A polycaprolactone microsphere with a narrow particle size distribution and a preparation method thereof

Abstract

The present invention belongs to the field of biomedicine, and particularly relates to a polycaprolactone microsphere with a narrow particle size distribution and a preparation method thereof. The preparation method comprises the following steps: S1, dissolving polycaprolactone in an organic solvent to obtain an oil-phase solution; S2, adding an emulsifier into water and stirring to completely dissolve the emulsifier to obtain an aqueous-phase solution; S3, adding the aqueous-phase solution into the oil-phase solution under stirring to obtain a primary emulsion; S4, passing the primary emulsion through the pores of a membrane tube under a pressurized condition to form polycaprolactone droplets in the aqueous-phase solution, and the polycaprolactone droplets are carried away by the circulating aqueous-phase solution to obtain a suspension emulsion; S5, stirring the above suspension emulsion to remove the organic solvent and solidify the microspheres to obtain a polycaprolactone microsphere suspension; S6, washing and sieving the above polycaprolactone microsphere suspension with water to obtain wet microspheres; S7, collecting the above wet microspheres, screening after drying to obtain polycaprolactone microspheres, with a high yield, uniform particle size, and a particle size span ≤ 0.8.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a polycaprolactone microsphere with a narrow particle size distribution and a preparation method thereof. Background Art

[0002] Polycaprolactone is an aliphatic polyester polymer with good biocompatibility, biodegradability, and bioabsorbability. Compared with other biodegradable polymers, it has more excellent viscoelasticity, which makes polycaprolactone easy to be processed into different material structures such as microspheres, fibers, nanofibers, etc.

[0003] In the field of medical aesthetics, polycaprolactone is a commonly used facial filling material. Polycaprolactone microspheres are dispersed in a gel material, and after injection, they stimulate fibroblasts in the skin tissue to produce collagen, which can maintain the filling effect of skin wrinkles for a long time.

[0004] Currently, the commonly used microsphere preparation methods mainly include mechanical dispersion method, spray drying method, membrane emulsification method, etc. The microspheres prepared by the mechanical dispersion method and the spray drying method have non-uniform particle sizes and a wide particle size distribution, making it difficult to control the particle size and distribution of the microspheres, and the preparation process has poor reproducibility. Although there are studies on improving the preparation process of polycaprolactone microspheres, there are still many problems. For example, the patent application CN114369263A discloses a polycaprolactone microsphere and a preparation method thereof. The polycaprolactone particles pulverized in liquid nitrogen are added to a hot aqueous solution containing a surfactant and stirred, and then after wet sieving, washing, centrifugation, drying, and dry sieving, polycaprolactone microspheres are obtained. Although this method avoids the use of organic solvents, the roundness of the microspheres prepared in its examples is poor under electron microscopy. Another example is that the patent application CN113694252A discloses a polycaprolactone microsphere of a soft tissue filler and a preparation method thereof. The emulsification solvent evaporation method is used to prepare polycaprolactone microspheres through the water-in-oil technology and the shear emulsification technology. The ratio of the water phase to the oil phase is too large. If the equipment volume is too large during production, it will increase the investment cost of the production line construction and make large-scale production difficult. Summary of the Invention

[0005] The present invention provides a polycaprolactone microsphere with a narrow particle size distribution and a preparation method thereof. The prepared polycaprolactone microspheres have a high yield, uniform particle sizes, a particle size span ≤ 0.8, good roundness, a smooth surface, and good fluidity.

[0006] The specific technical solutions are as follows:

[0007] The first object of the present invention is to provide a preparation method of a polycaprolactone microsphere with a narrow particle size distribution, comprising the following steps:

[0008] S1. Dissolve polycaprolactone in an organic solvent to obtain an oil phase solution;

[0009] S2. Add the emulsifier to water and stir to completely dissolve the emulsifier to obtain an aqueous solution.

[0010] S3. Add the aqueous solution to the oil phase solution under stirring to obtain a primary emulsion.

[0011] S4. Pass the primary emulsion through the pores of the membrane tube under pressure to form polycaprolactone droplets in the aqueous solution, and the droplets are carried away by the circulating aqueous solution to obtain a suspension emulsion.

