Polycaprolactone microspheres and their membrane emulsification preparation method, application, and filler

Abstract

Polycaprolactone microspheres, their membrane emulsification preparation method, applications, and fillers, relate to the field of microsphere preparation technology. The membrane emulsification preparation method for polycaprolactone microspheres comprises the following steps: using a polycaprolactone solution as the dispersed phase, forcing the dispersed phase through the membrane pores of a membrane tube at a pressure of 1 to 13 kPa, forming polycaprolactone droplets in the continuous phase, and the continuous phase carrying the polycaprolactone droplets away; wherein the concentration of polycaprolactone in the dispersed phase is 0.04 to 0.15 mg / mL, and the molecular weight of polycaprolactone is 0.5 to 15,000 Daltons; collecting the mixture of the polycaprolactone droplets and the continuous phase, and then stirring at a rate of 100 to 400 rpm to form polycaprolactone microspheres. This preparation method can effectively produce polycaprolactone microspheres with good roundness and essentially no fragmentation.

Description

Technical Field

[0001] The present application relates to the technical field of microsphere preparation, and in particular to a polycaprolactone microsphere and its membrane emulsification preparation method, application, and filler. Background Art

[0002] Currently, the main methods for preparing microspheres include spray drying, dripping, and membrane emulsification. The membrane emulsification method is often used in production because it can produce microspheres with relatively uniform particle size. The inventors of this application discovered through experiments that when using polycaprolactone with a relatively large molecular weight as the dispersed phase to prepare polycaprolactone microspheres, the membrane emulsification process parameters corresponding to the preparation of polycaprolactone microspheres are difficult to successfully prepare, resulting in the formation of fragments and failure to form microspheres.

[0003] Therefore, it has become a difficult problem to successfully prepare polycaprolactone microspheres with good roundness by using polycaprolactone with a smaller molecular weight as the raw material of the dispersed phase. Summary of the Invention

[0004] The present application provides a polycaprolactone microsphere and its membrane emulsification preparation method, application, and filler. When the polycaprolactone used in the preparation method is used as a raw material, polycaprolactone microspheres with good roundness can be effectively prepared without generating substantially any fragments.

[0005] This application is implemented as follows:

[0006] In a first aspect, the present application provides a method for preparing polycaprolactone microspheres by membrane emulsification, comprising the following steps:

[0007] A polycaprolactone solution is used as the dispersed phase, and the dispersed phase is pressed through the membrane pores of the membrane tube at a pressure of 1 to 13 kPa, forming polycaprolactone droplets in the continuous phase, which are then carried away by the continuous phase. The concentration of the polycaprolactone in the dispersed phase is 0.04 to 0.15 mg / mL, and the molecular weight of the polycaprolactone is 0.5 to 15,000 Daltons.

[0008] The mixed solution of the polycaprolactone droplets and the continuous phase is collected and then stirred at a speed of 100 to 400 rpm to form polycaprolactone microspheres.

[0009] In one possible embodiment, the continuous phase contains polyvinyl alcohol or gelatin, and the concentration of the polyvinyl alcohol or gelatin in the continuous phase is 0.01 to 0.05 mg / mL.

[0010] In one possible embodiment, the continuous phase carries away the polycaprolactone droplets at a flow rate of 300 to 800 mL / min.

[0011] In one possible embodiment, the temperature of the stirring step is 35 to 40° C., and the time is 2 to 24 hours.

[0012] In a possible embodiment, the membrane pore diameter of the membrane tube is 10 to 50 μm.

[0013] In one possible embodiment, the stirring speed is 200-300 rpm.

[0014] In one possible embodiment, the concentration of the polycaprolactone in the dispersed phase is 0.05 to 0.10 mg / mL.

[0015] In a second aspect, the present application provides polycaprolactone microspheres, which are prepared by the membrane emulsification preparation method of polycaprolactone microspheres according to the first aspect.

[0016] In a third aspect, the present application provides a use of the polycaprolactone microspheres according to the second aspect in the preparation of a drug sustained-release carrier, a skin filler, or a tissue engineering scaffold.

