Method for removing small-particle-size microspheres in polymer microspheres

Abstract

The invention provides a method for removing small-particle-size microspheres in polymeric microspheres. The method comprises the following steps: mixing a polymer and an organic solvent to form an oil phase, and mixing an emulsifier, a compound stabilizer and water to form a water phase; the compound stabilizer comprises a cationic surface active agent and a thickening agent; mixing the oil phase and the water phase, and sequentially emulsifying and curing to obtain polymer microspheres; measuring and evaluating the particle size and particle size distribution of the obtained polymer microspheres; the evaluation comprises the following conditions: if the particle size distribution of the polymer microspheres has no peak at 0.5-3 microns, ending the execution to obtain the polymer microspheres without small-particle-size microspheres; or if the particle size distribution of the polymer microspheres has a peak at 0.5-3 [mu] m, performing post-treatment to obtain the polymer microspheres without small-particle-size microspheres. According to the method disclosed by the invention, the small peak phenomenon of 0.5-3 microns in the particle size distribution of the polymer microspheres can be eliminated, so that the microspheres with more uniform particle sizes are obtained.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer microspheres and relates to a method for removing small-diameter microspheres in polymer microspheres. Background Art

[0002] Microspheres are spherical particles made of polymers, which have the characteristics of small volume but high specific surface area. In recent years, the application of microspheres in the medical field has attracted widespread attention, especially in the fields of diagnosis and pharmaceuticals. The application field of microspheres is very broad and is an important foundation for the development of modern industries. At present, the technical methods for preparing microspheres can be mainly divided into two categories: one is the method of directly emulsifying polymers to form emulsion droplets, and then forming microspheres through curing and cross-linking; the other is the method of directly polymerizing polymer monomers to form polymer microspheres.

[0003] For the quality control of microspheres, particle size and its distribution are crucial indicators. Laser particle size analyzer is a commonly used method for measuring the particle size and distribution of microspheres. It uses a laser beam to pass through the sample and measure the angle and intensity of the scattered light to calculate the average particle size and particle size distribution of the microspheres in the sample. This method has a wide measurement range and high accuracy, and is suitable for accurate testing of the particle size and distribution of microspheres.

[0004] However, after statistics and analysis of a large number of microsphere particle size and distribution test results, it was found that the particle size and distribution diagram of the polymer microspheres prepared by the emulsification method showed that there was always a small peak at 0.5-3 μm (such as Figure 1 As shown in Figure 2), this small peak seriously affects the value of the microsphere particle size, resulting in low values ​​of D10, D50 and D90; while the particle size and distribution diagram of the microspheres directly formed by monomer polymerization show that its particle size distribution has only a main peak and no small peak phenomenon (as shown in Figure 2). Figure 2 shown).

[0005] By comparing the particle size and distribution test results of the two methods, it can be found that the small peak of the polymer microspheres obtained by emulsification at 0.5-3μm should be related to the small particle size microspheres of 0.5-3μm existing in the emulsified microsphere system. After the emulsified microspheres were sieved and tested again, it was found that the small peak still existed (the particle size distribution diagrams before and after sieving are shown in Figure 2). Figure 3-4 As shown). It can be concluded that there is an attachment relationship between the small-size microspheres of 0.5 to 3 μm and the target polymer microspheres. The small-size microspheres cannot be removed by ordinary screening. The SEM image of the microspheres (as shown Figure 5 This can also be confirmed by ).

[0006] CN118126358A discloses a poly-L-lactic acid microsphere and a preparation method thereof, and a preparation method of a poly-L-lactic acid filler. The uniformity of the distribution of the obtained poly-L-lactic acid microspheres is improved by means of specific preparation steps and the coordination and joint action of specific parameters between the steps. However, according to the detection results of the particle size distribution, the problem of the small peak of 0.5 to 3 μm has not been solved, and the particle size distribution of the microspheres is relatively wide, which is not conducive to practical application.

[0007] CN116102748A discloses a polycaprolactone polyethylene glycol copolymer microsphere, a preparation method and an application thereof, wherein the copolymer microsphere is prepared by a conventional emulsification-solidification process, and then filtered, washed with water and ethanol for 1-5 times, and dried under reduced pressure or vacuum to obtain the polycaprolactone copolymer microsphere. The particle size distribution diagram of the polymer microsphere shows that the small peak at 1 μm cannot be removed in the microsphere obtained under the conventional process.

[0008] Therefore, there is an urgent need to provide a method for removing small-particle microspheres of 0.5 to 3 μm from polymer microspheres obtained by an emulsification process that is simple to operate, efficient, and highly universal. Summary of the invention

[0009] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for removing small-sized microspheres in polymer microspheres, which can not only completely eliminate small-sized microspheres with a particle size distribution of 0.5 to 3 μm in the polymer microspheres, but also effectively avoid the mutual aggregation and merging of microspheres, thereby achieving the effect of uniform particle size distribution of microspheres.

