the technical field of medicines, and can effectively solve the problem of nonuniform preparation of the polymer microspheres. Firstly, dissolving a polymer in an organic solvent, then dropwise adding the polymer into an external water phase under mechanical stirring to obtain a primary emulsion, then quickly carrying out secondary emulsification on the primary emulsion at a high rotating speed by adopting a high-speed homogenizer to obtain a final emulsion, stirring the final emulsion at a lower speed to volatilize the organic solvent so as to solidify the final emulsion, washing the final emulsion with deionized water, and carrying out freeze drying to obtain the polymer microsphere. The microspheres prepared by the method have uniform particle size distribution, and provide possibility for the subsequent preparation of a uniform targeted drug sustained-release delivery system.
Description
Technical Field
The invention relates to a preparation method of uniform polymer microspheres, belonging to the technical field of biological medicines.
Background
The incidence of cancer worldwide has increased dramatically each year due to increasing environmental pollution, chaotic life rhythm, and aging population. The current means for treating cancer mainly comprise surgical treatment, radiotherapy, chemotherapy and the like. However, these treatments all have serious toxic and side effects, so that how to treat cancer with high efficiency, simplicity and no toxic and side effects is a hot spot of research of various researchers. In recent years, drug sustained-release delivery systems have been rapidly developed, and particularly, a great deal of research and study has been conducted in the pharmaceutical and material science aspects, and drug carriers with different sizes, structures and various surface properties have been designed, including liposomes, microspheres, polymer particles, micelles, and inorganic micro-nano particles composed of iron oxide, quantum dots, gold or metal oxide frameworks, and the like.
The carrier material of the drug delivery system has a plurality of sources and is rich in selection, in order to achieve an excellent anti-tumor effect, the carrier material has good biocompatibility and hydrophilicity, degradation products are non-toxic and harmless, the carrier material can be discharged out of a body along with metabolism of a human body, the carrier material has good loading capacity and good slow release performance, so that the drug can be slowly released at a tumor part for a long time, the stability is maintained, and the drug concentration at a target area is improved. Therefore, the selection of the desired support material is of crucial importance.
Polylactic acid (PLA) is a straight-chain aliphatic polyester prepared by fermenting corn, which is a fast-growing resource, serving as a main raw material, preparing lactic acid, and condensing the lactic acid, is a biodegradable material which is approved by the Food and Drug Administration (FDA) of the first batch, is officially included in the United states pharmacopoeia as a pharmaceutical adjuvant, and is widely applied to the fields of surgical sutures, bone fixators, drug sustained-release systems, tissue engineering scaffolds and the like. Polycaprolactone (PCL) is a degradable synthetic polymer material formed by ring-opening polymerization of epsilon-caprolactone under the catalysis of a metal anion complex catalyst. It is insoluble in water, but soluble in a variety of organic solvents; can be completely degraded into carbon dioxide and water in natural environment, the degradation product can be absorbed by organism or discharged out of body, and the good biocompatibility makes it be widely used in controlled release of medicine. And it has cell compatibility with some tissues of the human body, so it is also an ideal material for tissue engineering. Polylactic-co-glycolic acid (PLGA) is a lactic-co-glycolic acid polymer, and PLGAs obtained by polymerizing lactic acid and glycolic acid in different proportions have different properties. The polymer has no toxicity, good encapsulation and film forming property, no irritation and good biocompatibility, and can be used as a slow release carrier for various medicines.
The preparation method of the polymer microsphere is various, and the most basic method is an embedding method, namely, the polymer is dissolved in an organic phase, the organic phase is dripped into a water phase, and redundant substances are removed by means of continuous stirring, solvent evaporation, precipitation, atomization and the like, so that the polymer microsphere is obtained. Although the method has simple synthesis process, the microsphere prepared by the method has wider particle size distribution.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of uniform polymer microspheres, the preparation method of the microspheres comprises the steps of firstly dissolving a polymer in an organic solvent, then dropwise adding the polymer into an external water phase under mechanical stirring, then carrying out secondary emulsification by adopting a high-speed homogenizer at a high rotating speed, and finally stirring at a lower speed to volatilize the organic solvent for solidification, wherein the polymer microspheres prepared by the method have uniform particle size distribution.