[0012] S5. Stir the above suspension emulsion at an appropriate temperature to remove the organic solvent and solidify the microspheres to obtain a polycaprolactone microsphere suspension.

[0013] S6. Wash and screen the above polycaprolactone microsphere suspension with water to obtain wet microspheres.

[0014] S7. Collect the above wet microspheres, screen them after drying to obtain polycaprolactone microspheres.

[0015] Further, in step S1, the intrinsic viscosity of the polycaprolactone is 0.2 - 1.2 dL / g. Optionally, the intrinsic viscosity of the polycaprolactone is any value between 0.2 dL / g, 0.4 dL / g, 0.8 dL / g and 1.2 dL / g or any two of them.

[0016] Further, in step S1, when preparing the oil phase solution, the organic solvent for dissolving the polycaprolactone can be one or more of dichloromethane, chloroform, acetone and tetrahydrofuran, preferably dichloromethane.

[0017] Further, in step S1, the weight percentage of polycaprolactone to the organic solvent in the oil phase solution is 5 - 25% (w / w), for example, any value between 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), 9% (w / w), 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), 15% (w / w), 16% (w / w), 17% (w / w), 18% (w / w), 19% (w / w), 20% (w / w), 21% (w / w), 22% (w / w), 23% (w / w), 24% (w / w), 25% (w / w) or any value between any two of them, preferably 10 - 20% (w / w).

[0018] Further, in step S2, when preparing the aqueous solution, the emulsifier is one or more of polyvinyl alcohol, Tween 80 and polyvinylpyrrolidone, preferably polyvinyl alcohol.

[0019] Further, in step S2, the weight - volume percentage of the emulsifier to water in the aqueous solution is 0.15 - 1.5% (w / v), such as any value among 0.15% (w / v), 0.25% (w / v), 0.35% (w / v), 0.45% (w / v), 0.55% (w / v), 0.65% (w / v), 0.75% (w / v), 0.85% (w / v), 1.0% (w / v) and 1.5%, or any value between any two of them, and preferably 0.2 - 0.6% (w / v).

[0020] Further, in step S3, the volume ratio of the aqueous solution to the oil - phase solution is 1:5 - 1:30, such as any value among 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29 and 1:30, or any value between any two of them, and preferably 1:6 - 1:20; the stirring speed is 300 - 800 rpm, such as any value among 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm and 800 rpm, or any value between any two of them; the stirring time is 5 - 30 min, such as any value among 5 min, 10 min, 15 min, 20 min, 25 min and 30 min, or any value between any two of them.

[0021] Further, in step S4, pressurization is carried out with an inert gas, preferably nitrogen, and the pressure range of the nitrogen is 5 - 20 kPa, such as any value among 5 KPa, 6 KPa, 7 KPa, 8 KPa, 9 KPa, 10 KPa, 11 KPa, 12 KPa, 13 Kpa, 14 Kpa, 15 KPa, 16 Kpa, 17 Kpa, 18 Kpa, 19 Kpa and 20 KPa, or any value between any two of them; the pore diameter of the membrane tube is 10 - 25 μm, such as any value among 10 μm, 15 μm, 20 μm and 25 μm, or any value between any two of them.

[0022] Further, in step S4, the volume ratio of the primary emulsion to the aqueous solution is 1:8 - 1:20, such as any value among 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 and 1:20, or any value between any two of them.

[0023] Further, in step S5, the temperature for curing the microspheres is 25 to 40 °C, the stirring speed is 100 to 600 rpm, and the stirring time is 6 to 30 hours. For example, the curing temperature is any one of 25 °C, 30 °C, 35 °C, and 40 °C or a value between any two of them; the stirring speed is any one of 100 rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, and 600 rpm or a value between any two of them; the stirring time is any one of 8 hours, 12 hours, 16 hours, 18 hours, 22 hours, 26 hours, and 30 hours or a value between any two of them.

[0024] Further, in step S6, the pore sizes of the sieves used for filtering the polycaprolactone microsphere suspension are 60 μm and 25 μm, respectively.

[0025] Further, in step S7, the sieve used for sieving after drying is 60 μm, and polycaprolactone microspheres with a size of 25 to 60 μm are obtained. The D50 range of the polycaprolactone microspheres is 30 to 45 μm.

