A polycaprolactone microsphere prepared by an electrostatic spraying method, a preparation method thereof, and an application thereof

Abstract

The present invention provides polycaprolactone microspheres prepared by an electrostatic spraying method, a preparation method thereof and applications thereof. The preparation method includes mixing polycaprolactone, a compound solvent and a surfactant, and performing electrostatic spraying to obtain the polycaprolactone microspheres, and the compound solvent includes formic acid, acetic acid and water. The preparation method is simple to operate, and by selecting formic acid, acetic acid and water as the compound solvent, the prepared polycaprolactone microspheres have the characteristics of narrow particle size distribution, good microsphere morphology and high roundness, solving the problems of wide particle size distribution and poor microsphere morphology of polycaprolactone microspheres prepared by traditional methods such as the emulsion solvent evaporation method. At the same time, polycaprolactone microspheres with controllable particle size and morphology can be prepared by adjusting process parameters in the electrostatic spraying process, such as voltage, needle inner diameter, solution flow rate, etc.

Description

Technical Field

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

[0002] Microspheres are microspherical entities in which drugs are dispersed and embedded in a polymer matrix through microencapsulation technology. Through the drug-loaded microsphere intervention technique, various chemotherapeutic drugs can be loaded, playing a combined role of embolization and local high-concentration chemotherapy. Commonly used synthetic materials are mainly polyester materials, including polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL), etc.

[0003] PCL is a biodegradable synthetic polymer material formed by ring-opening polymerization of ε-caprolactone under the catalysis of a metal anion complex catalyst. It is insoluble in water but soluble in a variety of organic solvents; it can be completely degraded into carbon dioxide and water in the natural environment, and the degradation products can be absorbed by the body or excreted from the body. Its good biocompatibility makes it widely used in drug controlled release, and it also has cell compatibility with some tissues of the human body. Therefore, it is also an ideal material for tissue engineering. However, PCL itself has limitations such as a long degradation period and poor hydrophilicity.

[0004] The conventional preparation method of PCL microspheres is the emulsification method. The emulsification method is to dissolve PCL in an organic solvent and then drop it into the aqueous phase to form microspheres by high-speed shear stirring, and then wash, centrifuge and dry. For example, CN113769164A discloses a polycaprolactone microsphere, a preparation method thereof and a use thereof. The preparation method of the polycaprolactone microsphere includes: contacting an aqueous solution of hydroxypropyl methylcellulose and a dichloromethane solution of polycaprolactone and simultaneously performing shear emulsification to form a shear emulsification mixture; contacting an aqueous solution of polyvinyl alcohol with the shear emulsification mixture, mixing and heating until dichloromethane volatilizes completely; filtering to obtain microspheres with a particle size of 28 - 100 μm. However, the polycaprolactone microspheres prepared by the emulsification method have a wide particle size distribution and poor microsphere morphology, which limits their subsequent application range.

[0005] Therefore, in view of the above technical problems, there is an urgent need to develop a preparation method that can prepare polycaprolactone microspheres with a uniform particle size distribution, good morphology, and high roundness. Summary of the Invention

[0006] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide polycaprolactone microspheres prepared by an electrospray method, a preparation method thereof, and an application thereof. The preparation method is simple to operate, and the prepared polycaprolactone microspheres have the advantages of a narrow particle size distribution, good microsphere morphology, and high roundness. They can be mixed with a gel to be prepared into an injection filler, and have broad application prospects.

[0007] To achieve this goal, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a method for preparing polycaprolactone microspheres prepared by electrospray method. The preparation method includes: mixing polycaprolactone, a mixed solvent, and a surfactant, and performing electrospray to obtain the polycaprolactone microspheres;

[0009] The mixed solvent includes formic acid, acetic acid, and water.

[0010] Electrospray Technology refers to the process of using electrohydrodynamics technology to make polymer carrier solutions into micron, nano particles or fibers. It has the advantages of simple operation, plump product morphology, smooth appearance, and uniform particle size.

[0011] Based on the above content, the method for preparing polycaprolactone microspheres provided by the present invention uses a mixture of polycaprolactone and a surfactant as raw materials, and formic acid, acetic acid, and water are used as a mixed solvent. By using the electrospray method and adjusting the process parameters of electrospray, such as voltage, needle inner diameter, solution flow rate, etc., white dry powder-like polycaprolactone microspheres are directly prepared in one step, eliminating the cumbersome process steps such as mixing, shearing, curing, and water washing required by the conventional emulsion solvent evaporation method. And through observation, the polycaprolactone microspheres prepared by the preparation method provided by the present invention have characteristics such as narrow particle size distribution, good microsphere morphology, and high roundness, solving the problems of wide particle size distribution and poor microsphere morphology in the traditional method for preparing polycaprolactone microspheres, such as the emulsion solvent evaporation method.

[0012] Specifically, formic acid, acetic acid, and water are used as a mixed solvent. Especially adding water to the acid can change the dissolution state of polycaprolactone. Theoretically, introducing a small amount of water will reduce the dissolution ability of polycaprolactone. However, the inventors of the present invention have found that after adding water to formic acid and acetic acid with higher dielectric constants and using the wetting and emulsifying effects of the surfactant, polycaprolactone within a certain concentration range can not only achieve a good dissolved state in this system, but also adding water changes the dielectric constant of the solvent system, which is more conducive to subsequent electrospray. Due to the change in the dielectric constant of the new solvent system, electrospray can better utilize the electric potential to volatilize the solvent, thereby further improving the particle size uniformity and monodispersity of the prepared polycaprolactone microspheres.