The invention provides a preparation method of uniform polymer microspheres, which comprises the following steps:
step one, preparing an external water phase, namely weighing a certain amount of surfactant, and adding the surfactant into Phosphate Buffer Solution (PBS) with pH7.2-7.4 to prepare external water phase solution;
step two, preparation of an oil phase, namely weighing a certain amount of polymer, adding the polymer into an organic solvent, and carrying out ultrasonic oscillation for 5min to fully dissolve the polymer;
and step three, preparation of polymer microspheres, namely dripping the inner oil phase into the outer water phase, stirring for a period of time at the speed of less than 1000rpm to obtain a primary emulsion, then quickly carrying out secondary emulsification on the primary emulsion at a high rotating speed by adopting a high-speed homogenizer to obtain a final emulsion, stirring the final emulsion at a lower speed to volatilize an organic solvent so as to solidify the final emulsion, washing for 5 times by using deionized water, and freeze-drying to obtain the polymer microspheres.
Wherein the surfactant in the external water phase in the first step is 1 or 2 of polyvinyl alcohol (PVA), Sodium Dodecyl Sulfate (SDS) and polysorbate (Tween), preferably polyvinyl alcohol, and the mass percentage concentration of the surfactant is 0.5-5%; the organic solvent in the second step is dichloromethane containing a small amount of polar solvent, ethyl acetate, or a mixed solvent of dichloromethane and ethyl acetate, the polar solvent is 1 of methanol, ethanol, and dimethyl sulfoxide (DMSO), and the content of the polar solvent is less than 10%; in the third step, the proportion of the oil phase and the water phase is controlled to be 1: 5-1: 50, the high-speed homogenizing speed is controlled to be 1500-20000 rpm, and the polymer is 1 or 2 of polylactic acid, polycaprolactone and polylactic acid-glycolic acid copolymer.
The method is simple and feasible, is easy to operate, and the prepared polymer microspheres have uniform particle size distribution. The prepared microsphere can be used for embedding and controlled release of medicines, and can also be used for preparing magnetic polymer microspheres by encapsulating magnetic nanoparticles and magnetically driving micro robots.
Drawings
FIG. 1: scanning electron microscope images of the polylactic acid-glycolic acid microspheres.
FIG. 2: microscopic picture of polycaprolactone microspheres.
FIG. 3: microscopic image of polylactic acid microspheres.
FIG. 4: the particle size distribution diagram of the polylactic acid-glycolic acid microspheres.
FIG. 5: the cumulative particle size distribution diagram of the polylactic acid-glycolic acid microspheres.
Detailed Description
The following examples are given to illustrate the invention without limiting it, the scope of which is defined by the claims.
Example 1: preparation of PLGA microspheres
Preparation of external water phase: weighing a certain amount of PVA powder, adding the PVA powder into PBS (pH7.2-7.4) for swelling overnight, fully stirring and dissolving under the condition of heating in a water bath at 60 ℃ to prepare 1% PVA solution, and cooling for later use.
Preparation of an internal oil phase: weighing 200mg PLGA solid, adding into 2mL dichloromethane containing 0.1mL methanol, and oscillating in an ultrasonic instrument for 5min to fully dissolve to obtain PLGA-CH2Cl2And (3) solution.
Preparation of PLGA microspheres: and (3) dropwise adding the internal oil phase into 20mL 1% PVA stirred at 150rpm to obtain a primary emulsion, then quickly taking out, putting the primary emulsion in a high-speed homogenizer, emulsifying for 3min at 12000rpm to obtain a final emulsion, finally stirring at low speed at 600rpm, volatilizing an organic solvent to solidify the microspheres, washing for 5 times by using deionized water, and freeze-drying and storing.
Example 2: preparation of PLGA microspheres
Preparation of external water phase: weighing a certain amount of PVA powder, adding the PVA powder into PBS (pH7.2-7.4) for swelling overnight, fully stirring and dissolving the PVA powder under the condition of heating in a water bath at 60 ℃ to prepare 0.5% PVA solution, and cooling for later use.
Preparation of oil phase: weighing 200mg PLGA solid, adding into 2mL dichloromethane containing 0.1mL methanol, and oscillating in an ultrasonic instrument for 5min to fully dissolve to obtain PLGA-CH2Cl2And (3) solution.