[0010] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0011] The present invention provides a method for removing small-size microspheres in polymer microspheres, the method comprising the following steps:

[0012] (1) mixing a polymer and an organic solvent to form an oil phase, and mixing an emulsifier, a composite stabilizer and water to form a water phase;

[0013] The composite stabilizer includes a cationic surfactant and a thickener;

[0014] (2) mixing the oil phase and the water phase obtained in step (1), and sequentially emulsifying and solidifying to obtain polymer microspheres;

[0015] (3) measuring and evaluating the particle size and particle size distribution of the polymer microspheres obtained in step (2);

[0016] The evaluation includes the following:

[0017] If the particle size distribution of the polymer microspheres has no peak at 0.5 to 3 μm, the execution is terminated to obtain polymer microspheres with small particle size microspheres removed; or

[0018] If the particle size distribution of the polymer microspheres has a peak at 0.5 to 3 μm, post-treatment is performed to obtain polymer microspheres from which small-size microspheres are removed.

[0019] In the present invention, the small-size microspheres are microspheres with a particle size distribution of 0.5 to 3 μm. The method of mixing the emulsifier, the composite stabilizer and water is: first mix the emulsifier and water, and then add the composite stabilizer thereto. In the method provided by the present invention, during the emulsification and spherification process, by adding a composite stabilizer to the aqueous phase system, and then emulsifying and solidifying to form polymer microspheres, not only can the small-size microspheres with a particle size distribution of 0.5 to 3 μm in the polymer microspheres be eliminated, but also the mutual aggregation and merging of the target microspheres can be effectively avoided, thereby achieving the effect of uniform particle size distribution of the microspheres. In addition, if the small-size microspheres at 0.5 to 3 μm cannot be removed by improving the emulsification process, the small-size microspheres can be removed by post-processing methods.

[0020] It is worth noting that in the process of emulsification of microspheres, when the oil phase enters the water phase and is emulsified to form O / W type emulsion droplets, the O / W type emulsion droplets are gradually transformed from liquid to solid microspheres after solidification. However, in this process, some droplets with extremely small particle sizes are very easy to adhere to the vicinity of large O / W type emulsion droplets. After the droplets are solidified to form microspheres, this attachment phenomenon will form small particle size microspheres of 0.5 to 3 μm attached to the target microspheres, and eventually a small peak will be shown at 0.5 to 3 μm on the particle size and distribution diagram of the microspheres. Therefore, in order to eliminate the adhesion phenomenon of a small amount of emulsion droplets, the inventor uses a compound stabilizer formed by compounding a cationic surfactant and a thickener. The composite stabilizer molecules will be adsorbed on the surface of the emulsion droplets to form a stable film, thereby effectively preventing the aggregation and adsorption between the emulsion droplets, thereby achieving the purpose of removing small particle size microspheres.

[0021] As a preferred technical solution of the present invention, the polymer in step (1) includes any one of polylactic acid, polycaprolactone, polymethyl methacrylate or polyhydroxyalkanoate, or a combination of at least two thereof.

[0022] In the present invention, the molecular weight of the polymer used is not specifically limited. Those skilled in the art can appropriately select from commonly used polymers. For example, the molecular weight of the polymer can be 2000-200000Da, can be 10000Da, 20000Da, 30000Da, 40000Da, 50000Da, 80000Da, 100000Da, 120000Da, 15000Da or 180000Da, etc.

[0023] Preferably, the organic solvent in step (1) comprises any one of dichloromethane, chloroform, ethyl acetate or ethyl formate, or a combination of at least two thereof.

[0024] Preferably, the mass concentration of the polymer in the oil phase in step (1) is 5% to 20%, for example, it can be 6%, 7%, 8%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% or 19%, etc.

[0025] As a preferred technical solution of the present invention, the emulsifier in step (1) includes polyvinyl alcohol (PVA).

[0026] Preferably, the mass concentration of the emulsifier in the aqueous phase in step (1) is 1% to 2%, for example, it can be 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8% or 1.9%, etc.

[0027] As a preferred technical solution of the present invention, the cationic surfactant in step (1) includes cetyltrimethylammonium bromide (CTAB) and / or cetyltrimethylammonium chloride (CTAC).

[0028] Preferably, the thickener in step (1) comprises gelatin and / or hydroxypropyl methylcellulose (HPMC).

[0029] Preferably, the mass ratio of the cationic surfactant to the thickener in step (1) is 1:(4-9), for example, it can be 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8 or 1:8.5, etc.

[0030] It is worth noting that by further controlling the mass ratio range of the cationic surfactant and the thickener, on the one hand, the thickener can maintain a certain viscosity of the emulsified system, and the emulsified system with a certain viscosity can prevent the merging of O / W emulsion droplets. On the other hand, by adding a certain proportion of cationic surfactant to the system, the dispersion between O / W emulsion droplets can be made more stable, and merging and adsorption will not occur.

[0031] Preferably, the mass concentration of the composite stabilizer in the aqueous phase in step (1) is 0.8% to 4%, for example, it can be 1%, 1.2%, 1.5%, 1.6%, 1.8%, 2%, 2.2%, 2.5%, 2.6%, 2.8%, 3%, 3.2%, 3.5%, 3.6% or 3.8%, etc.

[0032] As a preferred technical solution of the present invention, the mixing in step (2) is: adding the oil phase into the water phase.

[0033] Preferably, the emulsification method in step (2) includes any one of shearing, membrane emulsification or microfluidics.

[0034] In the present invention, the relevant parameters of the emulsification process are not specifically limited, and those skilled in the art can make specific selections according to actual conditions.

[0035] Preferably, after the emulsification in step (2), O / W type emulsion droplets are obtained.

[0036] Preferably, after the solidification in step (2), washing, centrifugation and drying are performed in sequence.

