Polycaprolactone microspheres as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of polycaprolactone microspheres, and particularly relates to a polycaprolactone microsphere as well as a preparation method and application thereof. The preparation method comprises the following steps: dissolving polycaprolactone in an organic solvent to obtain a polycaprolactone oil phase solution; dissolving a drug in water to obtain a drug aqueous solution; mixing the polycaprolactone oil phase solution and the medicine aqueous solution, and performing homogeneous emulsification by adopting high-pressure microjet to obtain an emulsion; performing micro-fluidic molding on the emulsion and a surfactant aqueous solution to obtain gel microspheres; and putting the gel microspheres into a dopamine hydrochloride solution, and modifying to obtain the polycaprolactone microspheres. High-pressure microjet is used for homogeneous emulsification, and microfluidics is used for forming, so that the particle size uniformity of the polycaprolactone microspheres is improved; meanwhile, a dopamine hydrochloride solution is used for modifying the gel microspheres, and a polydopamine layer is self-assembled on the gel microspheres; the polydopamine layer increases the slow release effect of the drug and endows the polycaprolactone microspheres with photo-thermal responsiveness at the same time.

Description

Technical Field

[0001] The present invention relates to the technical field of polycaprolactone microspheres, and particularly to a polycaprolactone microsphere, a preparation method thereof and an application thereof. Background Art

[0002] Due to its good biocompatibility, good compatibility with organic polymers and good biodegradability, polycaprolactone microspheres are ideal supporting materials for cell growth and are widely used in drug carriers, tissue engineering, medical aesthetics and other aspects. Using polycaprolactone microspheres as carriers, loading lidocaine and administrating it by injection can increase the local drug concentration, prolong the drug release time, enhance the targeting property, reduce the systemic side effects, improve the patient compliance, enhance the anesthesia and analgesia effects, and can also load multiple drugs or functional molecules (such as growth factors, antibiotics) at the same time to achieve multi-functional treatment. Research shows that after the eighth week of polycaprolactone microspheres loaded with collagen, new collagen is continuously produced in the cortex stimulated by polycaprolactone. Until 24 weeks, it can be significantly found that the arrangement density and regularity of collagen fibers at the injection site are much higher than those before injection. At present, polycaprolactone microspheres are mainly prepared by the emulsification method, and the particle size distribution of the polycaprolactone microspheres prepared by the emulsification method is relatively wide. Summary of the Invention

[0003] In view of this, the purpose of the present invention is to provide a polycaprolactone microsphere, a preparation method thereof and an application thereof. The preparation method provided by the present invention can obtain polycaprolactone microspheres with uniform particle size distribution.

[0004] In order to achieve the above invention purpose, the present invention provides the following technical solutions:

[0005] The present invention provides a preparation method of polycaprolactone microspheres, comprising the following steps:

[0006] Dissolve polycaprolactone in an organic solvent to obtain a polycaprolactone oil phase solution;

[0007] Dissolve the drug in water to obtain a drug aqueous solution;

[0008] Mix the polycaprolactone oil phase solution and the drug aqueous solution, and perform high-pressure microfluidic homogenization emulsification to obtain an emulsion;

[0009] Perform microfluidic molding on the emulsion and an aqueous surfactant solution to obtain gel microspheres;

[0010] Place the gel microspheres in a hydrochloric acid dopamine solution for modification to obtain the polycaprolactone microspheres.

[0011] Preferably, the number-average molecular weight of the polycaprolactone is 2000 to 80000 Da, the organic solvent is a polar organic solvent, and the polar organic solvent includes one or more of dichloromethane, chloroform, acetone, and tetrahydrofuran; the concentration of the polycaprolactone oil-phase solution is 10 to 50 mg / mL.

[0012] Preferably, the drug includes lidocaine, and the concentration of the aqueous drug solution is 0.1 to 2 wt%.

[0013] Preferably, the volume ratio of the polycaprolactone oil-phase solution to the aqueous drug solution is 5 to 7:1; the pressure of the high-pressure microfluidization is 500 to 1200 psi; the time of the homogenization emulsification is 10 to 25 s; the high-pressure microfluidization is provided by a high-pressure microfluidization homogenizer.

[0014] Preferably, the surfactant in the aqueous surfactant solution includes one or more of polyvinyl alcohol, span 80, span 85, and tween 20; the concentration of the aqueous surfactant solution is 0.1 to 5 wt%.