Preparation of PLGA microspheres: and (3) dropwise adding the internal oil phase into 20mL 1% PVA stirred at 150rpm to obtain a primary emulsion, then quickly taking out, putting the primary emulsion in a high-speed homogenizer, emulsifying for 3min at 12000rpm to obtain a final emulsion, finally stirring at low speed at 600rpm, volatilizing an organic solvent to solidify the microspheres, washing for 5 times by using deionized water, and freeze-drying and storing.
Example 3: preparation of PLGA microspheres
Preparation of external water phase: weighing a certain amount of PVA powder, adding the PVA powder into PBS (pH7.2-7.4) for swelling overnight, fully stirring and dissolving under the condition of heating in a water bath at 60 ℃ to prepare 1% PVA solution, and cooling for later use.
Preparation of oil phase: weighing 200mg PLGA solid, adding into 2mL dichloromethane containing 0.1mL methanol, and oscillating in an ultrasonic instrument for 5min to fully dissolve to obtain PLGA-CH2Cl2And (3) solution.
Preparation of PLGA microspheres: and (3) dropwise adding the internal oil phase into 10mL of 1% PVA under stirring at 150rpm to obtain a primary emulsion, then quickly taking out, putting the primary emulsion in a high-speed homogenizer, emulsifying for 3min at 12000rpm to obtain a final emulsion, finally stirring at low speed at 600rpm, volatilizing an organic solvent to solidify the microspheres, washing for 5 times by using deionized water, and freeze-drying and storing.
Example 4: preparation of PLGA microspheres
Preparation of external water phase: weighing a certain amount of PVA powder, adding the PVA powder into PBS (pH7.2-7.4) for swelling overnight, fully stirring and dissolving under the condition of heating in a water bath at 60 ℃ to prepare 1% PVA solution, and cooling for later use.
Preparation of oil phase: weighing 200mg PLGA solid, adding into 2mL dichloromethane containing 0.1mL methanol, and oscillating in ultrasonic instrumentDissolving for 5min to obtain PLGA-CH2Cl2And (3) solution.
Preparation of PLGA microspheres: and (3) dropwise adding the internal oil phase into 20mL 1% PVA stirred at 150rpm to obtain a primary emulsion, then quickly taking out, putting the primary emulsion in a high-speed homogenizer, emulsifying for 3min at 15000rpm to obtain a final emulsion, finally stirring at a low speed at 600rpm, volatilizing an organic solvent to solidify the microspheres, washing for 5 times by using deionized water, and freeze-drying and storing.
Example 5: preparation of PCL microspheres
Preparation of external water phase: weighing a certain amount of PVA powder, adding the PVA powder into PBS (pH7.2-7.4) for swelling overnight, fully stirring and dissolving under the condition of heating in a water bath at 60 ℃ to prepare 1% PVA solution, and cooling for later use.
Preparation of oil phase: weighing 200mg PCL solid, adding into 2mL dichloromethane containing 0.1mL methanol, and shaking in ultrasonic instrument for 5min to dissolve completely to obtain PCL-CH2Cl2And (3) solution.
Preparing PCL microspheres: and (3) dropwise adding the internal oil phase into 20mL 1% PVA stirred at 150rpm to obtain a primary emulsion, then quickly taking out, putting the primary emulsion in a high-speed homogenizer, emulsifying for 3min at 12000rpm to obtain a final emulsion, finally stirring at low speed at 600rpm, volatilizing an organic solvent to solidify the microspheres, washing for 5 times by using deionized water, and freeze-drying and storing.
Example 6: preparation of PLA microspheres
Preparation of external water phase: weighing a certain amount of PVA powder, adding the PVA powder into PBS (pH7.2-7.4) for swelling overnight, fully stirring and dissolving under the condition of heating in a water bath at 60 ℃ to prepare 1% PVA solution, and cooling for later use.
Preparation of oil phase: weighing 200mg of PLA solid, adding the PLA solid into 2mL of dichloromethane containing 0.1mL of methanol, and oscillating the mixture in an ultrasonic instrument for 5min to fully dissolve the PLA solid to obtain PLA-CH2Cl2And (3) solution.
