Polymer microsphere and preparation method thereof

Abstract

The invention provides a polymer microsphere and a preparation method thereof. The method comprises the following steps: mixing an oil phase solution of a polymer and a water phase solution of a surfactant, emulsifying to obtain an emulsion, and removing a solvent from the emulsion to obtain the polymer microspheres. The invention provides a double-planetary emulsification method for mass production of polymer microspheres with uniform particle size.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer materials, and particularly relates to polymer microspheres and a preparation method thereof. Background Art

[0002] Emulsion is a liquid dispersed in another immiscible liquid in the form of droplets, and is widely used in the fields of food, cosmetics, pesticides, and pharmaceuticals. The size and particle size distribution of the droplets affect their subsequent applications, so uniform particle size distribution is a necessary prerequisite for the application of emulsions.

[0003] At present, the methods for preparing emulsions mainly include traditional emulsification methods and new technology emulsification methods. On the one hand. Traditional emulsification methods include colloidal grinding, mechanical stirring, high-pressure homogenization and ultrasound. The above emulsification methods have problems such as high energy consumption, poor system reproducibility and emulsion polydispersity. At the same time, the emulsion solution prepared by the above method produces droplet aggregation, agglomeration and stratification, resulting in poor product stability; on the other hand, the preparation conditions of the new technology emulsification method are mild, the prepared droplets are uniform in size and have good stability. However, the microfluidic emulsification method disclosed in the prior art is difficult to scale up for production, and the uniformity of the droplets of the membrane emulsification method cannot be guaranteed in mass production.

[0004] CN101683592A discloses a membrane emulsification and an emulsion preparation method thereof. The device can quickly emulsify and prepare emulsion droplets. However, in this method, the size of the particle size is closely related to the pore size of the membrane. If emulsion droplets of different particle sizes need to be prepared, different membrane tubes need to be replaced, and the diameter distance of the emulsion droplets is affected by the uniformity of the membrane pores. At the same time, when the above emulsification method is mass-produced, the diameter distance of the droplets will also increase due to the uneven pressure on the liquid in each membrane tube.

[0005] CN211329433U discloses a microfluidic emulsification system, and a microfluidic particle size control chip can realize the particle size control function of the sample. The prepared sample is transported to the high-pressure microfluidic chip by a high-pressure pump, and the particle size is controlled by impact force and shear force to reach the desired range. However, due to the large restrictions on its preparation method, it is difficult to achieve mass production.

[0006] Therefore, there is an urgent need for a method that can produce emulsion droplets of uniform size in large quantities with good batch stability. Summary of the invention

[0007] In view of the shortcomings of the prior art, the object of the present invention is to provide a polymer microsphere and a preparation method thereof. The present invention provides a double planetary emulsification method for mass production of polymer microspheres with uniform particle size.

[0008] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a method for preparing polymer microspheres, the method comprising the following steps:

[0010] The oil phase solution of the polymer and the water phase solution of the surfactant are mixed and emulsified to obtain an emulsion, and the solvent is removed from the emulsion to obtain polymer microspheres.

[0011] The present invention utilizes a double planetary emulsification method, that is, the spiral vortex field generated by the revolution and rotation of the container itself realizes the stirring of the material, and forms an emulsion by strongly stirring two immiscible liquids, the oil phase solution of the polymer and the water phase solution of the surfactant, in the presence of a suitable surfactant, and the uniformity of the particle size distribution of the generated emulsion droplets is good, so this method can still maintain excellent particle size uniformity when scaled up production.

[0012] On the one hand, the preparation method of the polymer microspheres provided by the present invention is simple to operate and easy to industrialize; on the other hand, the polymer microspheres prepared by the present invention have a smooth surface, adjustable particle size and good uniformity.

[0013] Preferably, the polymer includes any one of polylactic acid, polytrimethylene carbonate, polycaprolactone or polymethyl methacrylate, or a combination of at least two thereof.

[0014] Preferably, the weight average molecular weight of the polymer is 2000-100000 kDa, preferably 5000-50000 kDa, for example, it can be 2000 kDa, 3000 kDa, 4000 kDa, 5000 kDa, 6000 kDa, 7000 kDa, 8000 kDa, 9000 kDa, 10000 kDa, 20000 kDa, 30000 kDa, 40000 kDa, 50000 kDa, 60000 kDa, 70000 kDa, 80000 kDa, 90000 kDa, 100000 kDa, etc.

[0015] In the present invention, the weight average molecular weight of the polymer is adjusted so that the cured microspheres have good mechanical properties. If the molecular weight is too low, the mechanical properties of the microspheres will deteriorate. Otherwise, holes will be generated in the microspheres, resulting in poor mechanical properties.

