Preparation method of monodisperse polycaprolactone microspheres

Abstract

The application discloses a preparation method of monodisperse polycaprolactone microspheres, which comprises the following steps: S1) adding polymer seeds into an aqueous solution containing a first surfactant to form a uniformly dispersed seed suspension; S2) adding polycaprolactone into an organic solvent, stirring to completely dissolve the polycaprolactone to form a polycaprolactone oil phase; S3) mixing the polycaprolactone oil phase with an aqueous solution containing a second surfactant to prepare a polycaprolactone suspension; S4) dropping the polycaprolactone suspension into the seed suspension at a constant rate, and waiting for the polycaprolactone to be completely absorbed by the seeds and to be swelled to a predetermined particle size; and S5) removing the organic solvent by heating and evaporation to prepare the monodisperse polycaprolactone microspheres. The polymer seeds and the polycaprolactone are respectively formed into suspensions, are fully emulsified and dispersed, are fully dispersed in the system, and are prevented from being aggregated, so that the polycaprolactone microspheres with controllable particle size and high particle size uniformity can be prepared.

Description

Technical Field

[0001] This invention relates to the field of polycaprolactone microsphere preparation technology, and more particularly to a method for preparing monodisperse polycaprolactone microspheres. Background Technology

[0002] Polycaprolactone (PCL) is a biodegradable material in the human body, and PCL microspheres are widely used in the field of medical aesthetics. However, current PCL is presented in irregular or sheet-like forms rather than as microspheres, which is not conducive to subcutaneous injection into the epidermal tissue. Furthermore, PCL microspheres prepared using conventional methods are prone to agglomeration and have poor flowability. Therefore, the stability and durability of these microspheres are issues that need to be addressed when used as a filler material in the human body.

[0003] Application CN202111121807.7 discloses a method for preparing polycaprolactone microspheres and their uses. It describes contacting an aqueous solution of hydroxypropyl methylcellulose with a dichloromethane solution of polycaprolactone while simultaneously shear emulsifying to form a shear emulsion mixture. An aqueous solution of polyvinyl alcohol is then contacted with and mixed with the shear emulsion mixture, and heated until the dichloromethane has completely evaporated. The mixture is then filtered to obtain microspheres with a size of 28 μm to 100 μm, exhibiting good flowability and high dispersion uniformity. However, direct contact between the aqueous solution of hydroxypropyl methylcellulose and the dichloromethane solution of polycaprolactone leads to uneven distribution and agglomeration of polycaprolactone in the system, resulting in larger particle sizes and poor dispersibility of the polycaprolactone microspheres. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing monodisperse polycaprolactone microspheres. By forming suspensions of polymer seeds and polycaprolactone separately, sufficient emulsification and dispersion are achieved, ensuring that polycaprolactone is fully dispersed in the system and avoiding agglomeration. This method can prepare polycaprolactone microspheres with controllable particle size and uniform particle size.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is: a method for preparing monodisperse polycaprolactone microspheres, comprising the following steps: S1) Add polymer seeds to an aqueous solution containing a first surfactant to form a uniformly dispersed seed suspension; S2) Add polycaprolactone to an organic solvent and stir until it is completely dissolved to form a polycaprolactone oil phase; S3) The polycaprolactone oil phase is mixed with an aqueous solution containing a second surfactant to prepare a polycaprolactone suspension; S4) Add the polycaprolactone suspension dropwise to the seed suspension at a constant rate until the polycaprolactone is completely absorbed by the seeds and swells to reach the predetermined particle size. S5) The organic solvent is removed by heating and evaporation to obtain monodisperse polycaprolactone microspheres. The particle size of the monodisperse polycaprolactone microspheres can be controlled at any value within the range of 5-100 μm.

[0006] As a further optimization, the polymer seed in S1 is a polymethyl methacrylate seed or a polystyrene seed, preferably a polymethyl methacrylate seed.

[0007] As a further optimization, the polymer seeds in S1 have a particle size range of 2-5 μm and are uniform, with a CV ≤ 2.8%.

[0008] As a further optimization, the first surfactant in S1 is hydroxypropyl methylcellulose and / or carboxymethyl cellulose, and its mass ratio with the polymer seed is 1:(10-15), preferably 1:10.