[0037] In the present invention, the curing process may adopt conventional methods in the prior art, and related parameters thereof are not specifically limited, and those skilled in the art may make specific selections according to actual conditions.

[0038] As a preferred technical solution of the present invention, the measurement in step (3) is performed using a laser particle size analyzer.

[0039] As a preferred technical solution of the present invention, the post-processing in step (3) comprises the following steps:

[0040] (a) freeze-drying the polymer microspheres obtained in step (2) to obtain a first powder;

[0041] (b) mixing the first powder obtained in step (a) with chloride, and performing vibration screening to obtain a second powder;

[0042] (c) washing and solid-liquid separation are performed alternately several times on the second powder obtained in step (b) to obtain polymer microspheres from which small-sized microspheres are removed.

[0043] In the present invention, the surface of the post-treated polymer microspheres inevitably has some depressions after the small particles are peeled off (such as Figure 6 However, it does not affect subsequent applications.

[0044] In the present invention, the polymer microspheres are first freeze-dried to form a microsphere dry powder, and then mixed with chloride particles, and then the mixed powder is placed on a sieve for dry vibration screening, which can effectively remove small-size microspheres present in the polymer microspheres, thereby eliminating small-size microspheres with a particle size distribution of 0.5 to 3 μm in the polymer microspheres.

[0045] It is worth noting that in the process of dry vibration screening, since the chloride particles are irregular micron-sized hard particles, they can form severe friction with the polymer microspheres under strong mechanical vibration. This severe friction can effectively peel off the small particles adhering to the microspheres from the microspheres, and then separate them from the target microspheres through the mesh of the screen, which is equivalent to polishing the polymer microspheres, thereby removing the small particle size microspheres of the polymer microspheres at 0.5 to 3 μm, and the chloride can be removed by multiple water washings. In addition, dry vibration screening can also screen out some microspheres of non-target particle sizes, better control the particle size distribution of polymer microspheres, and thus obtain microspheres with more uniform particle sizes.

[0046] As a preferred technical solution of the present invention, the water content of the first powder obtained in step (a) is less than 1%, for example, it can be 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1%, etc.

[0047] Preferably, the chloride in step (b) comprises sodium chloride and / or potassium chloride.

[0048] Preferably, the average particle size of the chloride in step (b) is 200-500 μm, for example, it can be 220 μm, 250 μm, 280 μm, 300 μm, 320 μm, 350 μm, 380 μm, 400 μm, 420 μm, 450 μm, 460 μm or 480 μm, etc.

[0049] Preferably, in step (b), the mass ratio of the first powder to the chloride is 1:(10-50), for example, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40 or 1:45, etc.

[0050] As a preferred technical solution of the present invention, the frequency of the vibration screening in step (b) is 1000 to 2000 times / min, for example, it can be 1100 times / min, 1200 times / min, 1400 times / min, 1500 times / min, 1600 times / min, 1800 times / min or 1900 times / min, etc.

[0051] In the present invention, by controlling the frequency of vibration screening within the range of 1000 to 2000 times / min, the chloride particles and the microspheres are strongly rubbed under the action of high-frequency vibration. Under the action of such strong friction, some small particles attached to the target microspheres will be peeled off and then screened through the screen under mechanical vibration, thereby achieving separation of small-size microspheres from target microspheres.

[0052] Preferably, the vibration screening time in step (b) is 30 to 60 min, for example, 35 min, 40 min, 45 min, 50 min, 55 min or 58 min.

[0053] In the present invention, the vibration screening time is controlled within the range of 30 to 60 minutes to ensure that all attached target microspheres can be fully rubbed.

[0054] In the present invention, after several washings and solid-liquid separations, the chloride particles and microspheres can be completely separated, and then freeze-dried again to measure the particle size and distribution of the polymer microspheres.

[0055] As a preferred technical solution of the present invention, the method comprises the following steps:

[0056] (1) mixing a polymer and an organic solvent to form an oil phase, and mixing an emulsifier, a composite stabilizer and water to form a water phase;

[0057] The mass concentration of the emulsifier in the water phase is 1% to 2%; the composite stabilizer includes a cationic surfactant and a thickener in a mass ratio of 1:(4 to 9); the cationic surfactant includes hexadecyltrimethylammonium bromide and / or hexadecyltrimethylammonium chloride; the cationic surfactant includes hexadecyltrimethylammonium bromide and / or hexadecyltrimethylammonium chloride; the mass concentration of the composite stabilizer in the water phase is 0.8% to 4%;

[0058] (2) mixing the oil phase and the water phase obtained in step (1), emulsifying to obtain O / W type emulsion droplets, and then sequentially solidifying, washing, centrifuging and drying to obtain polymer microspheres;

[0059] (3) measuring and evaluating the particle size and particle size distribution of the polymer microspheres obtained in step (2);

[0060] The measurement is performed using a laser particle size analyzer;

[0061] The evaluation includes the following:

[0062] If the particle size distribution of the polymer microspheres has no peak at 0.5 to 3 μm, the execution is terminated to obtain polymer microspheres with small particle size microspheres removed; or

[0063] If the particle size distribution of the polymer microspheres has a peak at 0.5 to 3 μm, post-treatment is performed;

[0064] The post-processing comprises the following steps:

[0065] (a) freeze-drying the polymer microspheres obtained in step (2) to obtain a first powder having a water content of less than 1%;

[0066] (b) mixing the first powder obtained in step (a) and the chloride in a mass ratio of 1:(10-50), and vibrating and sieving at a frequency of 1000-2000 times / min for 30-60 min to obtain a second powder;

[0067] The chloride includes sodium chloride and / or potassium chloride; the average particle size of the chloride is 200 to 500 μm;

[0068] (c) washing and solid-liquid separation are performed alternately several times on the second powder obtained in step (b) to obtain polymer microspheres from which small-sized microspheres are removed.