[0016] Preferably, the oil phase solvent of the oil phase solution includes any one of dichloromethane, chloroform, ethyl acetate or n-propyl acetate, or a combination of at least two thereof.

[0017] Preferably, the mass concentration of the oil phase solution of the polymer is 1-20wt%, preferably 4-15wt%, for example, it can be 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, 16wt%, 17wt%, 18wt%, 19wt%, 20wt% and the like.

[0018] In the present invention, the viscosity of the oil phase is controlled within an appropriate range by regulating the mass concentration of the oil phase solution. Too low a mass concentration will lead to a decrease in yield, whereas a too high a mass concentration will lead to the appearance of water-in-oil-in-water emulsion droplets, which will then lead to the presence of holes in the microspheres.

[0019] Preferably, the surfactant includes any one of polyvinyl alcohol, Span 60, Span 80, sodium dodecyl sulfate or hexadecyltrimethylammonium bromide, or a combination of at least two thereof.

[0020] Preferably, the mass concentration of the aqueous solution of the surfactant is 0.1-10wt%, preferably 0.5-5wt%, for example, 0.1wt%, 0.2wt%, 0.5wt%, 0.8wt%, 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%.

[0021] In the present invention, the amount of the surfactant is kept within a suitable range by regulating the mass concentration of the aqueous phase solution. If the mass concentration is too low, the micro-emulsion droplets will be aggregated into large droplets again, and vice versa, the difficulty of subsequent cleaning will be increased.

[0022] Preferably, the mass ratio of the oil phase in the oil phase solution to the water phase in the water phase solution is 1:(2-20), preferably 1:(3-15), for example, it can be 1:2, 1:3, 1:5, 1:7, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, etc.

[0023] In the present invention, the emulsification process is stabilized by adjusting the mass ratio of the oil phase and the water phase. If the mass ratio is too low, water-in-oil-in-water emulsion droplets will appear, which will lead to holes in the microspheres. Otherwise, the yield will be reduced.

[0024] Preferably, the emulsification equipment adopts a double planetary mixer.

[0025] In the present invention, the double planetary mixer is a bladeless mixing device, which utilizes the combined effect of the rotation and revolution of the container. The rotation axis of the container is usually inclined at a certain angle to the revolution axis to improve the mixing performance; since there is no stirring paddle during the mixing process, the shear force between the two immiscible liquids is uniform and gentle, the particle size distribution of the generated emulsion droplets is uniform, and this method can still maintain good particle size uniformity when the production is scaled up.

[0026] Preferably, the rotation speed of the double planetary agitator is 500rpm to 2500rpm, for example, it can be 500rpm, 600rpm, 700rpm, 800rpm, 900rpm, 1000rpm, 1200rpm, 1500rpm, 1800rpm, 2000rpm, 2200rpm, 2500rpm, etc.

[0027] In the present invention, the rotation speed of the double planetary agitator is adjusted to keep the vortex flow field strength within a suitable range. If the rotation speed is too low, a vortex cannot be formed to continue stirring the two phases, whereas if the rotation speed is too high, too small droplets will be formed.

[0028] Preferably, the rotation-revolution ratio of the double planetary agitator is (0.5-1):1, for example, it can be 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, etc.

[0029] In the present invention, the rotation-revolution ratio of the double planetary agitator is adjusted to make the vortex intensity within a suitable range. If the ratio is too low, a vortex cannot be generated, whereas if it is too high, turbulence will be caused, interfering with the formation of emulsion droplets.

[0030] Preferably, the rotation time of the double planetary agitator is 1 to 10 min, for example, it can be 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, etc.

[0031] Preferably, the method for removing the solvent is heating.

[0032] Preferably, the heating is performed under stirring.

[0033] Preferably, the stirring rate is 100-1000 rpm, for example, 100 rpm, 200 rpm, 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, etc.

[0034] Preferably, the heating temperature is 20-50°C, for example, 20°C, 30°C, 40°C, 50°C, etc.; the heating time is 6-24h, for example, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, etc.

[0035] Preferably, the removal of the solvent further includes washing, precipitation and drying treatments.

[0036] Preferably, the washing solvent is ultrapure water.

[0037] Preferably, the drying method is freeze-drying.

[0038] In a second aspect, the present invention provides a polymer microsphere, wherein the polymer microsphere is prepared by the method for preparing polymer microsphere according to the first aspect.