[0026] The second object of the present invention is to provide a polycaprolactone microsphere with a narrow particle size distribution, which is prepared by the preparation method described above, and the particle size span of the polycaprolactone microsphere is ≤0.8.

[0027] It should be noted that the particle size span (Span) = (D90 - D10) / D50, where D10 refers to the particle size corresponding to when the cumulative particle size distribution number of the polycaprolactone microspheres reaches 10%. D50 refers to the particle size corresponding to when the cumulative particle size distribution percentage of the polycaprolactone microspheres reaches 50%. D90 refers to the particle size corresponding to when the cumulative particle size distribution number of the polycaprolactone microspheres reaches 90%. A smaller particle size span of the microspheres indicates that their particle sizes are more uniform.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0029] In the preparation method of the present invention, first, an aqueous solution is added to an oil-phase solution to prepare a water-in-oil (w / o) primary emulsion. Then, the primary emulsion is added to an aqueous solution through the membrane pores of a membrane tube under pressure to prepare a water-in-oil-in-water (w / o / w) polycaprolactone suspension emulsion. After that, through steps such as curing, washing and sieving, and drying, polycaprolactone microspheres are obtained. Specifically, polycaprolactone with an intrinsic viscosity of 0.2 - 1.2 dL / g is used. By controlling the concentration of polycaprolactone in the oil-phase solution to be 5 - 25% (w / w) and the concentration of the emulsifier in the aqueous solution to be 0.15 - 1.5% (w / w), when preparing the primary emulsion, the volume ratio of the aqueous solution to the oil-phase solution is 1:5 - 1:30. The pressure for the primary emulsion to pass through the membrane tube is controlled to be 5 - 20 Kpa, and the volume ratio of the primary emulsion to the aqueous solution is 1:8 - 1:20. After stirring at 25 - 40 °C and a stirring speed of 100 - 600 rpm for 6 - 30 hours, the organic solvent is volatilized to complete curing. After washing and sieving with 60 μm and 25 μm sieve meshes and drying, passing through a 60 μm sieve mesh, polycaprolactone microspheres with uniform particle size, good roundness, smooth surface, and good fluidity can be prepared, and the prepared polycaprolactone microspheres have a high particle yield, a narrow particle size distribution, a small particle size span, and the particle size span ≤ 0.8. Description of the Drawings

[0030] Figure 1 It is a microscope image of the polycaprolactone microspheres prepared in Example 1 of the present invention;

[0031] Figure 2 It is a microscope image of the polycaprolactone microspheres prepared in Example 2 of the present invention;

[0032] Figure 3 It is a microscope image of the polycaprolactone microspheres prepared in Example 3 of the present invention;

[0033] Figure 4 It is a microscope image of the polycaprolactone microspheres prepared in Example 4 of the present invention;

[0034] Figure 5 It is a microscope image of the polycaprolactone microspheres prepared in Example 5 of the present invention;

[0035] Figure 6 It is a microscope image of the polycaprolactone microspheres prepared in Example 6 of the present invention;

[0036] Figure 7 It is a microscope image of the polycaprolactone microspheres prepared in Comparative Example 1 of the present invention;

[0037] Figure 8 It is a microscope image of the polycaprolactone microspheres prepared in Comparative Example 2 of the present invention;

[0038] Figure 9 It is a microscope image of the polycaprolactone microspheres prepared in Comparative Example 3 of the present invention;

[0039] Figure 10 Electron microscope of the polycaprolactone microspheres prepared in Example 4 of the present invention Figure 1 ;

[0040] Figure 11 Electron microscope of the polycaprolactone microspheres prepared in Example 4 of the present invention Figure 2 ;

[0041] Figure 12 Electron microscope of the polycaprolactone microspheres prepared in Example 4 of the present invention Figure 3 。 Detailed implementation manners

[0042] The principles and features of the present invention will be described below in conjunction with examples. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0043] Example 1

[0044] A method for preparing polycaprolactone microspheres with a narrow particle size distribution, comprising the following steps:

[0045] S1. Dissolve 10 g of polycaprolactone with an intrinsic viscosity of 0.22 dL / g in 100 g of dichloromethane to obtain an oil-phase solution;

[0046] S2. Dissolve 1.5 g of polyvinyl alcohol in 1000 ml of water to obtain an aqueous-phase solution;