[0017] In a fourth aspect, the present application provides a filler comprising: collagen and the polycaprolactone microspheres of the second aspect.

[0018] This application has at least the following beneficial effects:

[0019] The membrane emulsification preparation method of polycaprolactone microspheres of the present application uses polycaprolactone with a molecular weight of 0.5 to 15,000 Daltons as the raw material of the dispersed phase. When the concentration of polycaprolactone in the dispersed phase is 0.04 to 0.15 mg / mL, a pressure of 1 to 13 kPa can be used to press the dispersed phase through the membrane pores of the membrane tube, forming polycaprolactone droplets in the continuous phase. After collecting the mixed liquid of the polycaprolactone droplets and the continuous phase, low-speed stirring is performed by limiting the stirring rate to 100 to 400 rpm, thereby effectively preparing polycaprolactone microspheres. Basically no fragments are generated during the preparation process, and the prepared polycaprolactone microspheres are relatively round. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following is a brief introduction to the drawings required for use in the embodiments. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without creative work.

[0021] Figure 1 This is a microscope image of the polycaprolactone microspheres of Example 1 of the present application;

[0022] Figure 2 This is a microscope image of the polycaprolactone microspheres of Example 2 of the present application;

[0023] Figure 3 This is a microscope image of the polycaprolactone microspheres of Example 3 of the present application;

[0024] Figure 4 This is a microscope image of the polycaprolactone microspheres of Example 4 of the present application;

[0025] Figure 5 This is a microscope image of the polycaprolactone microspheres of Example 5 of the present application;

[0026] Figure 6 This is a microscope image of the polycaprolactone microspheres of Example 6 of the present application;

[0027] Figure 7 This is a microscope image of the polycaprolactone microspheres of Example 7 of the present application;

[0028] Figure 8 This is a microscope image of the polycaprolactone microspheres of Example 8 of the present application;

[0029] Figure 9 This is a microscope image of the polycaprolactone microspheres of Example 9 of the present application;

[0030] Figure 10 This is a microscope image of the polycaprolactone microspheres of Example 10 of the present application;

[0031] Figure 11 This is a microscope image of the polycaprolactone microspheres of Comparative Example 1 of the present application;

[0032] Figure 12 This is a microscope image of the polycaprolactone microspheres of Comparative Example 2 of this application;

[0033] Figure 13 This is a microscope image of the polycaprolactone microspheres of Comparative Example 3 of the present application;

[0034] Figure 14 This is a microscope image of the polycaprolactone microspheres of Comparative Example 4 of the present application;

[0035] Figure 15 This is a microscope image of the polycaprolactone microspheres of Comparative Example 5 of the present application;

[0036] Figure 16 This is a microscope image of the polycaprolactone microspheres of Comparative Example 6 of the present application;

[0037] Figure 17 This is a microscope image of the polycaprolactone microspheres of Comparative Example 7 of the present application;

[0038] Figure 18 This is a microscope image of the polycaprolactone microspheres of Comparative Example 8 of the present application;

[0039] Figure 19 This is a microscope image of the polycaprolactone microspheres of Comparative Example 9 of the present application;

[0040] Figure 20 This is a microscope image of the polycaprolactone microspheres of Comparative Example 10 of the present application;

[0041] Figure 21 This is a microscope picture of the polycaprolactone microspheres of Comparative Example 11 of the present application. DETAILED DESCRIPTION

[0042] The embodiments of the present application will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present application and should not be considered as limiting the scope of the present application. In the examples, if specific conditions are not specified, the conditions are carried out according to conventional conditions or manufacturer recommendations. The reagents or instruments used are not specified by the manufacturer and are conventional products that can be purchased commercially.