[0039] Preferably, the average particle size of the polymer microspheres is between 10 and 100 μm, for example, 10 μm, 12 μm, 15 μm, 18 μm, 20 μm, 22 μm, 25 μm, 28 μm, 30 μm, 32 μm, 35 μm, 38 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, etc., and the diameter distance is 0.6 to 1.2, for example, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, etc.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] The present invention provides a method for preparing polymer microspheres, which utilizes a double planetary emulsification method, i.e., a spiral vortex field generated by the revolution and rotation of a container itself is used to achieve material stirring, and two immiscible liquids, an oil phase solution of a polymer and an aqueous phase solution of a surfactant, are strongly stirred in the presence of a suitable surfactant to form an emulsion, and the uniformity of the particle size distribution of the generated emulsion droplets is good, so this method can still maintain excellent particle size uniformity when scaled up for production.

[0042] On the one hand, the preparation method of the polymer microspheres provided by the present invention is simple to operate and easy to industrialize; on the other hand, the polymer microspheres prepared by the present invention have a smooth surface, adjustable particle size and good uniformity. DETAILED DESCRIPTION

[0043] 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.

[0044] Example 1

[0045] This embodiment provides a polycaprolactone microsphere and a preparation method thereof, which comprises the following steps:

[0046] Weigh 100 g of polycaprolactone with a weight average molecular weight of 20,000 kDa, add it into dichloromethane, stir and dissolve it, and obtain an oil phase solution of polycaprolactone with a mass concentration of 4 wt%;

[0047] Weigh 30 g of polyvinyl alcohol and add it into deionized water, stir and dissolve to obtain an aqueous phase solution of polyvinyl alcohol with a mass concentration of 1 wt %;

[0048] Pour 3000g of polyvinyl alcohol aqueous solution and 1000g of polycaprolactone oil solution into the container, cover the lid and put it into the double planetary stirrer, set the speed to 1500rpm, the rotation ratio to 0.5:1, and the rotation time to 5min to obtain an emulsion;

[0049] The emulsion was heated to 40° C. and stirred at a rate of 400 rpm. After stirring for 24 hours, the emulsion was washed, precipitated and freeze-dried to obtain polycaprolactone microspheres.

[0050] Embodiments 2 to 9

[0051] Examples 2 to 9 are based on the steps of Example 1 with parameter changes, and the specific changed parameters are shown in Table 1:

[0052] Table 1

[0053]

[0054]

[0055] Example 10

[0056] This embodiment provides a polymethyl methacrylate microsphere and a preparation method thereof, which comprises the following steps:

[0057] Weigh 100 g of polymethyl methacrylate with a weight average molecular weight of 100,000 kDa, add it into dichloromethane, stir and dissolve it, and obtain an oil phase solution of polymethyl methacrylate with a mass concentration of 5 wt%;

[0058] Weigh 30 g of polyvinyl alcohol and add it into deionized water, stir and dissolve to obtain an aqueous phase solution of polyvinyl alcohol with a mass concentration of 1 wt %;

[0059] Pour 3000 g of polyvinyl alcohol aqueous solution and 1000 g of polymethyl methacrylate oil solution into the container, cover the container and put it into a double planetary stirrer, set the speed to 1500 rpm, the rotation ratio to 0.5:1, and the rotation time to 5 min to obtain an emulsion;

[0060] The emulsion was heated to 50° C. and stirred at a rate of 400 rpm. After stirring for 10 h, the emulsion was washed, precipitated and freeze-dried to obtain polymethyl methacrylate microspheres.

[0061] Examples 11 to 18

[0062] Examples 11 to 18 are based on the steps of Example 10 with parameter changes, and the specific changed parameters are shown in Table 2:

[0063] Table 2

[0064]

[0065] Embodiment 19

[0066] The difference between this embodiment and embodiment 1 is that the weight average molecular weight of polycaprolactone is 1000 kDa, and the rest is the same as embodiment 1.

[0067] Embodiment 20

[0068] The difference between this embodiment and embodiment 1 is that the mass concentration of the oil phase solution of polycaprolactone is 25wt%, and the rest is the same as embodiment 1.

[0069] Embodiment 21

[0070] The difference between this embodiment and embodiment 1 is that the mass concentration of the aqueous phase solution of polyvinyl alcohol is 15wt%, and the rest is the same as embodiment 1.

[0071] Embodiment 22

[0072] The difference between this embodiment and embodiment 1 is that the mass ratio of the oil phase to the water phase is 1:1, and the rest is the same as embodiment 1.

[0073] Embodiment 23

[0074] The difference between this embodiment and embodiment 1 is that the mass ratio of the oil phase to the water phase is 1:25, and the rest is the same as embodiment 1.

[0075] Embodiment 24

[0076] The difference between this embodiment and embodiment 1 is that the rotation-revolution ratio of the double planetary agitator is 0.1:1, and the rest is the same as embodiment 1.