[0047] S3. Measure 4 ml of the aqueous-phase solution, add it to 80 ml of the oil-phase solution, and stir at 400 rpm for 10 min to obtain a primary emulsion;

[0048] S4. Pass the primary emulsion through a membrane tube with a pore diameter of 10 μm under a nitrogen pressure of 9 kPa to form polycaprolactone droplets in 900 ml of circulating aqueous-phase solution, and the droplets are carried away by the circulating aqueous-phase solution to obtain a suspension emulsion;

[0049] S5. Stir the above suspension emulsion at 300 rpm for 12 h at 30 °C to remove the organic solvent dichloromethane and solidify the microspheres to obtain a polycaprolactone microsphere suspension;

[0050] S6. Rinse the above polycaprolactone microsphere suspension with water and filter it through a sieve. The sieve with a pore diameter of 60 μm is on top and the sieve with a pore diameter of 25 μm is at the bottom. Collect the microspheres between the 25-μm and 60-μm sieves to obtain wet microspheres;

[0051] S7. After drying the above wet microspheres at 35 °C, pass them through a 60-μm sieve again to obtain polycaprolactone microspheres.

[0052] Example 2

[0053] A method for preparing polycaprolactone microspheres with a narrow particle size distribution, comprising the following steps:

[0054] S1. Dissolve 12.5 g of polycaprolactone with an intrinsic viscosity of 0.22 dL / g in 50 g of dichloromethane to obtain an oil-phase solution;

[0055] S2. Dissolve 3 g of polyvinyl alcohol in 600 ml of water to obtain an aqueous-phase solution;

[0056] S3. Measure 2 ml of the aqueous-phase solution and add it to 40 ml of the oil-phase solution, and stir at 350 rpm for 8 min to obtain a primary emulsion;

[0057] S4. Pass the primary emulsion through a membrane tube with a pore diameter of 15 μm under a nitrogen pressure of 11 kPa, and form polycaprolactone droplets in 500 ml of circulating aqueous-phase solution, and be carried away by the circulating aqueous-phase solution to obtain a suspension emulsion;

[0058] S5. Stir the above suspension emulsion at 300 rpm at 36 °C for 10 h to remove the organic solvent dichloromethane and solidify the microspheres to obtain a polycaprolactone microsphere suspension;

[0059] S6. Rinse the above polycaprolactone microsphere suspension with water and filter it through a sieve. The sieve with a pore diameter of 60 μm is on top and the sieve with a pore diameter of 25 μm is at the bottom, and collect the microspheres between the 25-μm and 60-μm sieves to obtain wet microspheres;

[0060] S7. After drying the above wet microspheres at 35 °C, pass them through a 60-μm sieve again to obtain polycaprolactone microspheres.

[0061] Example 3

[0062] A method for preparing polycaprolactone microspheres with a narrow particle size distribution, comprising the following steps:

[0063] S1. Dissolve 10 g of polycaprolactone with an intrinsic viscosity of 0.22 dL / g in 50 g of dichloromethane to obtain an oil-phase solution;

[0064] S2. Dissolve 2.5 g of polyvinyl alcohol in 900 ml of water to obtain an aqueous-phase solution;

[0065] S3. Measure 5.5 ml of the aqueous-phase solution and add it to 40 ml of the oil-phase solution, and stir at 350 rpm for 8 min to obtain a primary emulsion;

[0066] S4. Pass the primary emulsion through a membrane tube with a pore diameter of 15 μm under a nitrogen pressure of 10.5 kPa, and form polycaprolactone droplets in 800 ml of circulating aqueous-phase solution, and be carried away by the circulating aqueous-phase solution to obtain a suspension emulsion;

[0067] S5. Stir the above suspension emulsion at 36 °C at a rotation speed of 300 rpm for 10 h, remove the organic solvent dichloromethane, and solidify the microspheres to obtain a polycaprolactone microsphere suspension;

[0068] S6. Wash the above polycaprolactone microsphere suspension with water and filter it through a sieve. The sieve with a pore size of 60 μm is on top, and the sieve with a pore size of 25 μm is at the bottom. Collect the microspheres between the 25-μm and 60-μm sieves to obtain wet microspheres;

[0069] S7. After drying the above wet microspheres at 35 °C, pass them through a 60-μm sieve again to obtain polycaprolactone microspheres.

