A controllable and fast degradable composite polycaprolactone microsphere and its preparation method

Abstract

The invention discloses a controllable and fast-degradable composite polycaprolactone microsphere and a preparation method thereof, belonging to the technical field of medical material preparation. The microsphere comprises PCL, in which one or two of PLLA microspheres or PLGA microspheres are uniformly dispersed. The preparation method comprises the following steps: S1, preparing PLLA microspheres or PLGA microspheres, preparing molten PCL; S2, fully mixing the prepared PLLA microspheres or PLGA microspheres with the molten PCL; S3, adding a surfactant and fully mixing; S4, cooling and solidifying under stirring conditions; S5, washing and drying to obtain the controllable and fast-degradable composite polycaprolactone microspheres, the degradation time of the microspheres is short, the degradation time is controllable, the problem of nodules or swelling caused by long-term retention and stimulation of tissues is avoided, and the safety of the product is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of medical material preparation, and in particular relates to a controllable and rapidly degradable composite polycaprolactone microsphere and a preparation method thereof. Background Art

[0002] PCL (polycaprolactone) has been widely used in long-term implantation and controlled drug release applications. However, in tissue engineering, PCL has disadvantages such as slow degradation, poor mechanical properties, and low cell adhesion.

[0003] Since PCL microspheres take a long time to degrade, attention should be paid to the injection location and amount during the injection process. For example, the product is not suitable for subcutaneous fat areas. When injecting in thinner skin areas such as lips, eyelids, and between eyebrows, strict attention should be paid to the injection amount. In general, the adverse reactions after PCL microsphere injection are mainly nodules or swelling.

[0004] The main ingredient of the commercially available regenerative medical beauty product "Girl Needle" is polycaprolactone microspheres, but the microspheres do not have specific dissolving enzymes. If the injection over-stimulates collagen regeneration, there is no "regret medicine" and you can only wait for it to slowly metabolize itself after a year.

[0005] In recent years, biodegradable polymer materials have developed rapidly, among which polyhydroxy esters are more important, such as polylactic acid, which is often used as surgical repair and drug sustained release materials. Amorphous polyesters degrade quickly, and their strength decreases rapidly after body erosion, making them unsuitable for long-term drug release and surgical suture applications; polycaprolactone is also a biodegradable polyester with excellent drug permeability, but its degradation rate is slow due to its crystallinity; the degradation of polycaprolactone in the body is divided into two stages. The first stage (before 30 months) is characterized by a continuous decrease in relative molecular weight, but deformation and mass loss occur. The second stage (after 30 months) refers to the relative molecular weight dropping to 5000, when the material begins to become fragments and mass loss occurs, and then it is gradually absorbed and excreted by the body. Under the current technical level, the application of polycaprolactone microspheres in medical and aesthetic materials is greatly limited. Summary of the invention

[0006] To solve the above problems, the present invention provides a controllable and fast degradable composite polycaprolactone microsphere and a preparation method thereof. The composite polycaprolactone microsphere has a faster degradation rate than the traditional implanted polycaprolactone solid microsphere, and the degradation time can be controlled, which significantly reduces the residence time of the microsphere in the body and avoids the nodule problem caused by excessive stimulation of collagen regeneration. The specific scheme is as follows:

[0007] Firstly, the present invention provides a controllably rapidly degradable composite polycaprolactone microsphere, wherein the composite polycaprolactone microsphere comprises PCL, in which one or both of PLLA microspheres or PLGA microspheres are uniformly dispersed.

[0008] Preferably, the mass proportion of one or both of PLLA microspheres or PLGA microspheres in the composite polycaprolactone microspheres is 2%-40%.

[0009] Preferably, the particle size of the composite polycaprolactone microspheres is 20-100 μm; the particle size of the PLLA microspheres is 0.1-10 μm, and the particle size of the PLGA microspheres is 0.1-10 μm.