[0069] The numerical range described in the present invention not only includes the point values ​​listed above, but also includes any point values ​​between the above numerical ranges that are not listed. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0070] Compared with the prior art, the present invention has the following beneficial effects:

[0071] (1) The method provided by the present invention, in the process of emulsification and spheronization, by adding a composite stabilizer of a specific component into the aqueous phase system, and then emulsifying and curing to form polymer microspheres, can not only eliminate the small peak phenomenon of 0.5 to 3 μm in the particle size distribution of the polymer microspheres, but also effectively avoid the mutual aggregation and merging of the target microspheres, thereby achieving the effect of uniform particle size distribution of the microspheres;

[0072] (2) If the small peak phenomenon cannot be eliminated by the emulsification process, the method provided by the present invention is subjected to post-processing. By mixing the freeze-dried microspheres with the chloride particles and then performing dry screening and polishing, not only can the small-sized microspheres in the polymer microspheres be effectively removed, but also some microspheres of non-target particle sizes can be screened out, thereby better controlling the particle size distribution of the polymer microspheres, thereby obtaining microspheres with more uniform particle sizes;

[0073] (3) The method provided by the present invention is simple to operate, efficient and highly universal, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 This is a particle size distribution diagram of polymer microspheres prepared by the emulsification method provided by the present invention.

[0075] Figure 2 It is a particle size distribution diagram of polymer microspheres prepared by the monomer polymerization method provided by the present invention.

[0076] Figure 3 This is a particle size distribution diagram of polymer microspheres prepared by the emulsification method provided by the present invention without screening.

[0077] Figure 4The present invention provides a particle size distribution diagram of polymer microspheres prepared by the emulsification method after screening.

[0078] Figure 5 This is a SEM picture of the polymer microspheres prepared by the emulsification method provided by the present invention.

[0079] Figure 6 This is a high-power microscope picture of polymer microspheres prepared by the improved emulsification method combined with post-treatment provided by the present invention.

[0080] Figure 7 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Example 1.

[0081] Figure 8 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Example 2.

[0082] Fig. 9 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Example 3.

[0083] Fig.10 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Example 4.

[0084] Fig.11 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Example 5.

[0085] Fig.12 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) of Example 5.

[0086] Fig.13 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) of Example 6.

[0087] Fig.14 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) in Example 7.

[0088] Fig.15 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Example 8.

[0089] Fig.16 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Example 9.

[0090] Fig.17 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) of Example 10.

[0091] Fig.18 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) in Example 11.

[0092] Fig.19 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) in Example 12.

[0093] Fig. 20 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) of Comparative Example 1.

[0094] Fig.21 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Comparative Example 2.

[0095] Fig. 22 This is the particle size distribution diagram of the polymer microspheres obtained in step (2) in Comparative Example 3.

[0096] Fig.23 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) of Comparative Example 4.

[0097] Fig.24 This is the particle size distribution diagram of the polymer microspheres obtained in step (4) of Comparative Example 5. DETAILED DESCRIPTION

[0098] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0099] The materials used in the specific embodiments of the present invention can be purchased from the market or prepared by conventional methods in the prior art.

[0100] Example 1

[0101] This embodiment provides a method for removing small-size microspheres in polymer microspheres, the method comprising the following steps:

[0102] (1) polylactic acid and dichloromethane are mixed to form an oil phase, polyvinyl alcohol (PVA-388) is dissolved in hot water to form a polyvinyl alcohol solution with a mass concentration of 1%, a composite stabilizer is added thereto after cooling, and the mixture is mixed to obtain a water phase;

[0103] The mass concentration of the polylactic acid in the oil phase is 10%; the composite stabilizer is CTAB and gelatin in a mass ratio of 1:4; the mass concentration of the composite stabilizer in the water phase is 4%;

[0104] (2) adding the oil phase obtained in step (1) to the water phase, emulsifying at a shear rate of 800 rpm to obtain O / W type emulsion droplets, and then solidifying by heating and stirring at a temperature of 40° C., and then washing, centrifuging and drying in sequence to obtain polymer microspheres;

[0105] (3) using a laser particle size analyzer to measure the particle size and particle size distribution of the polymer microspheres obtained in step (2), and then evaluating them;

[0106] The evaluation is: Figure 7 It can be seen that the volume average particle size D(4,3) of the polymer microspheres is 20.0 μm, and the particle size distribution has no peak at 0.5 to 3 μm, so the execution is terminated to obtain polymer microspheres with small particle size microspheres removed.