[0015] Preferably, during the microfluidic molding process, the flow rate ratio of the emulsion to the aqueous surfactant solution is 1:1 to 10.

[0016] Preferably, the microfluidic molding is carried out in a droplet preparation instrument.

[0017] Preferably, the concentration of the dopamine hydrochloride solution is 0.15 to 2 wt%, the modification temperature is 15 to 35 °C, and the time is 2 to 24 h.

[0018] The present invention also provides polycaprolactone microspheres prepared by the preparation method described in the above technical solution.

[0019] The present invention also provides the application of the polycaprolactone microspheres described in the above technical solution in drug carriers, tissue engineering, or beauty.

[0020] The present invention provides a method for preparing polycaprolactone microspheres, comprising the following steps:

[0021] Dissolve polycaprolactone in an organic solvent to obtain a polycaprolactone oil-phase solution;

[0022] Dissolve the drug in water to obtain an aqueous drug solution;

[0023] Mix the polycaprolactone oil-phase solution and the aqueous drug solution, and perform homogenization emulsification by high-pressure microfluidization to obtain an emulsion;

[0024] Perform microfluidic molding on the emulsion and the aqueous surfactant solution to obtain gel microspheres;

[0025] Place the gel microspheres in a dopamine hydrochloride solution for modification to obtain the polycaprolactone microspheres.

[0026] The preparation method of the present invention uses high-pressure microfluidics for homogenization emulsification and microfluidics for shaping, improving the particle size uniformity of the polycaprolactone microspheres. At the same time, the present invention uses a dopamine hydrochloride solution to modify the gel microspheres, and a polydopamine layer self-assembles on the gel microspheres. The polydopamine layer enhances the drug sustained-release effect of the polycaprolactone microspheres and improves the patient's comfort. At the same time, polydopamine is structurally similar to natural melanin. Melanin is a biopolymer widely distributed in all organisms, with good biocompatibility, high pH sensitivity, excellent physiological stability, and strong near-infrared light absorption. That is, polydopamine also has good biocompatibility, high pH sensitivity, excellent physiological stability, and strong near-infrared light absorption. The high pH sensitivity of polydopamine makes the polycaprolactone microspheres have intelligent responsiveness. When irradiated with an infrared lamp, the polydopamine coating absorbs light energy and rapidly generates local heating. The glass transition temperature of polycaprolactone is about 60-65°C. When the infrared light irradiation makes the surface temperature of the polycaprolactone microspheres close to or exceed Tg, the molecular chain segment mobility of polycaprolactone is significantly enhanced, and polycaprolactone changes from a rigid glass state to a soft high-elastic state. When the temperature exceeds Tg, the molecular chain segments of the polycaprolactone microspheres rearrange, resulting in changes in the internal pores of the microspheres, thereby accelerating the diffusion and release of the drug. That is, the near-infrared response of polydopamine realizes the controlled release of the drug in the polycaprolactone microspheres. The controlled release of the drug can reduce the inflammatory response and improve the patient's comfort. Description of the Drawings

[0027] Figure 1 SEM image of the polycaprolactone microspheres prepared in Example 1;

[0028] Figure 2 Optical microscope image of the polycaprolactone microspheres prepared in Example 1;

[0029] Figure 3 SEM image of the polycaprolactone microspheres prepared in Example 2;

[0030] Figure 4 Optical microscope image of the polycaprolactone microspheres prepared in Example 3;

[0031] Figure 5 Particle size cumulative distribution curve of the polycaprolactone microspheres prepared in Example 4;

[0032] Figure 6 Fluorescence microscopy image of cell adhesion of the polycaprolactone microspheres prepared in Example 5;

[0033] Figure 7 SEM image of cell adhesion of the polycaprolactone microspheres prepared in Example 5;

[0034] Figure 8 Fluorescence micrograph of cell adhesion of polycaprolactone microspheres prepared in Comparative Example 1;

[0035] Figure 9 SEM image of cell adhesion of polycaprolactone microspheres prepared in Comparative Example 1;

[0036] Figure 10 Optical micrograph of polycaprolactone microspheres obtained in Comparative Example 2;

[0037] Figure 11 Optical micrograph of polycaprolactone microspheres obtained in Comparative Example 3. Detailed implementation mode

[0038] The present invention provides a method for preparing polycaprolactone microspheres, comprising the following steps:

[0039] Dissolve polycaprolactone in an organic solvent to obtain a polycaprolactone oil-phase solution;

[0040] Dissolve the drug in water to obtain a drug aqueous solution;

[0041] Mix the polycaprolactone oil-phase solution and the drug aqueous solution, and perform homogenization emulsification using high-pressure microfluidics to obtain an emulsion;

[0042] Perform microfluidic molding on the emulsion and an aqueous surfactant solution to obtain gel microspheres;

[0043] Place the gel microspheres in a dopamine hydrochloride solution for modification to obtain the polycaprolactone microspheres.