[0010] Preferably, in the composite polycaprolactone microspheres, the weight average molecular weight of PCL is 10KDa-100KDa, the weight average molecular weight of PLLA microspheres is 10KDa-50KDa, and the weight average molecular weight of PLGA microspheres is 10KDa-50KDa.

[0011] Preferably, in the composite polycaprolactone microspheres, the melting point of the PCL is at least 30° C. lower than that of PLLA and PLGA.

[0012] Second, the present invention provides a method for preparing the above-mentioned controllable and rapidly degradable composite polycaprolactone microspheres, comprising the following steps:

[0013] S1, preparing PLLA microspheres or PLGA microspheres, preparing molten PCL;

[0014] S2, fully mixing the prepared PLLA microspheres or PLGA microspheres with the molten PCL;

[0015] S3, adding surfactant and mixing thoroughly;

[0016] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0017] S5, cooling and solidification under stirring conditions;

[0018] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0019] Preferably, the total proportion of the PLLA microspheres or PLGA microspheres in the mixed material in step S2 is 2%-40wt%.

[0020] Preferably, the amount of surfactant added in step S3 is 1-2 wt %.

[0021] Preferably, the surfactant in step S3 includes one or both of polyvinyl pyrrolidone and polysorbate 80.

[0022] Preferably, the temperature of the aqueous phase solution in S4 is 80-100° C., the aqueous phase solution is an aqueous surfactant solution, and the stirring emulsification time is 1-2 h.

[0023] Preferably, the surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 10-20 wt % of the solution.

[0024] Preferably, the stirring in step S5 has a stirring speed of 500-2000 rpm.

[0025] Preferably, the cooling and curing in step S5 is performed at a temperature 5-15° C. lower than the melting point of PCL.

[0026] Preferably, step S5 specifically includes: keeping the cooling and curing temperature 5°C lower than the melting point of PCL, stirring at 500rpm for 20-30min; continuing to cool by 5°C, stirring at 1500rpm for 30-50min; continuing to cool by 5°C, stirring at 2000rpm for 10-20min.

[0027] Preferably, the washing in step S6 uses deionized water or a mixed solution of anhydrous ethanol and deionized water in a volume ratio of 1:1.

[0028] Preferably, the method for preparing PLLA microspheres comprises:

[0029] (1) dissolving PLLA in a solvent;

[0030] (2) Spray drying to obtain microspheres.

[0031] Preferably, the solvent in step (1) is dichloromethane.

[0032] Preferably, the molecular weight of the PLLA is 26,000-45,000, and the concentration of PLLA in the solvent is 0.05-0.08 g / mL.

[0033] Preferably, in the spray drying, the air inlet temperature is 50-75°C, the air outlet temperature is 10-50°C, the peristaltic speed is 15-20rpm, the fan frequency is 20-50HZ, the needle pressure is 0.3-0.4MPa, and the spray pressure is 0.2-0.35MPa.

[0034] Preferably, the obtained PLLA microspheres have a particle size of 0.1-10 μm.

[0035] Preferably, the method for preparing PLGA microspheres comprises:

[0036] (1) dissolving PLGA in a solvent;

[0037] (2) Spray drying to obtain microspheres.

[0038] Preferably, the solvent in step (1) is dichloromethane.

[0039] Preferably, the molecular weight of the PLGA is 26,000-45,000, and the concentration of PLGA in the solvent is 0.05-0.08 g / mL.

[0040] Preferably, in the spray drying, the air inlet temperature is 60-80°C, the air outlet temperature is 5-30°C, the peristaltic speed is 10-15rpm, the fan frequency is 20-50HZ, the needle pressure is 0.35-0.45MPa, and the spray pressure is 0.3-0.4MPa.

[0041] Preferably, the obtained PLGA microspheres have a particle size of 0.1-10 μm.