[0107] Example 2

[0108] This embodiment provides a method for removing small-size microspheres in polymer microspheres, the method comprising the following steps:

[0109] (1) polycaprolactone and dichloromethane are mixed to form an oil phase, polyvinyl alcohol (PVA-388) is dissolved in hot water to form a polyvinyl alcohol solution with a mass concentration of 2%, a composite stabilizer is added thereto after cooling, and the mixture is mixed to obtain a water phase;

[0110] The mass concentration of the polycaprolactone in the oil phase is 20%; the composite stabilizer includes CTAB and hydroxypropyl methylcellulose in a mass ratio of 1:9; the mass concentration of the composite stabilizer in the water phase is 0.8%;

[0111] (2) adding the oil phase obtained in step (1) to the water phase, emulsifying by SPG membrane emulsification to obtain O / W type emulsion droplets, and then solidifying by heating and stirring at a temperature of 40° C., followed by washing, centrifugation and drying in sequence to obtain polymer microspheres;

[0112] The pore size of the SPG membrane is 20 μm;

[0113] (3) using a laser particle size analyzer to measure the particle size and particle size distribution of the polymer microspheres obtained in step (2), and then evaluating them;

[0114] The evaluation is: Figure 8 It can be seen that the volume average particle size D(4,3) of the polymer microspheres is 34.0 μm, and the particle size distribution has no peak at 0.5 to 3 μm, so the execution is terminated to obtain polymer microspheres with small particle size microspheres removed.

[0115] Example 3

[0116] This embodiment provides a method for removing small-size microspheres in polymer microspheres, the method comprising the following steps:

[0117] (1) mixing polymethyl methacrylate and dichloromethane to form an oil phase, dissolving polyvinyl alcohol (PVA-388) in hot water to form a polyvinyl alcohol solution with a mass concentration of 1.8%, adding a composite stabilizer to the solution after cooling, and mixing to obtain a water phase;

[0118] The mass concentration of the polymethyl methacrylate in the oil phase is 15%; the composite stabilizer includes CTAB and hydroxypropyl methylcellulose in a mass ratio of 1:6; the mass concentration of the composite stabilizer in the water phase is 2%;

[0119] (2) adding the oil phase obtained in step (1) to the water phase, emulsifying by SPG membrane emulsification to obtain O / W type emulsion droplets, and then solidifying by heating and stirring at a temperature of 40° C., followed by washing, centrifugation and drying in sequence to obtain polymer microspheres;

[0120] The pore size of the SPG membrane is 30 μm;

[0121] (3) using a laser particle size analyzer to measure the particle size and particle size distribution of the polymer microspheres obtained in step (2), and then evaluating them;

[0122] The evaluation is: Fig. 9 It can be seen that the volume average particle size D(4,3) of the polymer microspheres is 53.7 μm, and the particle size distribution has no peak at 0.5 to 3 μm, so the execution is terminated to obtain polymer microspheres with small particle size microspheres removed.

[0123] Example 4

[0124] This embodiment provides a method for removing small-size microspheres in polymer microspheres, the method comprising the following steps:

[0125] (1) mixing polyhydroxyalkanoate and dichloromethane to form an oil phase, dissolving polyvinyl alcohol (PVA-388) in hot water to form a polyvinyl alcohol solution with a mass concentration of 1.5%, adding a composite stabilizer to the solution after cooling, and mixing to obtain a water phase;

[0126] The mass concentration of the polyhydroxyalkanoate in the oil phase is 8%; the composite stabilizer includes CTAB and hydroxypropyl methylcellulose in a mass ratio of 1:8; the mass concentration of the composite stabilizer in the water phase is 3%;

[0127] (2) adding the oil phase obtained in step (1) to the water phase, emulsifying by microfluidics to obtain O / W type emulsion droplets, and then solidifying by heating and stirring at a temperature of 40° C., followed by washing, centrifugation and drying in sequence to obtain polymer microspheres;

[0128] (3) using a laser particle size analyzer to measure the particle size and particle size distribution of the polymer microspheres obtained in step (2), and then evaluating them;

[0129] The evaluation is: Fig.10It can be seen that the volume average particle size D(4,3) of the polymer microspheres is 34.9 μm, and the particle size distribution has no peak at 0.5 to 3 μm, so the execution is terminated to obtain polymer microspheres with small particle size microspheres removed.

[0130] Example 5

[0131] This embodiment provides a method for removing small-size microspheres in polymer microspheres, the method comprising the following steps:

[0132] (1) polylactic acid and dichloromethane are mixed to form an oil phase (10%), polyvinyl alcohol (PVA-388) is dissolved in hot water to form a polyvinyl alcohol solution with a mass concentration of 1%, a composite stabilizer is added thereto after cooling, and the mixture is mixed to obtain a water phase;

[0133] The mass concentration of the polylactic acid in the oil phase is 10%; the composite stabilizer is CTAB and gelatin in a mass ratio of 1:1; the mass concentration of the composite stabilizer in the water phase is 0.4%;

[0134] (2) adding the oil phase obtained in step (1) to the water phase, emulsifying at a shear rate of 800 rpm to obtain O / W type emulsion droplets, and then solidifying by heating and stirring at a temperature of 40° C., and then washing, centrifuging and drying in sequence to obtain polymer microspheres;

[0135] (3) using a laser particle size analyzer to measure the particle size and particle size distribution of the polymer microspheres obtained in step (2), and then evaluating them;

[0136] The evaluation is: Fig.11 It can be seen that the particle size distribution of polymer microspheres has a small peak at 0.5-3 μm, so post-treatment is performed;

[0137] (4) The polymer microspheres obtained in step (2) are subjected to a first freeze-drying to obtain a first powder having a water content of less than 1%, the first powder is mixed with sodium chloride having an average particle size of 350 μm in a mass ratio of 1:10, and the mixture is placed on a sieve and vibrated for 60 min at a frequency of 1000 times / min to obtain a second powder, the obtained second separation is subjected to three alternate pure water washing and precipitation, and finally a second freeze-drying is performed, and the particle size and particle size distribution of the obtained polymer microsphere powder are measured using a laser particle size analyzer.