[0044] Unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0045] The present invention dissolves polycaprolactone in an organic solvent to obtain a polycaprolactone oil-phase solution.

[0046] In the present invention, the number-average molecular weight of the polycaprolactone is preferably 2000 - 80000 Da, specifically preferably 2000 Da or 4500 Da. In the present invention, the organic solvent is preferably a polar organic solvent, and the polar organic solvent preferably includes one or more of dichloromethane, chloroform, acetone, and tetrahydrofuran, and more preferably dichloromethane. In the present invention, the concentration of the polycaprolactone oil-phase solution is preferably 10 - 50 mg / mL, specifically preferably 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, or 50 mg / mL. The present invention does not make specific limitations on the dissolution operation.

[0047] The present invention dissolves a drug in water to obtain an aqueous drug solution. In the present invention, the drug can be selected by those skilled in the art according to actual needs. In a specific embodiment of the present invention, the drug preferably includes lidocaine. In the present invention, the water is preferably deionized water. In the present invention, the concentration of the aqueous drug solution is preferably 0.1 - 2 wt%, specifically preferably 0.1 wt%, 0.25 wt%, 0.5 wt%, 1 wt%, 1.5 wt% or 2 wt%. The present invention does not specifically limit the way of dissolving the drug. In the present invention, the wt% refers to the mass - volume concentration.

[0048] After obtaining the polycaprolactone oil - phase solution and the aqueous drug solution, the present invention mixes the polycaprolactone oil - phase solution and the aqueous drug solution, and performs homogenizing emulsification by high - pressure microfluidization to obtain an emulsion.

[0049] In the present invention, the volume ratio of the polycaprolactone oil - phase solution to the aqueous drug solution is preferably 5 - 7:1, specifically preferably 5:1, 6:1 or 7:1.

[0050] In the present invention, the pressure of the high - pressure microfluidization is preferably 500 - 1200 psi, specifically preferably 500 psi, 600 psi, 700 psi, 800 psi, 900 psi, 1000 psi, 1100 psi or 1200 psi. In the present invention, the high - pressure microfluidization is preferably provided by a high - pressure microfluidization homogenizer.

[0051] In the present invention, the time of the homogenizing emulsification is preferably 10 - 25 s, specifically preferably 10 s, 15 s, 20 s or 25 s.

[0052] In a specific embodiment of the present invention, the mixing of the polycaprolactone oil - phase solution and the aqueous drug solution and the homogenizing emulsification by high - pressure microfluidization preferably include the following steps: measuring the polycaprolactone oil - phase solution and the aqueous drug solution, sequentially placing the polycaprolactone oil - phase solution and the aqueous drug solution into a high - pressure microfluidization homogenizer, setting the pressure of the high - pressure microfluidization homogenizer, and performing homogenizing emulsification.

[0053] In the present invention, high - pressure microfluidization can form an emulsion by spraying two immiscible phases (the polycaprolactone oil - phase solution and the aqueous drug solution) under high pressure, disperse the aqueous phase (the aqueous drug solution) in the form of small droplets in the oil phase (the polycaprolactone oil - phase solution), and form a uniform emulsion; the formation of the uniform emulsion is beneficial to the formation of polycaprolactone microspheres with uniform particle sizes.

[0054] After obtaining the emulsion, the present invention performs microfluidic molding on the emulsion and an aqueous surfactant solution to obtain gel microspheres.

[0055] In the present invention, the surfactant in the surfactant aqueous solution preferably includes one or more of polyvinyl alcohol, Span 80, Span 85 and Tween 20, and more preferably polyvinyl alcohol. In the present invention, the concentration of the surfactant aqueous solution is preferably 0.1-5wt%, more preferably 1-5wt%, and specifically preferably 0.1wt%, 0.5wt%, 1wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt% or 5wt%. In the present invention, the water in the surfactant aqueous solution is preferably deionized water.

