Polycaprolactone microspheres with narrow particle size distribution and preparation method thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a polycaprolactone microsphere with 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 until the emulsifier is completely dissolved to obtain a water-phase solution; s3, adding the water-phase solution into the oil-phase solution while stirring to obtain a primary emulsion; s4, enabling the primary emulsion to pass through membrane holes of a membrane tube under a pressurization condition, forming polycaprolactone liquid drops in the aqueous phase solution, and taking away the polycaprolactone liquid drops by the circularly flowing aqueous phase solution to obtain a suspension emulsion; s5, stirring the suspension emulsion, removing the organic solvent, and curing the microspheres to obtain a polycaprolactone microsphere suspension; s6, the polycaprolactone microsphere suspension is washed with water and sieved, and wet pellets are obtained; s7, the wet pellets are collected, dried and screened, the polycaprolactone microspheres are obtained, the yield is high, the particle size is uniform, and the particle size span is smaller than or equal to 0.8.

Description

Technical Field

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

[0002] Polycaprolactone is a biocompatible, biodegradable, and bioabsorbable aliphatic polyester polymer. Compared with other biodegradable polymers, it has superior viscoelasticity, which makes it easy to process polycaprolactone into different material structures such as microspheres, fibers, nanofibers, etc.

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

[0004] At present, the commonly used microsphere preparation method mainly includes mechanical dispersion method, spray drying method, membrane emulsification method, etc. The microsphere particle size prepared by mechanical dispersion method and spray drying method is uneven, and the particle size distribution is wide, it is difficult to regulate the particle size and distribution of microspheres, and the preparation process has poor reproducibility. Although there are studies to improve the preparation process of polycaprolactone microspheres, there are still many problems. For example, invention patent application CN114369263A discloses a kind of polycaprolactone microsphere and its preparation method, the polycaprolactone particles crushed in liquid nitrogen are added to the hot aqueous solution containing surfactant and stirred, and then after wet ball screening, washing, centrifugation, drying, dry ball screening, polycaprolactone microspheres are obtained. Although this method avoids the use of organic solvents, the microspheres prepared by its embodiment are poor in roundness under electron microscope observation. For another example, invention patent application CN113694252A discloses polycaprolactone microspheres for soft tissue fillers and a preparation method thereof. The polycaprolactone microspheres are prepared by an emulsified solvent volatilization method, using water-in-oil technology and 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, the investment cost of the production line construction will increase, making production more difficult. Summary of the invention

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

[0006] The specific technical solutions are as follows: The first object of the present invention is to provide a method for preparing polycaprolactone microspheres with narrow particle size distribution, comprising 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 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 at an appropriate temperature, removing the organic solvent, and solidifying the microspheres to obtain a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and sieving it to obtain wet microspheres; S7. Collect the wet balls, dry them and sieve them to obtain polycaprolactone microspheres.

[0007] 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 one of 0.2 dL / g, 0.4 dL / g, 0.8 dL / g and 1.2 dL / g or a value between the two.

[0008] Furthermore, in step S1, when preparing the oil phase solution, the organic solvent for dissolving polycaprolactone can be one or more of dichloromethane, chloroform, acetone and tetrahydrofuran, preferably dichloromethane.

[0009] Further, in step S1, the weight percentage of polycaprolactone to organic solvent in the oil phase solution is 5-25% (w / w), for example, 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), any one or a value between two of them, preferably 10-20% (w / w).

[0010] Furthermore, in step S2, when preparing the aqueous phase solution, the emulsifier is one or more of polyvinyl alcohol, Tween 80 and povidone, preferably polyvinyl alcohol.

[0011] Further, in step S2, the weight volume percentage of the emulsifier and water in the aqueous phase solution is 0.15-1.5% (w / v), for example, 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, preferably 0.2-0.6% (w / v).

[0012] Further, in step S3, the volume ratio of the aqueous phase solution to the oil phase solution is 1:5 to 1:30, for example, 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. Any one or a value between the two is preferably 1:6-1:20; the stirring speed is 300-800 rpm, for example, any one or a value between 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm and 800 rpm; the stirring time is 5-30 min, for example, any one or a value between 5 min, 10 min, 15 min, 20 min, 25 min and 30 min.