[0138] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows: Fig.12 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 33.0 μm, and there is no peak at 0.5 to 3 μm.

[0139] In this embodiment, when the proportion of the thickener in the composite stabilizer in step (1) is reduced to a concentration outside the effective range, and the mass concentration of the composite stabilizer in the aqueous phase is lower than 0.8%, the viscosity of the system is relatively low at this time. The low viscosity cannot maintain the collision and adhesion between the O / W type emulsion droplets during the emulsification process, and thus the purpose of removing the small peak cannot be achieved. On the other hand, the amount of cationic surfactant in the system also decreases significantly as the mass concentration of the composite stabilizer in the aqueous phase is lower than 0.8%, and the O / W type emulsion droplets cannot be effectively dispersed, so that small particles will be adsorbed on the microspheres. However, by post-treating the polymer microspheres obtained in step (2), first freeze-drying the polymer microspheres to form a microsphere dry powder, then mixing with chloride particles, and then placing the mixed powder on a sieve for dry vibration screening, the small-sized microspheres present in the polymer microspheres can be effectively removed, thereby eliminating the small-sized microspheres with a particle size distribution of 0.5 to 3 μm in the polymer microspheres.

[0140] Example 6

[0141] The present embodiment provides a method for removing small-sized microspheres from polymer microspheres, except that step (4) is adjusted as follows: the polymer microspheres obtained in step (2) are first freeze-dried to obtain a first powder having a water content of less than 1%, the first powder obtained is mixed with potassium chloride having an average particle size of 400 μm in a mass ratio of 1:50, and then the mixture is placed on a sieve and vibrated for 30 minutes at a frequency of 2000 times / min to obtain a second powder, the obtained second separation is alternately washed with pure water and precipitated for 3 times, and finally a second freeze-drying is performed, and the particle size and particle size distribution of the obtained polymer microsphere powder are measured using a laser particle size analyzer;

[0142] Other conditions are the same as those in Example 5.

[0143] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows: Fig.13 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 32.6 μm, and there is no peak at 0.5 to 3 μm.

[0144] Example 7

[0145] This embodiment provides a method for removing small-sized microspheres from polymer microspheres, except that step (4) is adjusted to:

[0146] The polymer microspheres obtained in step (2) are subjected to a first freeze-drying to obtain a first powder having a water content of less than 1%, the first powder is mixed with sodium chloride having an average particle size of 200 μm in a mass ratio of 1:40, and the mixture is placed on a sieve and vibrated for 50 min at a frequency of 1500 times / min to obtain a second powder, the obtained second separation is subjected to three alternate pure water washing and precipitation, and finally a second freeze-drying is performed, and the particle size and particle size distribution of the obtained polymer microsphere powder are measured using a laser particle size analyzer;

[0147] Other conditions are the same as those in Example 5.

[0148] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows: Fig.14 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 21.3 μm, and there is no peak at 0.5 to 3 μm.

[0149] According to the methods provided in the above Examples 1-7, the obtained polymer microspheres have no peaks at 0.5-3 μm, thereby achieving the removal of small-size microspheres in the polymer microspheres.

[0150] Example 8

[0151] This embodiment provides a method for removing small-size microspheres in polymer microspheres. Except that the composite stabilizer is CTAB and gelatin in a mass ratio of 1:2, other conditions are the same as those in Example 1.

[0152] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (2) is as follows: Fig.15 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 21.1 μm, and the obtained polymer microspheres have a small peak at 0.5 to 3 μm.

[0153] Example 9

[0154] This embodiment provides a method for removing small-size microspheres in polymer microspheres. Except that the composite stabilizer is CTAB and gelatin in a mass ratio of 1:12, other conditions are the same as those in Example 1.

[0155] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (2) is as follows: Fig.16 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 24.2 μm, and the obtained polymer microspheres have a small peak at 0.5 to 3 μm.

[0156] By comparing Example 1 and Example 8-9, it can be seen that when the proportion of gelatin in the composite stabilizer is too high, the amount of thickener in the system is relatively large, and the viscosity is relatively large. When a certain shear force is applied, the viscous system will increase the shear between the liquids (oil phase and water phase), thereby causing more O / W type emulsion droplets to collide and break, forming more small droplets, and forming more small particle microspheres after solidification, thereby increasing the probability of small particle size microspheres adhering to normal microspheres. When the proportion of gelatin in the composite stabilizer is low, the viscosity of the system is relatively low at this time, and the low viscosity cannot maintain the collision and adhesion between O / W type emulsion droplets during the emulsification process, thereby failing to achieve the purpose of removing small peaks.

[0157] Example 10

[0158] This embodiment provides a method for removing small-sized microspheres in polymer microspheres. Except that the average particle size of the sodium chloride is 100 μm, other conditions are the same as those in Example 5.

[0159] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows: Fig.17 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 44.3 μm, and the obtained polymer microspheres have a small peak at 0.5 to 3 μm.

[0160] Embodiment 11

[0161] This embodiment provides a method for removing small-sized microspheres in polymer microspheres. Except that the average particle size of the sodium chloride is 1000 μm, other conditions are the same as those in Example 5.