[0056] In the present invention, during the microfluidic forming process, the flow rate ratio of the emulsion and the surfactant aqueous solution is preferably 1:1 to 10, and specifically preferably 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10. In the present invention, the flow rate of the emulsion is preferably 5 to 30 μL / min, and specifically preferably 5 μL / min, 10 μL / min, 15 μL / min, 20 μL / min, 25 μL / min or 30 μL / min.

[0057] In the present invention, the microfluidic molding is preferably carried out in a droplet preparation instrument. In the present invention, the droplet preparation instrument can control the outflow speed of the surfactant aqueous solution and the emulsion. When the two liquid phases meet in the T-shaped structure, the oil phase is divided into tiny droplets by the effect of surface tension to form droplets with highly consistent particle sizes. The flow rate ratio of the emulsion and the surfactant aqueous solution is set to ensure that the gel microspheres with uniform size distribution can be prepared.

[0058] In the present invention, the surfactant has high surface activity, strong dispersing ability and strong thickening ability. It is wrapped on the surface of the emulsion and can disperse the emulsion into the continuous phase to prevent the microsphere droplets from sticking and merging. Combined with microfluidics, gel microspheres with good dispersibility and uniform particle size distribution can be prepared, and finally polycaprolactone microspheres with uniform size distribution are obtained.

[0059] After obtaining the gel microspheres, the present invention places the gel microspheres in a dopamine hydrochloride solution for modification to obtain the polycaprolactone microspheres.

[0060] In the present invention, the concentration of the dopamine hydrochloride solution is preferably 0.15-2 wt %. In the present invention, the solvent of the dopamine hydrochloride solution is preferably deionized water, physiological saline or phosphate buffer solution.

[0061] In the present invention, the temperature for modification is preferably 15 - 35°C, specifically preferably 15°C, 20°C, 25°C, 30°C or 35°C; the time is preferably 2 - 24 h, specifically preferably 2 h, 6 h, 9 h, 12 h, 15 h, 18 h or 24 h.

[0062] After the modification is completed, the present invention preferably further includes: stirring the obtained modified liquid under ventilation conditions until the organic solvent completely volatilizes and the liquid droplets solidify into spheres, followed by washing, centrifugation and freeze-drying in sequence to obtain the polycaprolactone microspheres. In the present invention, the stirring is preferably carried out in a fume hood; the reagent for washing is water, and the water is preferably deionized water.

[0063] In the present invention, the dopamine hydrochloride molecule has structural units catechol and active groups amino similar to the adhesion protein secreted by mussels. Under alkaline conditions, it can be deposited on the surfaces of various materials through oxidative self-polymerization to form a polydopamine coating layer rich in active groups. The present invention uses a dopamine hydrochloride solution to modify the gel microspheres, and a polydopamine layer self-assembles on the gel microspheres. Polydopamine is structurally similar to natural melanin. Natural melanin is a biopolymer widely distributed in all organisms, having good biocompatibility, high pH sensitivity, excellent physiological stability and strong near-infrared light absorption; that is, polydopamine also has good biocompatibility, high pH sensitivity, excellent physiological stability and strong near-infrared light absorption; the high pH sensitivity of polydopamine enables the polycaprolactone microspheres to have intelligent responsiveness; the near-infrared response of polydopamine can achieve the controlled release of drugs in the polycaprolactone microspheres; the controlled release of drugs can reduce the inflammatory response and improve the patient's comfort. At the same time, the presence of the polydopamine layer enhances the drug sustained-release effect and improves the patient's comfort.

[0064] The present invention also provides the polycaprolactone microspheres prepared by the preparation method described in the above technical solution. In the present invention, the interior of the polycaprolactone microspheres presents a three-dimensional network structure, and the surface is porous and rough, which is beneficial to cell adhesion.

[0065] The present invention also provides the application of the polycaprolactone microspheres described in the above technical solution in drug carriers, tissue engineering or cosmetology.

[0066] In the present invention, when the polycaprolactone microspheres are applied, they are preferably used alone or in the form of an injection. The injection preferably includes polycaprolactone microspheres and a liquid for dispersing the polycaprolactone microspheres; the liquid preferably includes water, a salt solution or a gel; the concentration of the polycaprolactone microspheres in the injection can be preferably set according to actual needs.