[0042] Beneficial Effects

[0043] The controllable fast-degradable composite polycaprolactone microspheres provided by the present invention have PLLA and PLGA microspheres with small particle sizes uniformly distributed inside. The water absorption rate of the microspheres is increased and the surface erosion is enhanced by filling with PLLA and PLGA, thereby accelerating the hydrolysis and degradation of the polylactone chains. In addition, due to the fast degradation rate of PLLA and PLGA microspheres, the lactic acid produced after degradation makes the interior of the polycaprolactone an acidic microenvironment, further accelerating the degradation of the polycaprolactone. By adjusting the mass proportion of PLLA or PLGA microspheres in the composite polycaprolactone microspheres, composite polycaprolactone microspheres with different degradation rates can be prepared. The microspheres can be used as regenerative medical and aesthetic facial fillers, which can stimulate collagen regeneration and complete degradation within a predetermined time, and then be excreted from the body through human metabolism. The degradation time of the microspheres is short and controllable, thereby avoiding long-term retention and stimulation of tissues to cause nodules or swelling, thereby improving the safety of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 Schematic diagram of the surface of solid homogeneous polycaprolactone microspheres in this embodiment;

[0045] Figure 2 It is a surface schematic diagram of the composite polycaprolactone microsphere of the present invention; in the figure, 1, composite polycaprolactone microsphere, 2, PLLA / PLGA microsphere;

[0046] Figure 3 This is a microscopic morphology of the composite polycaprolactone microspheres of the present invention;

[0047] Figure 4 This is the degradation rate detection curve of composite polycaprolactone microspheres.

[0048] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention. DETAILED DESCRIPTION

[0049] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0050] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only and are not intended to limit the content of this application.

[0051] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are purchased from commercial channels unless otherwise specified.

[0052] Preparation example:

[0053] 1. Preparation of PLLA microspheres:

[0054] (1) dissolving PLLA in a solvent;

[0055] (2) Spray drying to obtain microspheres.

[0056] The solvent in step (1) is dichloromethane.

[0057] The molecular weight of the PLLA is 26,000-45,000, and the concentration of PLLA in the solvent is 0.05-0.08 g / mL.

[0058] The spray drying has an air inlet temperature of 50-75°C, an air outlet temperature of 10-50°C, a peristaltic speed of 15-20rpm, a fan frequency of 20-50HZ, a needle pressure of 0.3-0.4MPa, and a spray pressure of 0.2-0.35MPa.

[0059] The particle size of the obtained PLLA microspheres is 0.1-10 μm.

[0060] 2. Preparation of PLGA microspheres:

[0061] (1) dissolving PLGA in a solvent;

[0062] (2) Spray drying to obtain microspheres.

[0063] The solvent in step (1) is dichloromethane.

[0064] The molecular weight of the PLGA is 26,000-45,000, and the concentration of PLGA in the solvent is 0.05-0.08 g / mL.

[0065] The spray drying has an air inlet temperature of 60-80°C, an air outlet temperature of 5-30°C, a peristaltic speed of 10-15rpm, a fan frequency of 20-50HZ, a needle pressure of 0.35-0.45MPa, and a spray pressure of 0.3-0.4MPa.

[0066] The particle size of the obtained PLGA microspheres is 0.1-10 μm.

[0067] Example 1

[0068] Reference Figure 2 A composite polycaprolactone microsphere B is prepared, which is a composite polycaprolactone microsphere comprising PLLA microspheres encapsulated in PCL, with a particle size of 20-40 microns and a weight average molecular weight of 11.2 KDa, wherein the particle size of the PLLA microspheres is 0.1-10 microns and the weight average molecular weight is 23.5 KDa, and the mass of the PLLA microspheres accounts for 5% of the mass of the polycaprolactone composite microspheres.

[0069] Preparation method:

[0070] S1. preparing molten PCL;

[0071] S2, fully mixing the prepared PLLA microspheres with the molten PCL;

[0072] S3, adding surfactant and mixing thoroughly;

[0073] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0074] S5, cooling and solidification under stirring conditions;

[0075] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0076] The total proportion of the PLLA microspheres in the mixed material in step S2 is 5wt%.

[0077] The amount of surfactant added in step S3 is 1 wt %.