[0013] Further, in step S4, pressurization is performed by an inert gas, preferably nitrogen, and the pressure range of the nitrogen is 5-20 kPa, for example, any one of 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 a value between any two of them; the pore size of the membrane tube is 10-25 μm, for example, any one of 10 μm, 15 μm, 20 μm and 25 μm, or a value between any two of them.

[0014] Further, in step S4, the volume ratio of the primary emulsion to the aqueous phase solution is 1:8 to 1:20, for example, any one of 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 a value between any two of them.

[0015] Further, in step S5, the microsphere curing temperature is 25-40°C, the stirring speed is 100-600rpm, and the stirring time is 6-30 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 100rpm, 200rpm, 300rpm, 400rpm, 500rpm and 600rpm 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.

[0016] Furthermore, in step S6, the mesh sizes used for filtering the polycaprolactone microsphere suspension are 60 μm and 25 μm respectively.

[0017] Furthermore, in step S7, the sieve used for screening after drying is 60 μm, and polycaprolactone microspheres of 25 to 60 μm are obtained, and the D50 range of the polycaprolactone microspheres is 30 to 45 μm.

[0018] The second object of the present invention is to provide polycaprolactone microspheres with narrow particle size distribution, which are prepared by the preparation method as described above, and the particle size span of the polycaprolactone microspheres is ≤0.8.

[0019] It should be noted that the particle size span (Span) = (D90-D10) / D50, D10 refers to the particle size corresponding to the cumulative particle size distribution of polycaprolactone microspheres reaching 10%. D50 refers to the particle size corresponding to the cumulative particle size distribution of polycaprolactone microspheres reaching 50%. D90 refers to the particle size corresponding to the cumulative particle size distribution of polycaprolactone microspheres reaching 90%. The smaller the particle size span of the microspheres, the more uniform their particle size.

[0020] Compared with the prior art, the present invention has the following beneficial effects: In the preparation method of the present invention, an aqueous phase solution is first added to an oil phase solution to prepare a water-in-oil (w / o) primary emulsion, and then the primary emulsion is added to the aqueous phase 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, and then the polycaprolactone microspheres are obtained through the steps of solidification, washing, screening, drying, etc. Specifically, polycaprolactone with an intrinsic viscosity of 0.2 to 1.2 dL / g is used, and the concentration of polycaprolactone in the oil phase solution is controlled to be 5 to 25% (w / w), and the concentration of the emulsifier in the aqueous phase solution is controlled to be 0.15 to 1.5% (w / w). When preparing the primary emulsion, the water The volume ratio of the phase solution to the oil phase solution is 1:5-1:30, the pressure of the primary emulsion passing through the membrane tube is controlled to be 5-20Kpa, the volume ratio of the primary emulsion to the water phase solution is 1:8-1:20, and the organic solvent is volatilized and removed after stirring at 25-40°C and a stirring speed of 100-600rpm for 6-30 hours to complete solidification, and the mixture is washed and sieved with 60μm and 25μm sieves, and then dried and sieved with a 60μm sieve to obtain polycaprolactone microspheres with uniform particle size, good roundness, smooth surface and good fluidity. The prepared polycaprolactone microspheres have high yield, narrow particle size distribution, small particle size span, and a particle size span of ≤0.8. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a microscope image of the polycaprolactone microspheres prepared in Example 1 of the present invention; Figure 2 This is a microscope image of the polycaprolactone microspheres prepared in Example 2 of the present invention; Figure 3 This is a microscope image of the polycaprolactone microspheres prepared in Example 3 of the present invention; Figure 4 This is a microscope image of polycaprolactone microspheres prepared in Example 4 of the present invention; Figure 5 This is a microscope image of the polycaprolactone microspheres prepared in Example 5 of the present invention; Figure 6 This is a microscope image of the polycaprolactone microspheres prepared in Example 6 of the present invention; Figure 7 This is a microscope image of the polycaprolactone microspheres prepared in Comparative Example 1 of the present invention; Figure 8 This is a microscope image of the polycaprolactone microspheres prepared in Comparative Example 2 of the present invention; Fig. 9 This is a microscope image of the polycaprolactone microspheres prepared in Comparative Example 3 of the present invention; Fig.10 Electron microscopy of polycaprolactone microspheres prepared in Example 4 of the present invention Figure 1 ; Fig.11 Electron microscopy of polycaprolactone microspheres prepared in Example 4 of the present invention Figure 2; Fig.12 Electron microscopy of polycaprolactone microspheres prepared in Example 4 of the present invention Figure 3 . DETAILED DESCRIPTION

[0022] The principles and features of the present invention are described below in conjunction with examples. The examples are only used to explain the present invention and are not used to limit the scope of the present invention.