[0043] At present, the commonly used methods for preparing microspheres are spray drying, dripping, and membrane emulsification. The inventors of this application attempted to use a membrane emulsification process to prepare polycaprolactone (PCL) microspheres in their research and found that when polycaprolactone with a molecular weight of 25,000 Daltons is used as the raw material for the dispersed phase, and the concentration of polycaprolactone in the dispersed phase is 0.05-0.10 mg / mL, a pressure of 2-4 kPa can be used to press the dispersed phase through the membrane pores of the membrane tube, forming polycaprolactone droplets in the continuous phase (polyvinyl alcohol or gelatin aqueous solution with a concentration of 0.01-0.05 mg / mL). After collecting the mixture of the polycaprolactone droplets and the continuous phase, stirring is performed to allow the solvent in the continuous phase to evaporate, and finally, relatively round polycaprolactone microspheres are formed. However, when the inventors of this application replaced the 25,000-Dalton polycaprolactone with a polycaprolactone of 0.5-15,000 Daltons as the dispersed phase raw material, using the previous membrane emulsification process parameters and without changing the composition and concentration of the continuous phase, they still encountered a phenomenon of large amounts of fragments being easily generated during the preparation process, and microspheres could not be formed well. Therefore, how to successfully prepare polycaprolactone microspheres with good roundness and no fragmentation using a smaller molecular weight polycaprolactone as the dispersed phase raw material became a difficult problem.

[0044] Based on this, the present application provides a membrane emulsification preparation method for polycaprolactone microspheres, which can effectively prepare polycaprolactone microspheres with good roundness and no fragments are generated during the preparation process.

[0045] The following is a detailed description of the polycaprolactone microspheres and their membrane emulsification preparation method, application, and filler of the embodiments of the present application:

[0046] In a first aspect, the present application provides a method for preparing polycaprolactone microspheres by membrane emulsification, comprising the following steps:

[0047] A polycaprolactone solution is used as the dispersed phase, and a pressure of 1 to 13 kPa is applied to force the dispersed phase through the membrane pores of the membrane tube, forming polycaprolactone droplets in the continuous phase, which then carry the polycaprolactone droplets away. The concentration of the polycaprolactone in the dispersed phase is 0.04 to 0.15 mg / mL, and the molecular weight of the polycaprolactone is 0.5 to 15,000 Daltons.

[0048] The mixed solution of the polycaprolactone droplets and the continuous phase is collected and then stirred at a rate of 100 to 400 rpm to form polycaprolactone microspheres.

[0049] The membrane emulsification preparation method of polycaprolactone microspheres of the present application uses polycaprolactone with a molecular weight of 0.5 to 15,000 Daltons as a raw material for the dispersed phase. When the concentration of polycaprolactone in the dispersed phase is 0.04 to 0.15 mg / mL, a pressure of 1 to 13 kPa is used to press the dispersed phase through the membrane pores of the membrane tube, forming polycaprolactone droplets in the continuous phase. After collecting the mixed liquid of the polycaprolactone droplets and the continuous phase, the polycaprolactone microspheres can be effectively prepared by limiting the stirring rate to 100 to 400 rpm for low-speed stirring. No fragments are generated during the preparation process, and the prepared polycaprolactone microspheres are relatively round. Optionally, the molecular weight of the polycaprolactone is one of 0.5,000 Daltons, 10,000 Daltons, 12,000 Daltons and 15,000 Daltons, or a value between any two of them.

[0050] The dispersed phase can be forced through the membrane pores of the membrane tube by applying pressure to the dispersed phase by introducing an inert gas. Examples of the inert gas include nitrogen and argon. Alternatively, the dispersed phase can be forced through the membrane pores of the membrane tube by providing pumping power using a pumping mechanism. For example, the pressure is any one of 1 kPa, 2 kPa, 3 kPa, 4 kPa, 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, 10 kPa, 11 kPa, 12 kPa, and 13 kPa, or any value between any two of these.

[0051] The preparation step of the dispersed phase includes dissolving polycaprolactone in an organic solvent, which may be dichloromethane or chloroform. In some embodiments, the concentration of polycaprolactone in the dispersed phase is one of 0.04 mg / mL, 0.05 mg / mL, 0.08 mg / mL, 0.10 mg / mL, 0.12 mg / mL, and 0.15 mg / mL, or a value between any two of them. Alternatively, the concentration of polycaprolactone in the dispersed phase is 0.05 to 0.10 mg / mL.