[0162] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows: Fig.18 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 40.5 μm, and the obtained polymer microspheres have a small peak at 0.5 to 3 μm.

[0163] By comparing Example 5 and Examples 10-11, it can be seen that when the average particle size of the chloride is too small, the smaller particles cannot provide sufficient friction to the microspheres adsorbed by the small particles, thereby failing to effectively remove the small peaks; and when the average particle size of the chloride is too large, the larger particles cannot rub against the microspheres adsorbed by the small particles, thereby failing to remove the small particles, thereby failing to achieve the purpose of removing the small peaks.

[0164] Example 12

[0165] This embodiment provides a method for removing small-sized microspheres from polymer microspheres. Except that the frequency of the vibration screening is 500 times / min, other conditions are the same as those in Example 5.

[0166] In this embodiment, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows: Fig.19 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 30.5 μm, and the obtained polymer microspheres have a small peak at 0.5 to 3 μm.

[0167] From the comparison between Example 5 and Example 12, it can be seen that if the frequency of vibration screening is too low, the lower vibration frequency cannot ensure sufficient friction between the microspheres and the chloride and effective vibration screening, and thus cannot effectively remove the small peaks.

[0168] Comparative Example 1

[0169] This comparative example provides a method for preparing polymer microspheres by emulsification. Except that no composite stabilizer is added, other conditions are the same as those in Example 1.

[0170] In this comparative example, the particle size distribution diagram of the polymer microsphere powder obtained in step (2) is as follows Fig. 20 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 76.5 μm, with a small peak at 0.5 to 3 μm.

[0171] From the comparison between Example 1 and Comparative Example 1, it can be seen that if the composite stabilizer is not added, during the emulsification process, the droplets with extremely small particle sizes are very easy to adhere to the vicinity of the large O / W type emulsion droplets. After solidification to form microspheres, small particle size microspheres of 0.5 to 3 μm will be formed and attached to the polymer microspheres.

[0172] Comparative Example 2

[0173] This comparative example provides a method for removing small-sized microspheres in polymer microspheres. Except that the composite stabilizer is replaced with an equal amount of CTAB, other conditions are the same as those in Example 1.

[0174] In this comparative example, the particle size distribution diagram of the polymer microsphere powder obtained in step (2) is as follows Fig.21 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 27.6 μm, and the obtained polymer microspheres have a small peak at 0.5 to 3 μm.

[0175] From the comparison between Example 1 and Comparative Example 2, it can be seen that if the composite stabilizer contains only cationic surfactants, the cationic surfactants mainly play the role of dispersing the emulsion droplets in the system. The single dispersion effect cannot effectively achieve the effect of forming adhesion after the O / W type emulsion droplets are sheared and collided, and thus cannot remove the small-size microspheres in the polymer microspheres.

[0176] Comparative Example 3

[0177] This comparative example provides a method for removing small-sized microspheres in polymer microspheres. Except that the composite stabilizer is replaced with an equal amount of gelatin, other conditions are the same as those in Example 1.

[0178] In this comparative example, the particle size distribution diagram of the polymer microsphere powder obtained in step (2) is as follows Fig. 22 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 43.1 μm, and the obtained polymer microspheres have a small peak at 0.5 to 3 μm.

[0179] From the comparison between Example 1 and Comparative Example 3, it can be seen that if the composite stabilizer contains only a thickener, although the thickener can isolate the adhesion between the emulsion droplets, a dispersant is still required to stabilize the emulsion droplets, otherwise the small-size microspheres in the polymer microspheres cannot be removed.

[0180] Comparative Example 4

[0181] This comparative example provides a method for removing small-sized microspheres from polymer microspheres, except that step (4) is adjusted to: dilute the polymer microspheres obtained in step (2) to obtain a microsphere suspension, and then place the microsphere suspension on a sieve and vibrate and sieve it at a frequency of 2000 times / min for 60 minutes. Other conditions are the same as those in Example 5.

[0182] In this comparative example, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows Fig.23 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 32.8 μm with a small peak at 0.5-3 μm.

[0183] From the comparison between Example 5 and Comparative Example 4, it can be seen that if only the polymer microspheres are wet screened, no intense friction can be formed with the microspheres, and thus the small-sized microspheres attached to the polymer microspheres cannot be eliminated.

[0184] Comparative Example 5

[0185] This comparative example provides a method for removing small-sized microspheres from polymer microspheres, except that step (4) is adjusted to: freeze-drying the polymer microspheres obtained in step (2) to obtain a first powder with a water content of less than 1%, and then placing the first powder on a sieve and vibrating and sieving it at a frequency of 2000 times / min for 60 minutes. Other conditions are the same as those in Example 5.

[0186] In this comparative example, the particle size distribution diagram of the polymer microsphere powder obtained in step (4) is as follows Fig.24 As shown, the volume average particle size D(4,3) of the obtained polymer microspheres is 25.6 μm, with a small peak at 0.5-3 μm.

[0187] From the comparison between Example 5 and Comparative Example 5, it can be seen that if the polymer microsphere freeze-dried powder is directly subjected to dry screening, it cannot form severe friction with the microspheres, and thus cannot eliminate the small-sized microspheres attached to the polymer microspheres.