[0067] The preparation method and application of the polycaprolactone microspheres provided by the present invention will be described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0068] Example 1

[0069] Weigh 800 mg of polycaprolactone with a number average molecular weight of 2000 Da and dissolve it in 20 mL of dichloromethane to obtain a polycaprolactone oil phase solution with a concentration of 40 mg / mL.

[0070] Weigh 25 mg of lidocaine and dissolve it fully in 5 mL of deionized water to obtain a lidocaine aqueous solution with a concentration of 0.5 wt%.

[0071] Weigh 4 g of polyvinyl alcohol and dissolve it fully in 100 mL of deionized water to obtain a polyvinyl alcohol aqueous solution with a concentration of 4 wt%.

[0072] Measure the polycaprolactone oil phase solution and the lidocaine aqueous solution according to a volume ratio of 6:1. Add the polycaprolactone oil phase solution and the lidocaine aqueous solution to a high-pressure microfluidic homogenizer in sequence and perform homogenization emulsification for 15 s to form a homogeneous emulsion; set the pressure of the high-pressure microfluidic homogenizer to 800 psi.

[0073] Place the emulsion and the polyvinyl alcohol aqueous solution in a droplet preparation instrument. Set the flow rate ratio of the emulsion and the polyvinyl alcohol aqueous solution to 1:3. Among them, the flow rate of the emulsion is 10 μL / min. Use a hydrochloric acid dopamine solution (concentration: 1 wt%, solvent: deionized water) to collect and modify the gel microspheres. The modification temperature is 25 °C and the time is 4 h; after modification, place the obtained modified liquid in a fume hood and stir it to completely volatilize dichloromethane and solidify the droplets into spheres. Finally, stop stirring, wash the microsphere sample under pure water conditions, centrifuge it after washing, and then perform freeze-drying to obtain polycaprolactone microspheres.

[0074] The SEM image of the polycaprolactone microspheres prepared in Example 1 is as Figure 1 shown, and the optical microscope image is as Figure 2 shown. It can be seen from Figures 1 - 2 that the sizes of the polycaprolactone microspheres prepared in Example 1 are mainly distributed around 40 μm, with uniform distribution, uniform size, a three-dimensional structure inside, and slightly rough and porous surfaces, which is beneficial to the loading and release of substances. Use a near-infrared lamp to irradiate the microspheres, adjust the power and irradiation time of the near-infrared lamp, and the release rate of lidocaine will change, realizing the controlled release of the drug.

[0075] Example 2

[0076] Weigh 800 mg of polycaprolactone with a number average molecular weight of 4500 Da and dissolve it in 20 mL of dichloromethane to obtain a polycaprolactone oil phase solution with a concentration of 40 mg / mL.

[0077] Weigh 25 mg of lidocaine and dissolve it fully in 5 mL of deionized water to obtain a lidocaine aqueous solution with a concentration of 0.5 wt%.

[0078] Weigh 4 g of polyvinyl alcohol and dissolve it fully in 100 mL of deionized water to obtain a polyvinyl alcohol aqueous solution with a concentration of 4 wt%.

[0079] Measure the polycaprolactone oil phase solution and the lidocaine aqueous solution according to a volume ratio of 6:1. Add the polycaprolactone oil phase solution and the lidocaine aqueous solution to a high-pressure microfluidic homogenizer in sequence and carry out homogenization emulsification for 15 s to form a homogeneous emulsion. Among them, set the pressure of the high-pressure microfluidic homogenizer to 800 psi.

[0080] Place the emulsion and the polyvinyl alcohol aqueous solution in a droplet preparation instrument. Set the flow rate ratio of the emulsion and the polyvinyl alcohol aqueous solution to 1:3. Among them, the flow rate of the emulsion is 20 μL / min. Use a dopamine hydrochloride solution (concentration is 1 wt%, solvent is deionized water) to collect and modify the gel microspheres. The modification temperature is 25 °C and the time is 4 h. After modification, place the obtained modified feed liquid in a fume hood and stir it to completely volatilize dichloromethane and solidify the droplets into spheres. Finally, stop stirring, wash the microsphere sample under pure water conditions, centrifuge after washing, and then carry out freeze-drying to obtain polycaprolactone microspheres.

[0081] The SEM image of the polycaprolactone microspheres prepared in Example 2 is as Figure 3 shown. From Figure 3 it can be seen that the size of the polycaprolactone microspheres prepared in Example 2 is mainly distributed around 60 μm, and the surface is porous and slightly rough, which is beneficial to the loading and release of substances. Use a near-infrared lamp to irradiate the microspheres, adjust the power and irradiation time of the near-infrared lamp, and the release rate of lidocaine will change, realizing the controlled release of drugs.