[0078] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0079] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0080] The stirring in step S5 has a stirring speed of 1500 rpm and a stirring time of 60 min.

[0081] The cooling and solidification in step S5 is performed at a temperature 5° C. lower than the melting point of PCL.

[0082] The washing in step S6 is performed using deionized water.

[0083] Example 2

[0084] Reference Figure 2 A composite polycaprolactone microsphere C is prepared, which is a composite polycaprolactone microsphere comprising PLLA microspheres encapsulated in PCL. The particle size is 20-40 microns and the weight average molecular weight is 11.2 KDa. The particle size of the PLLA microspheres is 0.1-10 microns and the weight average molecular weight is 23.5 KDa. The mass of the PLLA microspheres accounts for 30% of the mass of the polycaprolactone composite microspheres.

[0085] Preparation method:

[0086] S1. preparing molten PCL;

[0087] S2, fully mixing the prepared PLLA microspheres with the molten PCL;

[0088] S3, adding surfactant and mixing thoroughly;

[0089] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0090] S5, cooling and solidification under stirring conditions;

[0091] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0092] The total proportion of the PLLA microspheres in the mixed material in step S2 is 30wt%.

[0093] The amount of surfactant added in step S3 is 1 wt %.

[0094] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0095] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0096] The stirring in step S5 has a stirring speed of 1500 rpm and a stirring time of 60 min.

[0097] The cooling and solidification in step S5 is performed at a temperature 5° C. lower than the melting point of PCL.

[0098] The washing in step S6 is performed using deionized water.

[0099] Example 3

[0100] Reference Figure 2 A composite polycaprolactone microsphere D is prepared, which is a composite polycaprolactone microsphere containing PLGA microspheres encapsulated in PCL. The particle size is 20-40 microns and the weight average molecular weight is 11.2KDa. The particle size of the PLGA microspheres is 0.1-10 microns and the weight average molecular weight is 16.8KDa. The mass of the PLGA microspheres accounts for 5% of the mass of the polycaprolactone composite microspheres.

[0101] Preparation method:

[0102] S1. preparing molten PCL;

[0103] S2, fully mixing the prepared PLGA microspheres with the molten PCL;

[0104] S3, adding surfactant and mixing thoroughly;

[0105] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0106] S5, cooling and solidification under stirring conditions;

[0107] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0108] The total proportion of the PLGA microspheres in the mixed material is 5wt%.

[0109] The amount of surfactant added in step S3 is 1 wt %.

[0110] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0111] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0112] The stirring in step S5 has a stirring speed of 1500 rpm and a stirring time of 60 min.

[0113] The cooling and solidification in step S5 is performed at a temperature 5° C. lower than the melting point of PCL.

[0114] The washing in step S6 is performed using deionized water.

[0115] Example 4

[0116] Reference Figure 2Preparation of a composite polycaprolactone microsphere E is a composite polycaprolactone microsphere with PLGA microspheres encapsulated in PCL, the particle size of which is 20-40 microns and the weight average molecular weight is 11.2 KDa, wherein the particle size of the PLGA microspheres is 0.1-10 microns and the weight average molecular weight is 16.8 KDa, and the mass of the PLGA microspheres accounts for 30% of the mass of the polycaprolactone composite microspheres

[0117] Preparation method:

[0118] S1. preparing molten PCL;

[0119] S2, fully mixing the prepared PLGA microspheres with the molten PCL;

[0120] S3, adding surfactant and mixing thoroughly;

[0121] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0122] S5, cooling and solidification under stirring conditions;

[0123] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0124] The total proportion of the PLGA microspheres in the mixed material in step S2 is 30wt%.

[0125] The amount of surfactant added in step S3 is 1 wt %.

[0126] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0127] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0128] The stirring in step S5 has a stirring speed of 1500 rpm and a stirring time of 60 min.

[0129] The cooling and solidification in step S5 is performed at a temperature 5° C. lower than the melting point of PCL.

[0130] The washing in step S6 is performed using deionized water.