[0052] After collecting the mixture of the polycaprolactone droplets and the continuous phase, the mixture is stirred at a rate of 100 to 400 rpm to allow the organic solvent in the dispersed phase to fully evaporate, thereby forming polycaprolactone microspheres. In this process, no fragments are generated. In some embodiments, the stirring rate of the stirring step is any one of 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm, and 400 rpm, or a value between any two of them. Alternatively, the stirring rate of the stirring step is 200 to 300 rpm.

[0053] In some embodiments, the temperature of the stirring step is 35-40°C and the time is 2-24 hours. Exemplarily, the temperature of the stirring step is 35°C, 36°C, 37°C, 38°C, 39°C and 40°C, or a value between any two of them. Exemplarily, the time of the stirring step is 2 hours, 5 hours, 8 hours, 10 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours and 24 hours, or a value between any two of them.

[0054] After the dispersed phase passes through the membrane pores of the membrane tube, polycaprolactone droplets are formed in the continuous phase, and the continuous phase carries away the polycaprolactone droplets. Exemplarily, the continuous phase carries away the polycaprolactone droplets at a flow rate of 300 to 800 mL / min, for example, the flow rate of the continuous phase is any one of 300 mL / min, 400 mL / min, 500 mL / min, 600 mL / min, 700 mL / min and 800 mL / min, or a value between any two of them. The continuous phase can be pumped to the membrane tube by a pumping mechanism, which can optionally be a gear pump, a plunger pump, a peristaltic pump, or the like.

[0055] The continuous phase contains polyvinyl alcohol or gelatin, and the concentration of polyvinyl alcohol or gelatin in the continuous phase is 0.01 to 0.05 mg / mL, for example, any one of 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL and 0.05 mg / mL, or a value between any two of them.

[0056] Furthermore, the membrane pore diameter of the membrane tube is 10 to 50 μm, for example, any one of 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm and 50 μm, or a value between any two of them.

[0057] In a second aspect, the present application provides polycaprolactone microspheres, which are prepared by the membrane emulsification preparation method of polycaprolactone microspheres according to the first aspect.

[0058] The polycaprolactone microspheres prepared by the membrane emulsification preparation method of polycaprolactone microspheres of the present application have a relatively round shape and no fragments are produced. In some embodiments, the polycaprolactone microspheres prepared by the membrane emulsification preparation method of polycaprolactone microspheres of the present application have a D50 particle size of 30 to 100 μm and a particle size span of 0.5 to 1.5. It should be noted that the particle size span (Span) = (D90-D10) / D50, and D10 refers to the particle size corresponding to when the cumulative particle size distribution number of the degradable microspheres reaches 10%. D50 refers to the particle size corresponding to when the cumulative particle size distribution percentage of the degradable microspheres reaches 50%. D90 refers to the particle size corresponding to when the cumulative particle size distribution number of the degradable microspheres reaches 90%. Among them, the smaller the particle size span, the more uniform the particle size distribution of the microspheres. Illustratively, the D50 particle size of the polycaprolactone microspheres prepared by the membrane emulsification preparation method of the polycaprolactone microspheres of the present application is any one of 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm and 100 μm, or a value between any two of them.

[0059] In a third aspect, the present application provides a use of the polycaprolactone according to the second aspect in the preparation of a drug sustained-release carrier, a skin filler, or a tissue engineering scaffold.

[0060] In a fourth aspect, the present application provides a filler comprising collagen and the polycaprolactone microspheres of the second aspect, wherein the collagen may be cross-linked collagen or non-cross-linked collagen.