[0077] Embodiment 25

[0078] The difference between this embodiment and embodiment 1 is that the rotation-revolution ratio of the double planetary agitator is 3:1, and the rest is the same as embodiment 1.

[0079] Comparative Example 1

[0080] The difference between this comparative example and Example 1 is that a mechanical stirrer is used as the emulsification equipment, and the rest is the same as Example 1.

[0081] Examples 19 to 25 and Comparative Example 1 are based on the steps of Example 1 with parameter changes, and the particle sizes of the polymer microspheres prepared are shown in Table 3:

[0082] Table 3

[0083]

[0084]

[0085] From the data in Tables 1 to 3, it can be seen that the particle size of the microspheres prepared in Examples 1 to 18 is between 13 and 54 μm, and the diameter distance is between 0.662 and 1.163. Compared with Examples 19 to 25, the particle size is adjustable and uniform. Compared with Comparative Example 1, it not only has the advantages of adjustable and uniform particle size, but also has the advantages of simple preparation method and easy industrial production. Compared with Examples 19 to 25, the polymer microspheres prepared in Examples 1 to 18 have the advantage of smooth surface under electron microscope observation.

[0086] Example 19 shows the case where the weight average molecular weight of polycaprolactone exceeds the preferred range, indicating that by regulating the weight average molecular weight of the polymer, the cured microspheres have better mechanical properties; Examples 20-21 show that the mass concentrations of the oil phase solution and the aqueous phase solution are regulated to make the viscosity of the two phases appropriate; Examples 22-23 show the case where the mass ratio of the oil phase and the aqueous phase exceeds the preferred range, indicating that by regulating the mass ratio of the oil phase and the aqueous phase, the emulsification process is stabilized; Examples 24-25 show the case where the rotation-revolution ratio of the double planetary agitator exceeds the preferred range, indicating that the rotation-revolution ratio of the double planetary agitator is regulated to make the eddy current intensity within an appropriate range.

[0087] The applicant declares that the present invention illustrates the process method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned process steps, that is, it does not mean that the present invention must rely on the above-mentioned process steps to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing polymer microspheres, characterized in that: The method comprises the following steps: The oil phase solution of the polymer and the water phase solution of the surfactant are mixed and emulsified to obtain an emulsion, and the solvent is removed from the emulsion to obtain polymer microspheres.

2. The method according to claim 1, characterized in that The polymer includes any one of polylactic acid, polytrimethylene carbonate, polycaprolactone or polymethyl methacrylate or a combination of at least two thereof; Preferably, the weight average molecular weight of the polymer is 2000-100000 kDa, preferably 5000-50000 kDa.

3. The method according to claim 1 or 2, characterized in that: The oil phase solvent of the oil phase solution includes any one of dichloromethane, chloroform, ethyl acetate or n-propyl acetate, or a combination of at least two thereof.

4. The method according to any one of claims 1 to 3, characterized in that The mass concentration of the polymer oil phase solution is 1 to 20 wt %, preferably 4 to 15 wt %.

5. The method according to any one of claims 1 to 4, characterized in that The surfactant includes any one of polyvinyl alcohol, Span 60, Span 80, sodium dodecyl sulfate or hexadecyl trimethyl ammonium bromide or a combination of at least two thereof; Preferably, the mass concentration of the aqueous solution of the surfactant is 0.1 to 10 wt %, preferably 0.5 to 5 wt %.

6. The method according to any one of claims 1 to 5, characterized in that The mass ratio of the oil phase in the oil phase solution to the water phase in the water phase solution is 1:(2-20), preferably 1:(3-15).

7. The method according to any one of claims 1 to 6, characterized in that The emulsification equipment adopts a double planetary agitator; Preferably, the rotation speed of the double planetary agitator is 500 rpm to 2500 rpm; Preferably, the rotation-revolution ratio of the double planetary agitator is (0.5-1):1; Preferably, the rotation time of the double planetary agitator is 1 to 10 minutes.

8. The method according to any one of claims 1 to 7, characterized in that The method for removing the solvent adopts heating; Preferably, the heating is carried out under stirring; Preferably, the stirring rate is 100-1000 rpm; Preferably, the heating temperature is 20 to 50°C and the heating time is 6 to 24 hours; Preferably, the removal of the solvent further includes washing, precipitation and drying; Preferably, the washing solvent is ultrapure water; Preferably, the drying method is freeze-drying.

9. A polymer microsphere, characterized in that: The polymer microspheres are prepared by the method for preparing polymer microspheres according to any one of claims 1-8.

10. The polymer microsphere according to claim 9, characterized in that The average particle size of the polymer microspheres is 10-100 μm, and the diameter distance is 0.6-1.2.

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