[0131] Example 5

[0132] Reference Figure 2A composite polycaprolactone microsphere B' is prepared, which is a composite polycaprolactone microsphere containing PLLA microspheres in PCL, with a particle size of 20-40 microns and a weight average molecular weight of 11.2 KDa. The particle size of the PLLA microspheres is 0.1-10 microns, with a weight average molecular weight of 23.5 KDa, and the mass of the PLLA microspheres accounts for 5% of the mass of the polycaprolactone composite microspheres.

[0133] Preparation method:

[0134] S1. preparing molten PCL;

[0135] S2, fully mixing the prepared PLLA microspheres with the molten PCL;

[0136] S3, adding surfactant and mixing thoroughly;

[0137] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0138] S5. Cooling and curing under stirring conditions: keep the cooling and curing temperature 5°C lower than the melting point of PCL, and stir at 500 rpm for 20 min; continue to cool by 5°C, and stir at 1500 rpm for 30 min; continue to cool by 5°C, and stir at 2000 rpm for 10 min;

[0139] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0140] The total proportion of the PLLA microspheres in the mixed material in step S2 is 5wt%.

[0141] The amount of surfactant added in step S3 is 1 wt %.

[0142] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0143] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0144] The washing in step S6 is performed using deionized water.

[0145] Example 6

[0146] Reference Figure 2 A composite polycaprolactone microsphere C' was prepared, which was a composite polycaprolactone microsphere containing PLLA microspheres encapsulated in PCL. The particle size was 20-40 microns and the weight average molecular weight was 11.2 KDa. The particle size of the PLLA microspheres was 0.1-10 microns and the weight average molecular weight was 23.5 KDa. The mass of the PLLA microspheres accounted for 30% of the mass of the polycaprolactone composite microspheres.

[0147] Preparation method:

[0148] S1. preparing molten PCL;

[0149] S2, fully mixing the prepared PLLA microspheres with the molten PCL;

[0150] S3, adding surfactant and mixing thoroughly;

[0151] S4, cooling and curing under stirring conditions: keep the cooling and curing temperature 5°C lower than the melting point of PCL, and stir at 500rpm for 20min; continue to cool down by 5°C, and stir at 1500rpm for 30min; continue to cool down by 5°C, and stir at 2000rpm for 10min;

[0152] S5. After washing and drying, controllably rapidly degradable composite polycaprolactone microspheres are obtained.

[0153] The total proportion of the PLLA microspheres in the mixed material in step S2 is 30wt%.

[0154] The amount of surfactant added in step S3 is 1 wt %.

[0155] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0156] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0157] The washing in step S6 is performed using deionized water.

[0158] Example 7

[0159] Reference Figure 2 A composite polycaprolactone microsphere D' is prepared, which is a composite polycaprolactone microsphere containing PLGA microspheres in PCL, with a particle size of 20-40 microns and a weight average molecular weight of 11.2 KDa. The particle size of PLGA microspheres is 0.1-10 microns, with a weight average molecular weight of 16.8 KDa, and the mass of PLGA microspheres accounts for 5% of the mass of polycaprolactone composite microspheres.

[0160] Preparation method:

[0161] S1. preparing molten PCL;

[0162] S2, fully mixing the prepared PLGA microspheres with the molten PCL;

[0163] S3, adding surfactant and mixing thoroughly;

[0164] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0165] S5. Cooling and curing under stirring conditions: keep the cooling and curing temperature 5°C lower than the melting point of PCL, and stir at 500 rpm for 20 min; continue to cool by 5°C, and stir at 1500 rpm for 30 min; continue to cool by 5°C, and stir at 2000 rpm for 10 min;

[0166] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0167] The total proportion of the PLGA microspheres in the mixed material is 5wt%.

[0168] The amount of surfactant added in step S3 is 1 wt %.

[0169] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0170] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0171] The washing in step S6 is performed using deionized water.