[0061] The above-mentioned filler can be used for facial injection filling and can be used for injection into the urethra to treat stress urinary incontinence. After the filler is injected into the face or urethra, both collagen and polycaprolactone microspheres can have an immediate filling effect. When the collagen gradually degrades, the polycaprolactone microspheres will also degrade. The gradual degradation of the polycaprolactone microspheres will stimulate collagen regeneration, achieving the effect of supplementing collagen. Through the combined action of collagen and polycaprolactone microspheres, the filling effect is better and more lasting, thereby restoring the firmness of the facial or urethral sphincter. If tissues such as the urethral sphincter can maintain a tight state for a long time, their functions can be restored, thereby effectively treating stress urinary incontinence.

[0062] The polycaprolactone microspheres of the present application and their membrane emulsification preparation method, applications, and fillers are further described in detail below with reference to the examples.

[0063] Example 1

[0064] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0065] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.04 mg / mL;

[0066] S2: mixing polyvinyl alcohol with ultrapure water and heating to 65° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0067] S3: The continuous phase was pumped into the membrane tube at a flow rate of 600 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 4 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were then carried away by the continuous phase.

[0068] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 250 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0069] Example 2

[0070] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0071] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.04 mg / mL;

[0072] S2: mixing polyvinyl alcohol with ultrapure water and heating to 65° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0073] S3: The continuous phase was pumped into the membrane tube at a flow rate of 500 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 4 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were then carried away by the continuous phase.

[0074] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 250 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0075] Example 3

[0076] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0077] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0078] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0079] S3: The continuous phase was pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 5.5 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were carried away by the continuous phase.

[0080] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at a temperature of 37° C. and a stirring speed of 400 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0081] Example 4

[0082] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0083] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0084] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0085] S3: The continuous phase was pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 5.5 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were carried away by the continuous phase.

[0086] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 300 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0087] Example 5

[0088] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0089] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0090] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0091] S3: The continuous phase is pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen is introduced and the pressure is maintained at 8 kPa to force the dispersed phase through the membrane pores (pore diameter is 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0092] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 300 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0093] Example 6

[0094] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0095] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0096] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0097] S3: The continuous phase is pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen is introduced and maintained at a pressure of 10 kPa to force the dispersed phase through the membrane pores (pore diameter of the membrane tube is 15 μm), forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0098] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 300 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0099] Example 7

[0100] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0101] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0102] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0103] S3: The continuous phase was pumped into the membrane tube at a flow rate of 600 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 4 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were then carried away by the continuous phase.

[0104] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 250 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0105] Example 8

[0106] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0107] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0108] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0109] S3: The continuous phase was pumped into the membrane tube at a flow rate of 500 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 4 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were then carried away by the continuous phase.

[0110] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 250 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0111] Example 9

[0112] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0113] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0114] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0115] S3: The continuous phase is pumped into the membrane tube at a flow rate of 800 mL / min using a gear pump. Nitrogen is introduced and the pressure is maintained at 8 kPa to force the dispersed phase through the membrane pores (pore diameter of the membrane tube is 15 μm), forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0116] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 250 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0117] Example 10

[0118] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0119] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.15 mg / mL;

[0120] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.05 mg / mL;

[0121] S3: The continuous phase was pumped into the membrane tube at a flow rate of 300 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 13 kPa to force the dispersed phase through the membrane pores (pore size 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were then carried away by the continuous phase.

[0122] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 300 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0123] Example 11

[0124] This embodiment provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0125] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.06 mg / mL;

[0126] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.015 mg / mL;

[0127] S3: The continuous phase is pumped into the membrane tube at a flow rate of 300 mL / min using a gear pump. Nitrogen is introduced and maintained at a pressure of 1 kPa to force the dispersed phase through the membrane pores (pore diameter of the membrane tube is 15 μm), forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0128] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 200 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0129] Comparative Example 1

[0130] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0131] S1: dissolving polycaprolactone having a molecular weight of 25,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0132] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0133] S3: The continuous phase is pumped into the membrane tube at a flow rate of 400 mL / min using a gear pump. Nitrogen is introduced and maintained at a pressure of 4 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0134] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 600 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0135] Comparative Example 2