Preparing PLA microspheres: and (3) dropwise adding the internal oil phase into 20mL of 1% PVA stirred at 150rpm to obtain a primary emulsion, then quickly taking out, putting the primary emulsion in a high-speed homogenizer, emulsifying for 3min at 12000rpm to obtain a final emulsion, finally stirring at a low speed at 600rpm, volatilizing an organic solvent to solidify the microspheres, washing with deionized water for 5 times, and freeze-drying and storing.
Claims (7)
1. A method for preparing uniform polymer microspheres comprises the following steps:
(1) preparing an external water phase, namely weighing a certain amount of surfactant, and adding the surfactant into Phosphate Buffer Solution (PBS) with the pH value of 7.2-7.4 to prepare an external water phase solution;
(2) preparing an internal oil phase, weighing a certain amount of polymer, adding the polymer into an organic solvent, and carrying out ultrasonic oscillation for 5min to fully dissolve the polymer;
(3) and (2) preparing polymer microspheres, namely dripping the inner oil phase into the outer water phase, stirring for a period of time at the rotating speed of less than 1000rpm to obtain a primary emulsion, then quickly carrying out secondary emulsification on the primary emulsion at a high rotating speed by adopting a high-speed homogenizer to obtain a final emulsion, stirring the final emulsion at a lower speed to volatilize an organic solvent so as to solidify the final emulsion, washing for 5 times by using deionized water, and freeze-drying to obtain the polymer microspheres.
2. The method for preparing uniform polymer microspheres according to claim 1, wherein the surfactant in the external water phase is 1 or 2 of polyvinyl alcohol (PVA), Sodium Dodecyl Sulfate (SDS) and polysorbate (Tween), preferably polyvinyl alcohol, and the concentration of the surfactant in percentage by mass is 0.5-5%.
3. The method of claim 1, wherein the ratio of the inner oil phase to the outer water phase is 1:5 to 1: 50.
4. The method of claim 1, wherein the polymer is a mixture of 1 or 2 selected from polylactic acid, polycaprolactone, and polylactic-co-glycolic acid.
5. The method of claim 1, wherein the organic solvent is dichloromethane, ethyl acetate, or a mixture of dichloromethane and ethyl acetate.
6. A method for preparing uniform polymeric microspheres according to claims 1 and 5, wherein the organic solvent is dichloromethane containing a small amount of polar solvent, the polar solvent is one of methanol, ethanol, and dimethyl sulfoxide (DMSO), and the content of polar solvent is less than 10%.
7. The method of claim 1, wherein the high-speed homogenizing speed is 1500-20000 rpm.
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CN115969796A (en) * | 2022-12-06 | 2023-04-18 | 苏州大学 | JAK inhibitor long-acting microsphere and preparation method and application thereof |
Citations (4)
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CN101108168A (en) * | 2007-08-03 | 2008-01-23 | 西安力邦医药科技有限责任公司 | Method of manufacturing fulvestrant sustained-release microspheres |
CN102302457A (en) * | 2011-09-14 | 2012-01-04 | 中国科学院近代物理研究所 | Preparation method of ivermectin sustained-release microspheres |
CN103980506A (en) * | 2014-04-02 | 2014-08-13 | 大连大学 | Polylactic acid-polyethylene glycol block copolymer-based magnetic microsphere preparation method |
CN110051652A (en) * | 2019-05-30 | 2019-07-26 | 武汉理工大学 | PLGA/FK506 medicament-carrying nano-microsphere and its preparation method and application |
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CN101108168A (en) * | 2007-08-03 | 2008-01-23 | 西安力邦医药科技有限责任公司 | Method of manufacturing fulvestrant sustained-release microspheres |
CN102302457A (en) * | 2011-09-14 | 2012-01-04 | 中国科学院近代物理研究所 | Preparation method of ivermectin sustained-release microspheres |
CN103980506A (en) * | 2014-04-02 | 2014-08-13 | 大连大学 | Polylactic acid-polyethylene glycol block copolymer-based magnetic microsphere preparation method |
CN110051652A (en) * | 2019-05-30 | 2019-07-26 | 武汉理工大学 | PLGA/FK506 medicament-carrying nano-microsphere and its preparation method and application |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115969796A (en) * | 2022-12-06 | 2023-04-18 | 苏州大学 | JAK inhibitor long-acting microsphere and preparation method and application thereof |
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