[0172] Example 8

[0173] Reference Figure 2 Preparation of a composite polycaprolactone microsphere E' is a composite polycaprolactone microsphere encapsulated in PCL, the particle size is 20-40 microns, the weight average molecular weight is 11.2KDa, wherein the particle size of the PLGA microsphere is 0.1-10 microns, the weight average molecular weight is 16.8KDa, and the mass of the PLGA microsphere accounts for 30% of the mass of the polycaprolactone composite microsphere

[0174] Preparation method:

[0175] S1. preparing molten PCL;

[0176] S2, fully mixing the prepared PLGA microspheres with the molten PCL;

[0177] S3, adding surfactant and mixing thoroughly;

[0178] S4, adding the mixed materials into the aqueous solution and stirring and emulsifying;

[0179] S5. Cooling and curing under stirring conditions: keep the cooling and curing temperature 5°C lower than the melting point of PCL, and stir at 500 rpm for 20 min; continue to cool by 5°C, and stir at 1500 rpm for 30 min; continue to cool by 5°C, and stir at 2000 rpm for 10 min;

[0180] S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0181] The total proportion of the PLGA microspheres in the mixed material in step S2 is 30wt%.

[0182] The amount of surfactant added in step S3 is 1 wt %.

[0183] The surfactant in step S3 includes polyvinyl pyrrolidone.

[0184] In step S4, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0185] The washing in step S6 is performed using deionized water.

[0186] Comparative Example 1

[0187] Reference Figure 1 A homogeneous solid PCL polycaprolactone microsphere A was prepared, the particle size of which was 20-40 μm and the weight average molecular weight was 11.2 KDa.

[0188] Preparation method:

[0189] S1. preparing molten PCL;

[0190] S2, slowly add the melted solution into the aqueous phase and stir to emulsify;

[0191] S3, cooling and solidification under stirring conditions;

[0192] S4, after washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

[0193] In step S2, the temperature of the aqueous phase solution is 80° C., the aqueous phase solution is a surfactant aqueous solution, and the stirring emulsification time is 1 hour. The surfactant aqueous solution is a PVA aqueous solution, wherein the PVA accounts for 15 wt % of the solution.

[0194] The stirring in step S3 has a stirring speed of 1500 rpm and a stirring time of 60 min.

[0195] The cooling and solidification in step S3 is performed at a temperature 5°C lower than the melting point of PCL.

[0196] The washing in step S4 is performed using deionized water.

[0197] The main component of the PLGA microspheres is poly(lactide-glycol) copolymer, which is randomly polymerized from two monomers, lactic acid and glycolic acid, and is a degradable functional macromolecular organic compound with good biocompatibility, non-toxicity, and rapid degradability. The two products of PLGA hydrolysis, lactic acid and glycolic acid, are byproducts of the human metabolic pathway and are safe and non-toxic to the human body.

[0198] In vitro degradation test of polycaprolactone microspheres:

[0199] 10 g of each of the polycaprolactone microspheres A and composite polycaprolactones B, C, D, E, B', C', D', and E' were accurately weighed and placed in a 500 ml volumetric flask. PBS solution (0.2 M, PH = 7.4) was added to the volume and fixed to volume. The bottle mouth was sealed and placed in a constant temperature oscillation box at 37 ± 1 ° C for degradation experiment. Samples were centrifuged, washed with water, dried, and the weight-average molecular weight was detected at the 2nd week, 4th week, 6th week, 8th week, 12th week, 16th week, 24th week, 32nd week, 40th week, 48th week, 56th week, and 64th week, respectively. Fresh PBS solution was exchanged for the test results. Figure 4 , Figure 4 The horizontal axis is time, and the vertical axis is the detected molecular weight;

[0200] The time required for the solid homogeneous polycaprolactone microspheres A and the composite polycaprolactone microspheres B, C, D, E, B', C', D', and E' to degrade to the disintegration molecular weight is 64 weeks, 40 weeks, 32 weeks, 24 weeks, and 18 weeks, respectively. It can be seen that the composite polycaprolactone microspheres prepared by the method provided by the present invention have controllable rapid degradation characteristics.