[0136] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0137] S1: dissolving polycaprolactone having a molecular weight of 25,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0138] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0139] S3: The continuous phase is pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen is introduced and the pressure is maintained at 4 kPa to force the dispersed phase through the membrane pores (pore size is 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0140] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 500 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0141] Comparative Example 3

[0142] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0143] S1: dissolving polycaprolactone having a molecular weight of 25,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.10 mg / mL;

[0144] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0145] S3: The continuous phase is pumped into the membrane tube at a flow rate of 300 mL / min using a gear pump. Nitrogen is introduced and maintained at a pressure of 2 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0146] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 500 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0147] Comparative Example 4

[0148] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0149] S1: dissolving polycaprolactone having a molecular weight of 25,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.05 mg / mL;

[0150] S2: mixing gelatin with ultrapure water and heating to 50°C to obtain a continuous phase; wherein the concentration of gelatin in the continuous phase is 0.03 mg / mL;

[0151] S3: The continuous phase was pumped into the membrane tube at a flow rate of 300 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 3 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were then carried away by the continuous phase.

[0152] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 600 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0153] Comparative Example 5

[0154] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0155] S1: dissolving polycaprolactone having a molecular weight of 25,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.05 mg / mL;

[0156] S2: mixing gelatin with ultrapure water and heating to 50°C to obtain a continuous phase; wherein the concentration of gelatin in the continuous phase is 0.03 mg / mL;

[0157] S3: The continuous phase was pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 3.5 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were carried away by the continuous phase.

[0158] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 500 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0159] Comparative Example 6

[0160] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0161] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.05 mg / mL;

[0162] S2: mixing gelatin with ultrapure water and heating to 50°C to obtain a continuous phase; wherein the concentration of gelatin in the continuous phase is 0.03 mg / mL;

[0163] S3: The continuous phase was pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 3.5 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were carried away by the continuous phase.

[0164] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 500 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0165] Comparative Example 7

[0166] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0167] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0168] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0169] S3: The continuous phase is pumped into the membrane tube at a flow rate of 400 mL / min using a gear pump. Nitrogen is introduced and maintained at a pressure of 4 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0170] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 600 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0171] Comparative Example 8

[0172] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0173] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0174] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.02 mg / mL;

[0175] S3: The continuous phase is pumped into the membrane tube at a flow rate of 400 mL / min using a gear pump. Nitrogen is introduced and maintained at a pressure of 4 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0176] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 40° C. and 600 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0177] Comparative Example 9

[0178] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0179] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.15 mg / mL;

[0180] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0181] S3: The continuous phase was pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen was introduced and the pressure was maintained at 6.5 kPa to force the dispersed phase through the membrane pores (pore size of 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets were carried away by the continuous phase.

[0182] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 500 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0183] Comparative Example 10

[0184] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0185] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0186] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0187] S3: The continuous phase is pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen is introduced and maintained at a pressure of 2 kPa to force the dispersed phase through the membrane pores (pore diameter of the membrane tube is 40 μm), forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0188] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring the mixture at 37° C. and 600 rpm for 12 h to form polycaprolactone microspheres, and then filtering, washing, and drying the mixture to obtain polycaprolactone microspheres.

[0189] Comparative Example 11

[0190] This comparative example provides a method for preparing polycaprolactone by membrane emulsification, which comprises the following steps:

[0191] S1: dissolving polycaprolactone having a molecular weight of 10,000 Daltons in dichloromethane to obtain a dispersed phase; wherein the concentration of polycaprolactone in the dispersed phase is 0.08 mg / mL;

[0192] S2: mixing polyvinyl alcohol with ultrapure water and heating to 70° C. to obtain a continuous phase; wherein the concentration of polyvinyl alcohol in the continuous phase is 0.03 mg / mL;

[0193] S3: The continuous phase is pumped into the membrane tube at a flow rate of 350 mL / min using a gear pump. Nitrogen is introduced and the pressure is maintained at 4 kPa to force the dispersed phase through the membrane pores (pore size is 15 μm) of the membrane tube, forming polycaprolactone droplets in the continuous phase. The formed polycaprolactone droplets are then carried away by the continuous phase.