[0070] Example 4

[0071] A method for preparing polycaprolactone microspheres with a narrow particle size distribution, comprising the following steps:

[0072] S1. Dissolve 100 g of polycaprolactone with an intrinsic viscosity of 0.22 dL / g in 500 g of dichloromethane to obtain an oil-phase solution;

[0073] S2. Dissolve 12.5 g of polyvinyl alcohol in 5000 ml of water to obtain an aqueous-phase solution;

[0074] S3. Measure 36 ml of the aqueous-phase solution, add it to 450 ml of the oil-phase solution, and stir at 500 rpm for 8 min to prepare a primary emulsion;

[0075] S4. Pass the primary emulsion through a membrane tube with a pore size of 15 μm under a nitrogen pressure of 11 kPa to form polycaprolactone droplets in 4750 ml of circulating aqueous-phase solution, and be carried away by the circulating aqueous-phase solution to obtain a suspension emulsion;

[0076] S5. Stir the above suspension emulsion at 35 °C at a rotation speed of 400 rpm for 28 h, remove the organic solvent dichloromethane, and solidify the microspheres to obtain a polycaprolactone microsphere suspension;

[0077] S6. Wash the above polycaprolactone microsphere suspension with water and filter it through a sieve. The sieve with a pore size of 60 μm is on top, and the sieve with a pore size of 25 μm is at the bottom. Collect the microspheres between the 25-μm and 60-μm sieves to obtain wet microspheres;

[0078] S7. After drying the above wet microspheres at 35 °C, pass them through a 60-μm sieve again to obtain polycaprolactone microspheres.

[0079] Example 5

[0080] A method for preparing polycaprolactone microspheres with a narrow particle size distribution, comprising the following steps:

[0081] S1. Dissolve 15 g of polycaprolactone with an intrinsic viscosity of 0.43 dL / g in 100 g of dichloromethane to obtain an oil-phase solution;

[0082] S2. Dissolve 8 g of polyvinyl alcohol in 1000 ml of water to obtain an aqueous-phase solution;

[0083] S3. Measure 5 ml of the aqueous-phase solution and add it to 80 ml of the oil-phase solution. Stir at 350 rpm for 8 min to obtain a primary emulsion;

[0084] S4. Pass the primary emulsion through a membrane tube with a pore size of 10 μm under a nitrogen pressure of 13.5 kPa. Polycaprolactone droplets are formed in 900 ml of circulating aqueous-phase solution and are carried away by the circulating aqueous-phase solution to obtain a suspension emulsion;

[0085] S5. Stir the above suspension emulsion at 400 rpm for 10 h at 38 °C to remove the organic solvent dichloromethane and solidify the microspheres to obtain a polycaprolactone microsphere suspension;

[0086] S6. Rinse the above polycaprolactone microsphere suspension with water and filter it through a sieve. The sieve with a pore size of 60 μm is on top and the sieve with a pore size of 25 μm is at the bottom. Collect the microspheres between the 25-μm and 60-μm sieves to obtain wet microspheres;

[0087] S7. Dry the above wet microspheres at 35 °C and then pass them through a 60-μm sieve again to obtain polycaprolactone microspheres.

[0088] Example 6

[0089] A method for preparing polycaprolactone microspheres with a narrow particle size distribution, comprising the following steps:

[0090] S1. Dissolve 7 g of polycaprolactone with an intrinsic viscosity of 0.81 dL / g in 140 g of dichloromethane to obtain an oil-phase solution;

[0091] S2. Dissolve 15 g of polyvinyl alcohol and 7.5 g of Tween 80 in 1500 ml of water to obtain an aqueous-phase solution;

[0092] S3. Measure 6.6 ml of the aqueous-phase solution and add it to 110 ml of the oil-phase solution. Stir at 500 rpm for 12 min to obtain a primary emulsion;

[0093] S4. Pass the primary emulsion through a membrane tube with a pore size of 15 μm under a nitrogen pressure of 20 kPa. Polycaprolactone droplets are formed in 1400 ml of circulating aqueous-phase solution and are carried away by the circulating aqueous-phase solution to obtain a suspension emulsion;

[0094] S5. Stir the above suspension emulsion at 35 °C at a speed of 500 rpm for 14 h, remove the organic solvent dichloromethane to solidify the microspheres, and obtain a polycaprolactone microsphere suspension;

[0095] S6. Rinse the above polycaprolactone microsphere suspension with water and filter it through a sieve. The 60-μm aperture sieve is on top and the 25-μm aperture sieve is at the bottom. Collect the microspheres between the 25-μm and 60-μm sieves to obtain wet microspheres;

[0096] S7. After drying the above wet microspheres at 35 °C, pass them through a 60-μm sieve again to obtain polycaprolactone microspheres.