[0009] As a further optimization, the organic solvent mentioned in S2 is one or more of dichloromethane, dimethyl sulfoxide, or tetrahydrofuran.

[0010] As a further optimization, the second surfactant in S3 is hydroxypropyl methylcellulose and / or carboxymethyl cellulose, with a mass ratio of 1:(5-10) to the polycaprolactone oil phase, preferably 1:5.

[0011] As a further optimization, the drop rate in S4 is 0.1-100 mL / min.

[0012] As a further optimization, the heating rate in S5 is 1-10℃ / min, and the temperature is increased to 40-80℃.

[0013] The monodisperse polycaprolactone microspheres prepared by this invention can be applied in the field of medical aesthetics.

[0014] Compared with existing technologies, the beneficial effects of this invention are reflected in: This invention uses polymer seeds and polycaprolactone to form suspensions, achieving thorough emulsification and dispersion. This ensures that polycaprolactone is fully dispersed in the system, avoiding agglomeration, and can prepare polycaprolactone microspheres with controllable particle size and uniform particle size. Attached Figure Description

[0015] Figure 1 This is a microscope image of the polycaprolactone microspheres prepared in Example 4 of the present invention. Detailed Implementation

[0016] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the present invention is not limited to these embodiments.

[0017] Example 1 A method for preparing monodisperse polycaprolactone microspheres includes the following steps: S1) Under constant room temperature conditions, polymethyl methacrylate seeds (particle size 0.5 μm, CV = 2.8%) were added to an aqueous solution containing carboxymethyl cellulose and stirred thoroughly to form a uniformly dispersed seed suspension for later use. The polymer seed solid content in the seed suspension was 10 g / L, and the weight ratio of polymethyl methacrylate seeds to carboxymethyl cellulose was 10:1. S2) Add 2g of polycaprolactone to 10g of dichloromethane and stir until it is completely dissolved to form the polycaprolactone oil phase; S3) Prepare a polycaprolactone suspension by mixing the polycaprolactone oil phase from S2 with an aqueous solution containing carboxymethyl cellulose in a certain proportion; the weight ratio of the polycaprolactone oil phase to carboxymethyl cellulose is 5:1; S4) Add the polycaprolactone suspension to the seed suspension, controlling the addition rate of the polycaprolactone suspension to 5 mL / min. Stop adding the polycaprolactone once it has been completely absorbed by the seeds and swollen to reach the predetermined particle size. S5) Monodisperse polycaprolactone microspheres can be obtained by evaporation at 40°C to remove the organic solvent.

[0018] The particle size and particle size distribution of the prepared monodisperse polycaprolactone microspheres were determined using the Beckman Counter, and the results showed that the particle size was 5 μm and the coefficient of variation (CV) was 2.5%.

[0019] Example 2 A method for preparing monodisperse polycaprolactone microspheres includes the following steps: S1) Under constant room temperature conditions, polymethyl methacrylate seeds (particle size 3 μm, CV = 2.7%) were added to an aqueous solution containing carboxymethyl cellulose and stirred thoroughly to form a uniformly dispersed seed suspension for later use. The polymer seed solid content in the seed suspension was 10 g / L, and the weight ratio of polymethyl methacrylate seeds to carboxymethyl cellulose was 10:1. S2) Add 2g of polycaprolactone to 10g of dichloromethane and stir until it is completely dissolved to form the polycaprolactone oil phase; S3) Prepare a polycaprolactone suspension by mixing the polycaprolactone oil phase from S2 with an aqueous solution containing carboxymethyl cellulose in a certain proportion; the weight ratio of the polycaprolactone oil phase to carboxymethyl cellulose is 5:1; S4) Add the polycaprolactone suspension to the seed suspension, controlling the addition rate of the polycaprolactone suspension to 5 mL / min. Stop adding the polycaprolactone once it has been completely absorbed by the seeds and swollen to reach the predetermined particle size. S5) By evaporating the organic solvent at 50°C, polycaprolactone microspheres can be obtained.

[0020] The particle size and particle size distribution of the prepared monodisperse polycaprolactone microspheres were determined using the Beckman Counter, and the results showed that the particle size was 10 μm and the coefficient of variation (CV) was 2.6%.