[0194] S4: collecting the mixture of the dispersed phase droplets and the continuous phase, stirring it at 37° C. and 500 rpm for 12 hours to form polycaprolactone microspheres, and then filtering, washing, and drying to obtain polycaprolactone microspheres.

[0195] Test Example 1

[0196] The polycaprolactone microspheres prepared in Examples 1 to 10 and Comparative Examples 1 to 11 were observed under a microscope, and the obtained microscopic images were as follows: Figures 1 to 21 shown.

[0197] Among them, Examples 1 to 10 of the present application and Comparative Examples 6 to 11 all use polycaprolactone with a molecular weight of 10,000 Daltons to prepare polycaprolactone microspheres, and the polycaprolactone microspheres prepared in Comparative Examples 6 to 11 have more fragments (such as Figures 16 to 21 The polycaprolactone microspheres prepared in Examples 1 to 10 were essentially free of fragments and had good roundness. This indicates that the preparation process of the present invention can improve the problem of fragmentation when preparing microspheres with polycaprolactone of lower molecular weight (10,000 Daltons).

[0198] By comparing Comparative Example 1 and Comparative Example 7, it can be seen that the molecular weight of the polycaprolactone used in Comparative Example 1 is 25,000 Daltons, while the molecular weight of the polycaprolactone used in Comparative Example 7 is 10,000 Daltons. When all other preparation processes are the same, the polycaprolactone microspheres prepared in Comparative Example 7 produce a large amount of fragments, while the polycaprolactone microspheres prepared in Comparative Example 1 produce essentially no fragments. In addition, by comparing Comparative Example 7 and Comparative Example 8, it can be seen that although Comparative Examples 7 and 8 differ only in the stirring temperature in step S4, the polycaprolactone microspheres prepared in Comparative Example 8 also produce a large amount of fragments, indicating that, based on the preparation process of Comparative Example 7, changing the temperature to 40°C cannot solve the problem of fragmentation when preparing polycaprolactone microspheres using polycaprolactone with a molecular weight of 10,000 Daltons.

[0199] In addition, by comparing Examples 7 to 9 with Comparative Example 7, the continuous phase flow rate and stirring rate of Examples 7 and 8 were changed relative to those of Comparative Example 7, and the continuous phase flow rate, nitrogen pressure and stirring rate of Example 9 were changed relative to those of Comparative Example 7. It was found that the polycaprolactone microspheres prepared in Examples 7, 8 and 9 were basically free of fragments, indicating that the preparation processes of Examples 7, 8 and 9 of the present application can improve the situation in which fragments are generated when preparing microspheres with polycaprolactone having a molecular weight of 10,000 Daltons.

[0200] From Comparative Examples 5 and 6, it can be seen that the molecular weight of the polycaprolactone used in Comparative Example 5 is 25,000 Daltons, and the molecular weight of the polycaprolactone used in Comparative Example 6 is 10,000 Daltons. When all other preparation processes are the same, the polycaprolactone microspheres prepared in Comparative Example 6 have more fragments, and the polycaprolactone microspheres prepared in Comparative Example 5 are substantially free of fragments. In addition, by comparing Comparative Example 5 with Comparative Example 4 and Comparative Example 3, it is found that when the molecular weight of polycaprolactone is 25,000 Daltons, the continuous phase flow rate, nitrogen pressure and stirring rate of Comparative Example 5 are different from those of Comparative Example 4, and the concentration, continuous phase flow rate and nitrogen pressure of polycaprolactone of Comparative Example 5 and Comparative Example 3 are different, but the polycaprolactone microspheres prepared in Comparative Example 4 and Comparative Example 3 are also substantially free of fragments.