[0082] Example 3

[0083] Weigh 400 mg of polycaprolactone with a number average molecular weight of 4500 Da and dissolve it in 20 mL of dichloromethane to obtain a polycaprolactone oil phase solution with a concentration of 20 mg / mL.

[0084] Weigh 25 mg of lidocaine and dissolve it fully in 5 mL of deionized water to obtain a lidocaine aqueous solution with a concentration of 0.5 wt%.

[0085] Weigh 4 g of polyvinyl alcohol and dissolve it fully in 100 mL of deionized water to obtain a polyvinyl alcohol aqueous solution with a concentration of 4 wt%.

[0086] Measure the polycaprolactone oil phase solution and lidocaine aqueous solution according to a volume ratio of 6:1. Add the polycaprolactone oil phase solution and lidocaine aqueous solution to a high-pressure microfluidic homogenizer in sequence, and perform homogenization and emulsification for 15 s to form a homogeneous emulsion. The pressure of the high-pressure microfluidic homogenizer is set to 800 psi.

[0087] Place the emulsion and polyvinyl alcohol aqueous solution in a droplet preparation instrument. Set the flow rate ratio of the emulsion to the polyvinyl alcohol aqueous solution to 1:3. Among them, the flow rate of the emulsion is 10 μL / min. Collect and modify the gel microspheres with a dopamine hydrochloride solution (concentration: 1 wt%, solvent: deionized water). The modification temperature is 25 °C and the time is 4 h. After modification, place the obtained modified liquid in a fume hood and stir it to completely volatilize dichloromethane and solidify the droplets into spheres. Finally, stop stirring, wash the microsphere sample under pure water conditions, centrifuge after washing, and then perform freeze-drying to obtain polycaprolactone microspheres.

[0088] The optical microscope image of the polycaprolactone microspheres prepared in Example 3 is as Figure 4 shown. It can be seen from Figure 4 that the sizes of the polycaprolactone microspheres prepared in Example 3 are mainly distributed around 50 μm, with uniform distribution, uniform size, a three-dimensional structure inside, and slightly rough and porous surfaces, which is beneficial to the loading and release of substances. Irradiate the microspheres with a near-infrared lamp, adjust the power and irradiation time of the near-infrared lamp, and the release rate of lidocaine will change, realizing the controlled release of drugs.

[0089] Example 4

[0090] Weigh 400 mg of polycaprolactone with a number average molecular weight of 4500 Da and dissolve it in 20 mL of dichloromethane to obtain a polycaprolactone oil phase solution with a concentration of 20 mg / mL.

[0091] Weigh 12.5 mg of lidocaine and dissolve it fully in 5 mL of deionized water to obtain a lidocaine aqueous solution with a concentration of 0.25 wt%.

[0092] Weigh 4 g of polyvinyl alcohol and dissolve it fully in 100 mL of deionized water to obtain a polyvinyl alcohol aqueous solution with a concentration of 4 wt%.

[0093] Measure the polycaprolactone oil phase solution and lidocaine aqueous solution according to a volume ratio of 6:1. Add the polycaprolactone oil phase solution and lidocaine aqueous solution to a high-pressure microfluidic homogenizer in sequence, and perform homogenization and emulsification for 15 s to form a homogeneous emulsion. The pressure of the high-pressure microfluidic homogenizer is set to 800 psi.

[0094] The emulsion and the aqueous solution of polyvinyl alcohol were placed in a droplet preparation instrument, and the flow rate ratio of the emulsion to the aqueous solution of polyvinyl alcohol was set to 1:3. Among them, the flow rate of the emulsion was 10 μL / min. The gel microspheres were collected and modified with a hydrochloric acid dopamine solution (concentration: 1 wt%, solvent: deionized water). The modification temperature was 20 °C and the time was 4 h. After modification, the obtained modified feed liquid was placed in a fume hood and stirred to completely volatilize dichloromethane and solidify the droplets into spheres. Finally, the stirring was stopped, and the microsphere sample was washed under pure water conditions, centrifuged after washing, and then freeze-dried to obtain polycaprolactone microspheres.