[0021] Example 3 A method for preparing monodisperse polycaprolactone microspheres includes the following steps: S1) Under constant room temperature conditions, polymethyl methacrylate seeds (particle size 6 μm, CV = 2.8%) were added to an aqueous solution containing carboxymethyl cellulose and stirred thoroughly to form a uniformly dispersed seed suspension for later use. The polymer seed solid content in the seed suspension was 10 g / L, and the weight ratio of polymethyl methacrylate seeds to carboxymethyl cellulose was 10:1. S2) Add 2g of polycaprolactone to 10g of dichloromethane and stir until it is completely dissolved to form the polycaprolactone oil phase; S3) Prepare a polycaprolactone suspension by mixing the polycaprolactone oil phase from S2 with an aqueous solution containing carboxymethyl cellulose in a certain proportion; the weight ratio of the polycaprolactone oil phase to carboxymethyl cellulose is 5:1; S4) Add the polycaprolactone suspension to the seed suspension, controlling the addition rate of the polycaprolactone suspension to 5 mL / min. Stop adding the polycaprolactone once it has been completely absorbed by the seeds and swollen to reach the predetermined particle size. S5) Polycaprolactone microspheres can be obtained by evaporation at 60°C to remove the organic solvent.

[0022] The particle size and particle size distribution of the prepared monodisperse polycaprolactone microspheres were determined using the Beckman Counter, and the results showed that the particle size was 25 μm and the coefficient of variation (CV) was 2.7%.

[0023] Example 4 A method for preparing monodisperse polycaprolactone microspheres includes the following steps: S1) Under constant room temperature conditions, polymethyl methacrylate seeds (particle size 8 μm, CV = 2.6%) were added to an aqueous solution containing carboxymethyl cellulose and stirred thoroughly to form a uniformly dispersed seed suspension for later use. The polymer seed solid content in the seed suspension was 10 g / L, and the weight ratio of polymethyl methacrylate seeds to carboxymethyl cellulose was 10:1. S2) Add 2g of polycaprolactone to 10g of dichloromethane and stir until it is completely dissolved to form the polycaprolactone oil phase; S3) Prepare a polycaprolactone suspension by mixing the polycaprolactone oil phase from S2 with an aqueous solution containing carboxymethyl cellulose in a certain proportion; the weight ratio of the polycaprolactone oil phase to carboxymethyl cellulose is 5:1; S4) Add the polycaprolactone suspension to the seed suspension, controlling the addition rate of the polycaprolactone suspension to 5 mL / min. Stop adding the polycaprolactone once it has been completely absorbed by the seeds and swollen to reach the predetermined particle size. S5) Monodisperse polycaprolactone microspheres can be obtained by evaporation at 50°C to remove the organic solvent.

[0024] The particle size and particle size distribution of the prepared monodisperse polycaprolactone microspheres were determined using the Beckman Counter, and the results showed that the particle size was 30 μm and the coefficient of variation (CV) was 2.5%.

[0025] Example 5 A method for preparing monodisperse polycaprolactone microspheres includes the following steps: S1) Under constant room temperature conditions, polymethyl methacrylate seeds (particle size 10 μm, CV = 2.8%) were added to an aqueous solution containing carboxymethyl cellulose and stirred thoroughly to form a uniformly dispersed seed suspension for later use. The polymer seed solid content in the seed suspension was 10 g / L, and the weight ratio of polymethyl methacrylate seeds to carboxymethyl cellulose was 10:1. S2) Add 2g of polycaprolactone to 10g of dichloromethane and stir until it is completely dissolved to form the polycaprolactone oil phase; S3) Prepare a polycaprolactone suspension by mixing the polycaprolactone oil phase from S2 with an aqueous solution containing carboxymethyl cellulose in a certain proportion; the weight ratio of the polycaprolactone oil phase to carboxymethyl cellulose is 5:1; S4) Add the polycaprolactone suspension to the seed suspension, controlling the addition rate of the polycaprolactone suspension to 5 mL / min. Stop adding the polycaprolactone once it has been completely absorbed by the seeds and swollen to reach the predetermined particle size. S5) Monodisperse polycaprolactone microspheres can be obtained by evaporation at 50°C to remove the organic solvent.