[0023] Example 1 A method for preparing polycaprolactone microspheres with narrow particle size distribution comprises the following steps: S1, dissolving 10 g of polycaprolactone having an intrinsic viscosity of 0.22 dL / g in 100 g of dichloromethane to obtain an oil phase solution; S2, dissolving 1.5 g of polyvinyl alcohol in 1000 ml of water to obtain an aqueous phase solution; 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; S4, passing the primary emulsion through a membrane tube with a pore size of 10 μm under a nitrogen pressure of 9 kPa, forming polycaprolactone droplets in 900 ml of a circulating aqueous solution, and being carried away by the circulating aqueous solution to obtain a suspension emulsion; S5, stirring the suspension emulsion at 30° C. and 300 rpm for 12 h, removing the organic solvent dichloromethane to solidify the microspheres, and obtaining a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and filtering it with a sieve, with a 60 μm pore size sieve on top and a 25 μm pore size sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet balls; S7. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0024] Example 2 A method for preparing polycaprolactone microspheres with narrow particle size distribution comprises the following steps: S1, dissolving 12.5 g of polycaprolactone having an intrinsic viscosity of 0.22 dL / g in 50 g of dichloromethane to obtain an oil phase solution; S2, dissolving 3 g of polyvinyl alcohol in 600 ml of water to obtain an aqueous phase solution; S3, taking 2 ml of the aqueous phase solution, adding it to 40 ml of the oil phase solution, stirring at 350 rpm for 8 min, to obtain a primary emulsion; S4, passing the primary emulsion through a membrane tube with a pore size of 15 μm under a nitrogen pressure of 11 kPa, forming polycaprolactone droplets in 500 ml of a circulating aqueous solution, and being carried away by the circulating aqueous solution to obtain a suspension emulsion; S5, stirring the suspension emulsion at 36° C. and 300 rpm for 10 h, removing the organic solvent dichloromethane to solidify the microspheres, and obtaining a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and filtering it with a sieve, with a 60 μm pore size sieve on top and a 25 μm pore size sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet balls; S7. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0025] Example 3 A method for preparing polycaprolactone microspheres with narrow particle size distribution comprises the following steps: S1, dissolving 10 g of polycaprolactone having an intrinsic viscosity of 0.22 dL / g in 50 g of dichloromethane to obtain an oil phase solution; S2, dissolving 2.5 g of polyvinyl alcohol in 900 ml of water to obtain an aqueous phase solution; S3, measure 5.5 ml of the aqueous phase solution, add it to 40 ml of the oil phase solution, and stir at 350 rpm for 8 min to obtain a primary emulsion; S4, passing the primary emulsion through a membrane tube with a pore size of 15 μm under a nitrogen pressure of 10.5 kPa, forming polycaprolactone droplets in 800 ml of a circulating aqueous solution, and being carried away by the circulating aqueous solution to obtain a suspension emulsion; S5, stirring the suspension emulsion at 36° C. and 300 rpm for 10 h, removing the organic solvent dichloromethane to solidify the microspheres, and obtaining a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and filtering it with a sieve, with a 60 μm pore size sieve on top and a 25 μm pore size sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet balls; S7. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0026] Example 4 A method for preparing polycaprolactone microspheres with narrow particle size distribution comprises the following steps: S1, dissolving 100 g of polycaprolactone having an intrinsic viscosity of 0.22 dL / g in 500 g of dichloromethane to obtain an oil phase solution; S2, dissolving 12.5 g of polyvinyl alcohol in 5000 ml of water to obtain an aqueous phase solution; 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 obtain a primary emulsion; S4, passing the primary emulsion through a membrane tube with a pore size of 15 μm under a nitrogen pressure of 11 kPa, forming polycaprolactone droplets in 4750 ml of a circulating aqueous solution, and being carried away by the circulating aqueous solution to obtain a suspension emulsion; S5, stirring the suspension emulsion at 35° C. and 400 rpm for 28 h, removing the organic solvent dichloromethane to solidify the microspheres, and obtaining a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and filtering it with a sieve, with a 60 μm pore size sieve on top and a 25 μm pore size sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet balls; S7. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0027] Example 5 A method for preparing polycaprolactone microspheres with narrow particle size distribution comprises the following steps: S1, dissolving 15 g of polycaprolactone having an intrinsic viscosity of 0.43 dL / g in 100 g of dichloromethane to obtain an oil phase solution; S2, dissolving 8 g of polyvinyl alcohol in 1000 ml of water to obtain an aqueous phase solution; S3, take 5 ml of the aqueous phase solution, add it to 80 ml of the oil phase solution, and stir at 350 rpm for 8 min to obtain a primary emulsion; S4, passing the primary emulsion through a membrane tube with a pore size of 10 μm under a nitrogen pressure of 13.5 kPa, forming polycaprolactone droplets in 900 ml of a circulating aqueous solution, and being carried away by the circulating aqueous solution to obtain a suspension emulsion; S5, stirring the suspension emulsion at 38° C. and 400 rpm for 10 h, removing the organic solvent dichloromethane to solidify the microspheres, and obtaining a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and filtering it with a sieve, with a 60 μm pore size sieve on top and a 25 μm pore size sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet balls; S7. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0028] Example 6 A method for preparing polycaprolactone microspheres with narrow particle size distribution comprises the following steps: S1, dissolving 7 g of polycaprolactone having an intrinsic viscosity of 0.81 dL / g in 140 g of dichloromethane to obtain an oil phase solution; S2, dissolving 15 g of polyvinyl alcohol and 7.5 g of Tween 80 in 1500 ml of water to obtain an aqueous phase solution; S3, measure 6.6 ml of the aqueous phase solution, add it to 110 ml of the oil phase solution, and stir at 500 rpm for 12 min to obtain a primary emulsion; S4, passing the primary emulsion through a membrane tube with a pore size of 15 μm under a nitrogen pressure of 20 kPa, forming polycaprolactone droplets in 1400 ml of a circulating aqueous solution, and being carried away by the circulating aqueous solution to obtain a suspension emulsion; S5, stirring the suspension emulsion at 35° C. and 500 rpm for 14 h, removing the organic solvent dichloromethane to solidify the microspheres, and obtaining a polycaprolactone microsphere suspension; S6, washing the polycaprolactone microsphere suspension with water and filtering it with a sieve, with a 60 μm pore size sieve on top and a 25 μm pore size sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet balls; S7. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0029] Comparative Example 1 A method for preparing polycaprolactone microspheres comprises the following steps: S1, dissolving 10 g of polycaprolactone having an intrinsic viscosity of 0.22 dL / g in 90 g of dichloromethane to obtain an oil phase solution; S2, dissolving 10 g of methyl cellulose in 1000 ml of water to obtain an aqueous solution; S3, adding the oil phase solution to the aqueous phase solution under stirring, stirring at 1200 rpm for 25 min, to obtain a polycaprolactone suspension emulsion; S4, stirring the polycaprolactone suspension emulsion at 38° C. and 300 rpm for 14 h to obtain a polycaprolactone microsphere suspension; S5, filtering the polycaprolactone microsphere suspension through a sieve, with a 60 μm sieve on top and a 25 μm sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet microspheres; S6. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0030] Comparative Example 2 A method for preparing polycaprolactone microspheres comprises the following steps: S1, dissolving 24 g of polycaprolactone having an intrinsic viscosity of 0.22 dL / g in 90 g of dichloromethane to obtain an oil phase solution; S2, dissolving 20 g of sodium dodecyl sulfate in 1000 ml of water to obtain an aqueous solution; S3, passing the oil phase solution through a membrane tube with a pore size of 10 μm under a nitrogen pressure of 25 kPa, forming polycaprolactone droplets in 1000 ml of a circulating aqueous solution, and being carried away by the circulating aqueous solution to obtain a suspension emulsion; S4, stirring the suspension emulsion at 42° C. and 300 rpm for 14 h to obtain a polycaprolactone microsphere suspension; S5, filtering the polycaprolactone microsphere suspension through a sieve, with a 60 μm sieve on top and a 25 μm sieve on the bottom, collecting the microspheres between the 25 μm and 60 μm sieves to obtain wet microspheres; S6. Dry the wet balls at 35°C and pass them through a 60 μm sieve again to obtain polycaprolactone microspheres.