[0097] Comparative Example 1

[0098] A method for preparing polycaprolactone microspheres, comprising the following steps:

[0099] S1. Dissolve 10 g of polycaprolactone with an intrinsic viscosity of 0.22 dL / g in 90 g of dichloromethane to obtain an oil-phase solution;

[0100] S2. Dissolve 10 g of methylcellulose in 1000 ml of water to obtain an aqueous-phase solution;

[0101] S3. Add the oil-phase solution to the aqueous-phase solution under stirring and stir at 1200 rpm for 25 min to prepare a polycaprolactone suspension emulsion;

[0102] S4. Stir the above polycaprolactone suspension emulsion at 38 °C at a speed of 300 rpm for 14 h to obtain a polycaprolactone microsphere suspension;

[0103] S5. Filter the above polycaprolactone microsphere suspension through a sieve. The 60-μm sieve is on top and the 25-μm sieve is at the bottom. Collect the microspheres between the 25-μm and 60-μm sieves to obtain wet microspheres;

[0104] S6. After drying the above wet microspheres at 35 °C, pass them through a 60-μm sieve again to obtain polycaprolactone microspheres.

[0105] Comparative Example 2

[0106] A method for preparing polycaprolactone microspheres, comprising the following steps:

[0107] S1. Dissolve 24 g of polycaprolactone with an intrinsic viscosity of 0.22 dL / g in 90 g of dichloromethane to obtain an oil-phase solution;

[0108] S2. Dissolve 20 g of sodium dodecyl sulfate in 1000 ml of water to obtain an aqueous-phase solution;

[0109] S3. Pass the oil phase solution through a membrane tube with a pore diameter of 10 μm under a nitrogen pressure of 25 kPa, form polycaprolactone droplets in 1000 ml of circulating aqueous solution, and be carried away by the circulating aqueous solution to obtain a suspension emulsion;

[0110] S4. Stir the above suspension emulsion at 42 °C at a speed of 300 rpm for 14 h to obtain a polycaprolactone microsphere suspension;

[0111] S5. Filter the above polycaprolactone microsphere suspension with a sieve, with a 60 μm sieve on top and a 25 μm sieve on the bottom, collect the microspheres between the 25 μm and 60 μm sieves to obtain wet microspheres;

[0112] S6. After drying the above wet microspheres at 35 °C, pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0113] Comparative Example 3

[0114] A method for preparing polycaprolactone microspheres, comprising the following steps:

[0115] S1. Dissolve 10 g of polycaprolactone with an intrinsic viscosity of 0.22 dL / g in 90 g of dichloromethane to obtain an oil phase solution;

[0116] S2. Dissolve 5 g of polyvinyl alcohol in 1000 ml of water to obtain an aqueous solution;

[0117] S3. Pass the oil phase solution through a membrane tube with a pore diameter of 15 μm under a nitrogen pressure of 9.5 kPa in 1000 ml of circulating aqueous solution to form polycaprolactone droplets, and be carried away by the circulating aqueous solution to obtain a suspension emulsion;

[0118] S4. Stir the above suspension emulsion at 38 °C at a speed of 300 rpm for 14 h to obtain a polycaprolactone microsphere suspension;

[0119] S5. Filter the above polycaprolactone microsphere suspension with a sieve, with a 100 μm sieve on top and a 25 μm sieve on the bottom, collect the microspheres between the 25 μm and 100 μm sieves to obtain wet microspheres;

[0120] S6. After drying the above wet microspheres at 35 °C, pass them through a 100 μm sieve again to obtain polycaprolactone microspheres.