[0201] By comparing Comparative Example 2 and Comparative Example 11, it can be seen that the molecular weight of the polycaprolactone used in Comparative Example 2 is 25,000 Daltons, while the molecular weight of the polycaprolactone used in Comparative Example 11 is 10,000 Daltons. Under the same preparation processes, the polycaprolactone microspheres prepared in Comparative Example 11 produce a large amount of fragments, while the polycaprolactone microspheres prepared in Comparative Example 2 produce essentially no fragments. In addition, by comparing Comparative Example 10 and Comparative Example 11, it is found that although the nitrogen pressure and stirring rate in Comparative Example 10 are different from those in Comparative Example 11, the polycaprolactone microspheres prepared in Comparative Example 10 also produce a large amount of fragments.

[0202] In addition, by comparing Examples 3 to 6 and Comparative Example 11, the nitrogen pressure and stirring rate of Examples 3 to 6 were changed relative to Comparative Example 11, and the polycaprolactone microspheres prepared in Examples 3 to 6 were basically free of fragments, indicating that the preparation process of Examples 3 to 6 of the present application can improve the situation in which fragments are generated when preparing microspheres with polycaprolactone having a molecular weight of 10,000 Daltons.

[0203] Test Example 2

[0204] The polycaprolactone microspheres obtained after drying in Example 1, Example 2, and Example 7 to Example 9 were tested in a laser particle size analyzer. The test results of the particle size span (Span) and D50 particle size are shown in Table 1.

[0205] Table 1. Particle size span and D50 test results

[0206] Particle size span (Span) D50 / μm Example 1 1.041 88.32 Example 2 1.050 140.6 Example 7 1.268 80.13 Example 8 1.180 85.79 Example 9 0.997 77.39

[0207] From the results in Table 2, it can be seen that the particle size spans of the polycaprolactone microspheres prepared in Example 1, Example 2, and Examples 7 to 9 are all small, all less than 1.3, indicating that the polycaprolactone microspheres prepared by the preparation process of the examples of the present application have good particle size uniformity.

[0208] The foregoing description is merely a specific embodiment of the present application and is not intended to limit the present application. Persons skilled in the art will readily appreciate that various modifications and variations are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. A membrane emulsification method for preparing polycaprolactone microspheres, characterized in that: The following steps are involved: A polycaprolactone solution is used as the dispersed phase, and the dispersed phase is pressed through the membrane pores of the membrane tube at a pressure of 1 to 13 kPa, forming polycaprolactone droplets in the continuous phase. The continuous phase carries the polycaprolactone droplets away at a flow rate of 300 to 800 mL / min. The concentration of the polycaprolactone in the dispersed phase is 0.04 to 0.15 mg / mL, and the molecular weight of the polycaprolactone is 0.5 to 15,000 Daltons. The continuous phase contains polyvinyl alcohol or gelatin, and the concentration of the polyvinyl alcohol or gelatin in the continuous phase is 0.01 to 0.05 mg / mL. The mixed solution of the polycaprolactone droplets and the continuous phase is collected and then stirred at a rate of 100-400 rpm to form polycaprolactone microspheres.

2. The membrane emulsification preparation method of polycaprolactone microspheres according to claim 1, characterized in that: The temperature of the stirring step is 35-40°C and the time is 2-24 hours.

3. The membrane emulsification preparation method of polycaprolactone microspheres according to claim 1 or 2, characterized in that: The membrane pore diameter of the membrane tube is 10-50 μm.

4. The membrane emulsification preparation method of polycaprolactone microspheres according to claim 1 or 2, characterized in that: The stirring step was performed at a speed of 200-300 rpm.

5. The membrane emulsification preparation method of polycaprolactone microspheres according to claim 1 or 2, characterized in that: The concentration of the polycaprolactone in the dispersed phase is 0.05-0.10 mg / mL.

6. A polycaprolactone microsphere, characterized in that: The polycaprolactone microspheres are prepared by the membrane emulsification preparation method of any one of claims 1 to 5.

7. Use of the polycaprolactone microspheres according to claim 6 in the preparation of drug sustained-release carriers, skin fillers or tissue engineering scaffolds.

8. A filler, characterized in that It includes: Collagen and the polycaprolactone microspheres according to claim 6.

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