[0031] Comparative Example 3 A method for preparing polycaprolactone microspheres comprises the following steps: S1, dissolving 10 g of polycaprolactone having an intrinsic viscosity of 0.22 dL / g in 90 g of dichloromethane to obtain an oil phase solution; S2, dissolving 5 g of polyvinyl alcohol in 1000 ml of water to obtain an aqueous phase solution; S3, passing the oil phase solution through a membrane tube with a pore size of 15 μm under a nitrogen pressure of 9.5 KPa in a 1000 ml circulating aqueous solution to form polycaprolactone droplets, which are carried away by the circulating aqueous solution to obtain a suspension emulsion; S4, stirring the suspension emulsion at 38° C. and 300 rpm for 14 h to obtain a polycaprolactone microsphere suspension; S5, filtering the polycaprolactone microsphere suspension through a sieve with a 100 μm sieve on top and a 25 μm sieve on the bottom, collecting the microspheres between the 25 μm and 100 μm sieves to obtain wet microspheres; S6. Dry the wet balls at 35°C and pass them through a 100 μm sieve again to obtain polycaprolactone microspheres.

[0032] test: (1) The polycaprolactone microspheres obtained after drying in Examples 1 to 6 and Comparative Examples 1 to 3 were observed under a microscope. The results are as follows: Figures 1 to 9 shown.

[0033] By comparison Figure 1 to Figure 6 and Figure 7 to Figure 9 It can be seen that the polycaprolactone microspheres prepared in each embodiment of the present invention have a more rounded morphology and a more uniform particle size.

[0034] (2) The polycaprolactone microspheres obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were tested in a laser particle size analyzer, and the particle size distribution and span of the microspheres were statistically analyzed. The yield of the polycaprolactone microspheres in Examples 1 to 6 and Comparative Examples 1 to 3 was calculated, and 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.

[0035] Table 1 Yield and span experimental data of each embodiment and comparative example

[0036] The results in Table 1 show that the yield of polycaprolactone microspheres prepared in each embodiment is significantly higher than that in each comparative example, and the span value is less than 0.8. Comparative Example 1 uses stirring and shearing to prepare polycaprolactone microspheres, with a wide particle size distribution and a low microsphere yield; the yield of polycaprolactone microspheres prepared in Comparative Examples 2 and 3 is higher than that in Comparative Example 1, but the span value is larger than that in the embodiment. In Comparative Example 3, due to the use of a 100 μm mesh for filtration, the microspheres obtained have a slightly larger span value than the microspheres obtained in Comparative Example 2.

[0037] (3) The polycaprolactone microspheres obtained in Example 4 were observed under an electron microscope. The results are as follows: Figure 10 to Figure 12 shown.

[0038] Figure 10 to Figure 12 It was observed under an electron microscope that the polycaprolactone microspheres prepared in Example 4 had good roundness, a smooth surface, and relatively uniform particle size.

[0039] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in 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. Collect the wet balls, dry them and sieve them to obtain polycaprolactone microspheres.

2. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: 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).

3. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: 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).

4. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: 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.

5. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: In step S4, the membrane is pressurized by an inert gas, the pressure range of the inert gas is 5 to 20 kPa; and the membrane pore diameter of the membrane tube is 10 to 25 μm.

6. The method for preparing polycaprolactone microspheres with narrow particle size distribution according to claim 1, characterized in that: In step S4, the volume ratio of the primary emulsion to the aqueous phase solution is 1:8 to 1:

20.

7. 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.

8. 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.

9. 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.

10. 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 9.

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