[0026] The particle size and particle size distribution of the prepared monodisperse polycaprolactone microspheres were determined using the Beckman Counter, and the results showed that the particle size was 40 μm and the coefficient of variation (CV) was 2.6%.

[0027] Example 6 A method for preparing monodisperse polycaprolactone microspheres includes the following steps: S1) Under constant room temperature conditions, polymethyl methacrylate seeds (particle size 15 μm, CV = 2.8%) were added to an aqueous solution containing carboxymethyl cellulose and stirred thoroughly to form a uniformly dispersed seed suspension for later use. The polymer seed solid content in the seed suspension was 10 g / L, and the weight ratio of polymethyl methacrylate seeds to carboxymethyl cellulose was 10:1. S2) Add 2g of polycaprolactone to 10g of dichloromethane and stir until it is completely dissolved to form the polycaprolactone oil phase; S3) Prepare a polycaprolactone suspension by mixing the polycaprolactone oil phase from S2 with an aqueous solution containing carboxymethyl cellulose in a certain proportion; the weight ratio of the polycaprolactone oil phase to carboxymethyl cellulose is 5:1; S4) Add the polycaprolactone suspension to the seed suspension, controlling the addition rate of the polycaprolactone suspension to 5 mL / min. Stop adding the polycaprolactone once it has been completely absorbed by the seeds and swollen to reach the predetermined particle size. S5) Monodisperse polycaprolactone microspheres can be obtained by evaporation at 60°C to remove the organic solvent.

[0028] The particle size and particle size distribution of the prepared monodisperse polycaprolactone microspheres were determined using the Beckman Counter, and the results showed that the particle size was 60 μm and the coefficient of variation (CV) was 2.5%.

[0029] The specific embodiments described herein are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains may make various modifications or additions to the described specific embodiments or use similar methods to substitute them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

Claims

1. A method for preparing monodisperse polycaprolactone microspheres, characterized in that, Includes the following steps: S1) Add polymer seeds to an aqueous solution containing a first surfactant to form a uniformly dispersed seed suspension; S2) Add polycaprolactone to an organic solvent and stir until it is completely dissolved to form a polycaprolactone oil phase; S3) The polycaprolactone oil phase is mixed with an aqueous solution containing a second surfactant to prepare a polycaprolactone suspension, wherein the second surfactant is hydroxypropyl methylcellulose and / or carboxymethyl cellulose, and the mass ratio of the second surfactant to the polycaprolactone oil phase is 1: (5-10). S4) Add the polycaprolactone suspension dropwise to the seed suspension at a constant rate until the polycaprolactone is completely absorbed by the seeds and swells to reach the predetermined particle size. S5) The organic solvent is removed by heating and evaporation to obtain monodisperse polycaprolactone microspheres. The particle size of the monodisperse polycaprolactone microspheres can be controlled at any value within the range of 5-100 μm.

2. The method for preparing monodisperse polycaprolactone microspheres according to claim 1, characterized in that, The polymer seed mentioned in S1 is a polymethyl methacrylate seed or a polystyrene seed.

3. The method for preparing monodisperse polycaprolactone microspheres according to claim 1, characterized in that, The polymer seeds described in S1 have uniform particle size, ranging from 2 to 5 μm, and their CV ≤ 2.8%.

4. The method for preparing monodisperse polycaprolactone microspheres according to claim 1, characterized in that, In S1, the first surfactant is hydroxypropyl methylcellulose and / or carboxymethyl cellulose, and its mass ratio with the polymer seed is 1:(10-15).

5. The method for preparing monodisperse polycaprolactone microspheres according to claim 1, characterized in that, The organic solvent mentioned in S2 is one or more of dichloromethane, dimethyl sulfoxide, or tetrahydrofuran.

6. The method for preparing monodisperse polycaprolactone microspheres according to claim 1, characterized in that, The drop rate in S4 is 0.1-100 mL / min.

7. The method for preparing monodisperse polycaprolactone microspheres according to claim 1, characterized in that, The heating rate in S5 is 1-10℃ / min, and the temperature rises to 40-80℃.

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