[0201] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

[0202] The present invention and its implementation methods are described above, which is not restrictive. The drawings are only one of the implementation methods of the present invention, and the actual application is not limited thereto. In short, if ordinary technicians in the field are inspired by it and do not deviate from the purpose of the invention, they can creatively design methods and embodiments similar to the technical solution, which should fall within the protection scope of the present invention.

Claims

1. A controllable and rapidly degradable composite polycaprolactone microsphere, characterized in that: The composite polycaprolactone microspheres include PCL, in which one or two of PLLA microspheres or PLGA microspheres are uniformly dispersed; in the composite polycaprolactone microspheres, the melting point of the PCL is lower than that of PLLA and PLGA by more than 30°C; the preparation method of the controllable and rapidly degradable composite polycaprolactone microspheres includes the following steps: S1, preparing PLLA microspheres or PLGA microspheres, preparing molten PCL; S2, fully mixing the prepared PLLA microspheres or PLGA microspheres with the molten PCL; S3, adding surfactant and mixing thoroughly; S4, adding the mixed materials into the aqueous solution and stirring and emulsifying; S5, cooling and solidification under stirring conditions; S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

2. The controllable and rapidly degradable composite polycaprolactone microspheres according to claim 1, characterized in that: The mass proportion of one or both of PLLA microspheres or PLGA microspheres in the composite polycaprolactone microspheres is 2%-40%.

3. The controllable and rapidly degradable composite polycaprolactone microspheres according to claim 1, characterized in that: The particle size of the composite polycaprolactone microsphere is 20-100 μm; the particle size of the PLLA microsphere is 0.1-10 μm, and the particle size of the PLGA microsphere is 0.1-10 μm.

4. The controllable and rapidly degradable composite polycaprolactone microspheres according to claim 1, characterized in that: In the composite polycaprolactone microspheres, the weight average molecular weight of PCL is 10KDa-100KDa, the weight average molecular weight of PLLA microspheres is 10KDa-50KDa, and the weight average molecular weight of PLGA microspheres is 10KDa-50KDa.

5. A method for preparing the controllable and rapidly degradable composite polycaprolactone microspheres according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1, preparing PLLA microspheres or PLGA microspheres, preparing molten PCL; S2, fully mixing the prepared PLLA microspheres or PLGA microspheres with the molten PCL; S3, adding surfactant and mixing thoroughly; S4, adding the mixed materials into the aqueous solution and stirring and emulsifying; S5, cooling and solidification under stirring conditions; S6. After washing, screening and drying, controllably fast degradable composite polycaprolactone microspheres are obtained.

6. The method for preparing controllable and rapidly degradable composite polycaprolactone microspheres according to claim 5, characterized in that: The total proportion of the PLLA microspheres or PLGA microspheres in the mixed material is 2%-40wt%.

7. The method for preparing controllable and rapidly degradable composite polycaprolactone microspheres according to claim 5, characterized in that: In step S3, the amount of surfactant added is 1-2wt%; the surfactant includes one or both of polyvinyl pyrrolidone and polysorbate 80; in step S4, the temperature of the aqueous phase solution is 80-100°C, the aqueous phase solution is an aqueous surfactant solution, and the stirring emulsification time is 1-2h.

8. The method for preparing controllable and rapidly degradable composite polycaprolactone microspheres according to claim 5, characterized in that: The stirring in step S5 has a stirring speed of 500-2000 rpm; the cooling and solidification in step S5 has a temperature 5-15° C. lower than the melting point of PCL.

9. The method for preparing controllable and rapidly degradable composite polycaprolactone microspheres according to claim 5, characterized in that: Step S5 specifically includes: maintaining the cooling and curing temperature 5°C lower than the melting point of PCL, stirring at 500rpm for 20-30min; continuing to cool by 5°C, stirring at 1500rpm for 30-50min; continuing to cool by 5°C, stirring at 2000rpm for 10-20min.

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