[0188] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for removing small-size microspheres from polymer microspheres, characterized in that: The method comprises the following steps: (1) mixing a polymer and an organic solvent to form an oil phase, and mixing an emulsifier, a composite stabilizer and water to form a water phase; The composite stabilizer includes a cationic surfactant and a thickener; (2) mixing the oil phase and the water phase obtained in step (1), and sequentially emulsifying and solidifying to obtain polymer microspheres; (3) measuring and evaluating the particle size and particle size distribution of the polymer microspheres obtained in step (2); The evaluation includes the following: If the particle size distribution of the polymer microspheres has no peak at 0.5 to 3 μm, the execution is terminated to obtain polymer microspheres with small particle size microspheres removed; or If the particle size distribution of the polymer microspheres has a peak at 0.5 to 3 μm, post-treatment is performed to obtain polymer microspheres from which small-size microspheres are removed.

2. The method according to claim 1, characterized in that The polymer in step (1) comprises any one of polylactic acid, polycaprolactone, polymethyl methacrylate or polyhydroxyalkanoate or a combination of at least two thereof; Preferably, the organic solvent in step (1) comprises any one of dichloromethane, chloroform, ethyl acetate or ethyl formate, or a combination of at least two thereof; Preferably, the mass concentration of the polymer in the oil phase in step (1) is 5% to 20%.

3. The method according to claim 1 or 2, characterized in that: The emulsifier in step (1) comprises polyvinyl alcohol; Preferably, the mass concentration of the emulsifier in the aqueous phase in step (1) is 1% to 2%.

4. The method according to any one of claims 1 to 3, characterized in that: The cationic surfactant in step (1) includes hexadecyltrimethylammonium bromide and / or hexadecyltrimethylammonium chloride; Preferably, the thickener in step (1) comprises gelatin and / or hydroxypropyl methylcellulose; Preferably, the mass ratio of the cationic surfactant to the thickener in step (1) is 1:(4-9); Preferably, the mass concentration of the composite stabilizer in the aqueous phase in step (1) is 0.8% to 4%.

5. The method according to any one of claims 1 to 4, characterized in that: The mixing in step (2) is as follows: adding the oil phase into the water phase; Preferably, the emulsification method in step (2) includes any one of shearing, membrane emulsification or microfluidics; Preferably, after the emulsification in step (2), O / W type emulsion droplets are obtained; Preferably, after the solidification in step (2), washing, centrifugation and drying are performed in sequence.

6. The method according to any one of claims 1 to 5, characterized in that: The measurement in step (3) is performed using a laser particle size analyzer.

7. The method according to any one of claims 1 to 6, characterized in that: The post-processing in step (3) comprises the following steps: (a) freeze-drying the polymer microspheres obtained in step (2) to obtain a first powder; (b) mixing the first powder obtained in step (a) with chloride, and performing vibration screening to obtain a second powder; (c) washing and solid-liquid separation are performed alternately several times on the second powder obtained in step (b) to obtain polymer microspheres from which small-sized microspheres are removed.

8. The method according to claim 7, characterized in that The water content of the first powder obtained in step (a) is less than 1%; Preferably, the chloride in step (b) comprises sodium chloride and / or potassium chloride; Preferably, the average particle size of the chloride in step (b) is 200 to 500 μm; Preferably, in step (b), the mass ratio of the first powder to the chloride is 1:(10-50).

9. The method according to claim 7 or 8, characterized in that: The frequency of the vibration screening in step (b) is 1000 to 2000 times / min; Preferably, the vibration screening time in step (b) is 30 to 60 minutes.

10. The method according to any one of claims 1 to 9, characterized in that: The method comprises the following steps: (1) mixing a polymer and an organic solvent to form an oil phase, and mixing an emulsifier, a composite stabilizer and water to form a water phase; The mass concentration of the emulsifier in the water phase is 1% to 2%; the composite stabilizer includes a cationic surfactant and a thickener in a mass ratio of 1:(4 to 9); the cationic surfactant includes hexadecyltrimethylammonium bromide and / or hexadecyltrimethylammonium chloride; the cationic surfactant includes hexadecyltrimethylammonium bromide and / or hexadecyltrimethylammonium chloride; the mass concentration of the composite stabilizer in the water phase is 0.8% to 4%; (2) mixing the oil phase and the water phase obtained in step (1), emulsifying to obtain O / W type emulsion droplets, and then sequentially solidifying, washing, centrifuging and drying to obtain polymer microspheres; (3) measuring and evaluating the particle size and particle size distribution of the polymer microspheres obtained in step (2); The measurement is performed using a laser particle size analyzer; The evaluation includes the following: If the particle size distribution of the polymer microspheres has no peak at 0.5 to 3 μm, the execution is terminated to obtain polymer microspheres with small particle size microspheres removed; or If the particle size distribution of the polymer microspheres has a peak at 0.5 to 3 μm, post-treatment is performed; The post-processing comprises the following steps: (a) freeze-drying the polymer microspheres obtained in step (2) to obtain a first powder having a water content of less than 1%; (b) mixing the first powder obtained in step (a) and the chloride in a mass ratio of 1:(10-50), and vibrating and sieving at a frequency of 1000-2000 times / min for 30-60 min to obtain a second powder; The chloride includes sodium chloride and / or potassium chloride; the average particle size of the chloride is 200 to 500 μm; (c) washing and solid-liquid separation are performed alternately several times on the second powder obtained in step (b) to obtain polymer microspheres from which small-sized microspheres are removed.

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