[0095] The cumulative particle size distribution curve of the polycaprolactone microspheres prepared in Example 4 is as Figure 5 shown. It can be seen from Figure 5 that the size of the polycaprolactone microspheres prepared in Example 4 is mainly distributed around 50 μm, with uniform distribution, uniform size, a three-dimensional structure inside, and slightly rough and porous surfaces, which is beneficial to the loading and release of substances. The microspheres were irradiated with a near-infrared lamp, and by adjusting the power and irradiation time of the near-infrared lamp, the release rate of lidocaine changed, realizing the controlled release of the drug.

[0096] Example 5

[0097] 400 mg of polycaprolactone with a number average molecular weight of 4500 Da was weighed and dissolved in 20 mL of dichloromethane to obtain a polycaprolactone oil-phase solution with a concentration of 20 mg / mL.

[0098] 12.5 mg of lidocaine was weighed and fully dissolved in 5 mL of deionized water to obtain an aqueous lidocaine solution with a concentration of 0.25 wt%.

[0099] 2 g of polyvinyl alcohol was weighed and fully dissolved in 100 mL of deionized water to obtain an aqueous polyvinyl alcohol solution with a concentration of 2 wt%.

[0100] The polycaprolactone oil-phase solution and the aqueous lidocaine solution were measured by volume ratio of 6:1, and the polycaprolactone oil-phase solution and the aqueous lidocaine solution were successively added to a high-pressure microfluidic homogenizer for 15 s of homogenization emulsification to form a homogeneous emulsion. Among them, the pressure of the high-pressure microfluidic homogenizer was set to 800 psi.

[0101] The emulsion and the aqueous solution of polyvinyl alcohol were placed in a droplet preparation instrument, and the flow rate ratio of the emulsion to the aqueous solution of polyvinyl alcohol was set to 1:3. Among them, the flow rate of the emulsion was 10 μL / min. The gel microspheres were collected and modified with a hydrochloric acid dopamine solution (concentration: 1 wt%, solvent: deionized water). The modification temperature was 25 °C and the time was 4 h. After modification, the obtained modified feed liquid was placed in a fume hood and stirred to completely volatilize dichloromethane and solidify the droplets into spheres. Finally, the stirring was stopped, and the microsphere sample was washed under pure water conditions, centrifuged after washing, and then freeze-dried to obtain polycaprolactone microspheres.

[0102] The cell adhesion fluorescence image and the SEM image of the cell adhesion of the polycaprolactone microspheres prepared in Example 5 are respectively as Figure 6 and Figure 7 shown. It can be seen from Figures 6 - 7 that the sizes of the polycaprolactone microspheres prepared in Example 5 are mainly distributed around 60 μm, with uniform distribution, uniform size, a three-dimensional structure inside, and a slightly rough and porous surface, which is beneficial to the loading and release of substances and has good cell adhesion. When the microspheres are irradiated with a near-infrared lamp and the power and irradiation time of the near-infrared lamp are adjusted, the release rate of lidocaine will change, realizing the controlled release of the drug.

[0103] Comparative Example 1

[0104] 400 mg of polycaprolactone with a number-average molecular weight of 4500 Da was weighed and dissolved in 20 mL of dichloromethane to obtain a polycaprolactone oil-phase solution with a concentration of 20 mg / mL.

[0105] 12.5 mg of lidocaine was weighed and fully dissolved in 5 mL of deionized water to obtain an aqueous lidocaine solution with a concentration of 0.25 wt%.

[0106] 2 g of polyvinyl alcohol was weighed and fully dissolved in 100 mL of deionized water to obtain an aqueous polyvinyl alcohol solution with a concentration of 2 wt%.

[0107] The polycaprolactone oil-phase solution and the aqueous lidocaine solution were measured by volume ratio of 6:1, and the polycaprolactone oil-phase solution and the aqueous lidocaine solution were successively added to a high-pressure microfluidic homogenizer for homogenization and emulsification for 15 s to form a homogeneous emulsion. Among them, the pressure of the high-pressure microfluidic homogenizer was set to 800 psi.

[0108] Place the emulsion and the aqueous solution of polyvinyl alcohol in a droplet preparation instrument, and set the flow rate ratio of the emulsion to the aqueous solution of polyvinyl alcohol to 1:3. Among them, the flow rate of the emulsion is 10 μL / min. Collect the gel microspheres with water, place the collected feed liquid system in a fume hood and stir it to completely volatilize dichloromethane and solidify the droplets into spheres. Finally, stop stirring, wash the microsphere sample under pure water conditions, centrifuge after washing, and then perform freeze-drying to obtain polycaprolactone microspheres.