[0121] Test:

[0122] (1) Observe the polycaprolactone microspheres obtained after drying in Examples 1-6 and Comparative Examples 1-3 under a microscope, and the results are as Figures 1 to 9 shown.

[0123] By comparison Figures 1 to 6 and Figures 7 to 9It can be seen that the polycaprolactone microspheres prepared in each embodiment of the present invention have a more regular shape and more uniform particle size.

[0124] (2) The polycaprolactone microspheres obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were detected by a laser particle size analyzer, the particle size distribution and span of the microspheres were statistically analyzed, and the yields of the polycaprolactone microspheres in Examples 1 to 6 and Comparative Examples 1 to 3 were calculated. The results are shown in Table 1. It should be noted that the yield = (weight of the dried microspheres received / weight of the polycaprolactone input) × 100%, and the microsphere span = (D90 - D10) / D50. The smaller the value, the better the particle size uniformity.

[0125] Table 1 Experimental data of yields and spans of each example and comparative example

[0126]

[0127] The results in Table 1 show that the yields of the polycaprolactone microspheres prepared in each example are significantly higher than those in each comparative example, and the span values are all less than 0.8. In Comparative Example 1, polycaprolactone microspheres were prepared by a stirring and shearing method, with a relatively wide particle size distribution and a low microsphere yield; the yields of the polycaprolactone microspheres prepared in Comparative Examples 2 and 3 were higher than that in Comparative Example 1, but the Span values were larger than those in the examples. In Comparative Example 3, due to filtration through a 100 μm sieve, the Span value of the obtained microspheres was slightly larger than that of the microspheres obtained in Comparative Example 2.

[0128] (3) The polycaprolactone microspheres obtained in Example 4 were observed under an electron microscope, and the results are as Figures 10 to 12 shown.

[0129] Figures 10 to 12 In, it was observed under the electron microscope that the polycaprolactone microspheres prepared in Example 4 had good roundness, a smooth surface, and relatively uniform particle sizes.

[0130] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing polycaprolactone microspheres with narrow particle size distribution, characterized in that: The following steps are involved: S1, dissolving polycaprolactone in an organic solvent to obtain an oil phase solution; S2, adding an emulsifier into water and stirring to completely dissolve the emulsifier to obtain an aqueous phase solution; S3, adding the aqueous phase solution to the oil phase solution under stirring to obtain a primary emulsion; S4, passing the primary emulsion through the membrane pores of the membrane tube under pressure to form polycaprolactone droplets in the aqueous solution, which are carried away by the circulating aqueous solution to obtain a suspension emulsion; S5, stirring the above suspension emulsion, removing the organic solvent, solidifying the microspheres, and obtaining a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and sieving it to obtain wet microspheres; S7, collecting the wet balls, drying them and sieving them to obtain polycaprolactone microspheres; Wherein, in step S1, the intrinsic viscosity of the polycaprolactone is 0.2-1.2 dL / g, and the weight percentage of the polycaprolactone and the organic solvent in the oil phase solution is 5-25% (w / w); In step S2, the emulsifier is one or more of polyvinyl alcohol, Tween 80 and povidone, and the weight volume percentage of the emulsifier and water in the aqueous phase solution is 0.15-1.5% (w / v); In step S3, the volume ratio of the aqueous phase solution to the oil phase solution is 1:5 to 1:30, the stirring speed is 300 to 800 rpm, and the stirring time is 5 to 30 min; In step S4, the inert gas is pressurized, and the pressure range of the inert gas is 5 to 20 kPa; the pore size of the membrane tube is 10 to 25 μm, and the volume ratio of the primary emulsion to the aqueous phase solution is 1:8 to 1:

20.

2. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: In step S5, the microspheres are solidified at a temperature of 25 to 40°C, a stirring speed of 100 to 600 rpm, and a stirring time of 6 to 30 hours.

3. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: In step S6, the mesh sizes used for filtering the polycaprolactone microsphere suspension are 60 μm and 25 μm respectively.

4. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: In step S7, the sieve used for sieving after drying is 60 μm, and polycaprolactone microspheres of 25 to 60 μm are obtained. The D50 range of the polycaprolactone microspheres is 30 to 45 μm.

5. A polycaprolactone microsphere with a narrow particle size distribution, characterized in that: The preparation is obtained by the preparation method according to any one of claims 1 to 4.

Images