[0109] The cell adhesion fluorescence image and the SEM image of the cell adhesion of the polycaprolactone microspheres prepared in Comparative Example 1 are respectively as Figure 8 and Figure 9 shown. From Figures 8 - 9 it can be seen that the size of the polycaprolactone microspheres prepared in Comparative Example 1 is mainly distributed around 60 μm, with uniform distribution, uniform size, a three-dimensional structure inside, very poor cell adhesion, and uncontrollable drug release.

[0110] Comparative Example 2

[0111] The difference from Example 1 is that the homogenization emulsification is carried out in a cell disruptor, and the ultrasonic power of the cell disruptor is 400 W and the time is 2 min. Other steps are the same as in Example 1.

[0112] The optical microscope image of the obtained polycaprolactone microspheres is as Figure 10 shown. From Figure 10 it can be seen that the size of the polycaprolactone microspheres prepared in Comparative Example 2 is mainly distributed around 50 μm, with a three-dimensional structure inside, but there are many empty shells, weak sphericity, very poor cell adhesion, and uncontrollable drug release.

[0113] Comparative Example 3

[0114] The difference from Example 1 is that the forming is carried out in an emulsifying machine. Specifically: after mixing the emulsion and the aqueous solution of polyvinyl alcohol, carry out forming in the emulsifying machine. The parameters of the emulsifying machine include: the flow rate of the air flow is 1500 r / min. Other steps are the same as in Example 1.

[0115] The optical microscope image of the obtained polycaprolactone microspheres is as Figure 11 shown. From Figure 11 it can be seen that: the size of the polycaprolactone microspheres prepared in Comparative Example 3 is mainly distributed around 40 μm, with a three-dimensional structure inside, but there are many empty shells, weak sphericity, very poor cell adhesion, and uncontrollable drug release.

[0116] The method provided by the present invention solves the problems of uneven particle size distribution, poor repeatability, obvious pain of patients, and poor intelligent responsiveness in the preparation of polycaprolactone microspheres at present.

[0117] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing polycaprolactone microspheres, characterized in that: The following steps are involved: dissolving polycaprolactone in an organic solvent to obtain a polycaprolactone oil phase solution; dissolving the drug in water to obtain a drug aqueous solution; The polycaprolactone oil phase solution and the drug aqueous solution are mixed, and homogenized and emulsified by high-pressure micro jet to obtain an emulsion; The emulsion and the surfactant aqueous solution are subjected to microfluidic molding to obtain gel microspheres; The gel microspheres are placed in a dopamine hydrochloride solution for modification to obtain the polycaprolactone microspheres.

2. The preparation method according to claim 1, characterized in that: The number average molecular weight of the polycaprolactone is 2000-80000Da, the organic solvent is a polar organic solvent, and the polar organic solvent includes one or more of dichloromethane, chloroform, acetone and tetrahydrofuran; the concentration of the polycaprolactone oil phase solution is 10-50 mg / mL.

3. The preparation method according to claim 1, characterized in that: The drug includes lidocaine, and the concentration of the drug aqueous solution is 0.1-2 wt %.

4. The preparation method according to claim 1, 2 or 3, characterized in that: The volume ratio of the polycaprolactone oil phase solution to the drug aqueous solution is 5-7:1; the pressure of the high-pressure microjet is 500-1200psi; the homogenization and emulsification time is 10-25s; and the high-pressure microjet is provided by a high-pressure microjet homogenizer.

5. The preparation method according to claim 1, characterized in that: The surfactant in the surfactant aqueous solution includes one or more of polyvinyl alcohol, Span 80, Span 85 and Tween 20; and the concentration of the surfactant aqueous solution is 0.1-5 wt %.

6. The preparation method according to claim 1, characterized in that: During the microfluidic forming process, the flow rate ratio of the emulsion to the surfactant aqueous solution is 1:1-10.

7. The preparation method according to claim 1 or 6, characterized in that: The microfluidic forming is carried out in a droplet preparation instrument.

8. The preparation method according to claim 1, characterized in that: The concentration of the dopamine hydrochloride solution is 0.15-2 wt %, the modification temperature is 15-35° C., and the modification time is 2-24 h.

9. Polycaprolactone microspheres prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the polycaprolactone microspheres according to claim 9 in drug carriers, tissue engineering or cosmetology.

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