[0013] Preferably, the weight average molecular weight of the polycaprolactone is 5000 - 100000, such as 5000, 6000, 7000, 8000, 9000, 10000, 20000, 40000, 60000, 80000, or 100000, etc.

[0014] Preferably, the volume ratio of acid to water in the compound solvent is 1:(0.1 - 0.3), such as 1:0.1, 1:0.12, 1:0.14, 1:0.16, 1:0.18, 1:0.2, 1:0.22, 1:0.24, 1:0.26, 1:0.28 or 1:0.3, etc., and the acid includes formic acid and acetic acid.

[0015] Preferably, the volume ratio of formic acid to acetic acid is 1:(1 - 3), such as 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8 or 1:3, etc.

[0016] Preferably, the surfactant includes any one or a combination of at least two of potassium monolauryl phosphate, sodium laurate, sodium dodecyl sulfate, dodecylamine or sodium dodecylbenzenesulfonate.

[0017] Preferably, the concentration of polycaprolactone in the obtained mixture is 0.01 - 0.05 g / mL, such as 0.01 g / mL, 0.015 g / mL, 0.02 g / mL, 0.025 g / mL, 0.03 g / mL, 0.035 g / mL, 0.04 g / mL, 0.045 g / mL or 0.05 g / mL, etc.

[0018] Preferably, the concentration of the surfactant in the obtained mixture is 0.01 - 0.03 g / mL, such as 0.01 g / mL, 0.012 g / mL, 0.014 g / mL, 0.016 g / mL, 0.018 g / mL, 0.02 g / mL, 0.022 g / mL, 0.024 g / mL, 0.026 g / mL, 0.028 g / mL or 0.03 g / mL, etc.

[0019] Preferably, the electrostatic spraying is carried out in an electrostatic spraying machine.

[0020] Preferably, the working voltage of the electrostatic spraying machine is 15 - 20 kV, such as 15 kV, 16 kV, 17 kV, 18 kV, 19 kV or 20 kV, etc.

[0021] Preferably, the receiving distance of the electrostatic spraying machine is 10 - 20 cm, such as 10 cm, 12 cm, 14 cm, 16 cm, 18 cm or 20 cm, etc.

[0022] Preferably, the inner diameter of the syringe needle in the electrostatic spraying machine is 0.69 - 1.6 mm, such as 0.69 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.4 mm or 1.6 mm, etc.

[0023] Preferably, the flow rate of the electrostatic sprayer is 0.2 - 0.4 mm / min, such as 0.2 mm / min, 0.24 mm / min, 0.28 mm / min, 0.3 mm / min, 0.32 mm / min, 0.36 mm / min or 0.4 mm / min, etc.

[0024] As a preferred technical solution, the preparation method specifically includes the following steps:

[0025] (1) Mix polycaprolactone evenly in a compound solvent including formic acid, acetic acid and water, and then add a surfactant and mix evenly to obtain a mixed solution;

[0026] (2) Add the mixed solution obtained in step (1) to a syringe, load it into an electrostatic sprayer, and perform electrostatic spraying. Among them, the spray needle is selected from 14 - 19G, the working voltage is 15 - 20 kV, the inner diameter of the needle is 0.69 - 1.6 mm, the flow rate is 0.2 - 0.4 mm / min, and the receiving distance is 10 - 20 cm to obtain the polycaprolactone microspheres.

[0027] In the second aspect, the present invention provides a kind of polycaprolactone microspheres, and the polycaprolactone microspheres are prepared by the preparation method as described in the first aspect.

[0028] Preferably, the particle size distribution of the polycaprolactone microspheres is 10 - 40 μm, and more preferably 10 - 25 μm.

[0029] In the third aspect, the present invention provides an application of the polycaprolactone microspheres prepared by the electrostatic spraying method as described in the second aspect in the preparation of injection fillers.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) The preparation method of polycaprolactone based on the electrostatic spraying method provided by the present invention includes the steps of mixing polycaprolactone, solvent and surfactant, and performing electrostatic spraying to obtain the polycaprolactone microspheres. The preparation method is simple to operate, and by selecting formic acid, acetic acid and water in combination as the solvent, the prepared caprolactone microspheres can have the characteristics of narrow particle size distribution, good microsphere morphology and high roundness, etc., solving the problems of wide particle size distribution and poor microsphere morphology in the traditional method such as the emulsion solvent evaporation method for preparing polycaprolactone microspheres;

[0032] (2) The preparation method of polycaprolactone provided by the present invention sprays out the surfactant and polycaprolactone mixed solution through the electrostatic spraying method. By adjusting the process parameters of electrostatic spraying, such as voltage, inner diameter of the needle, solution flow rate, etc., polycaprolactone microspheres with controllable particle size and morphology can be prepared. Description of the Drawings

[0033] Figure 1 A physical picture of the polycaprolactone microspheres provided in Example 3;

[0034] Figure 2 This is a scanning electron microscope image of the polycaprolactone microspheres provided in Example 3.

[0035] Figure 3 This is a scanning electron microscope image of the polycaprolactone microspheres provided for Comparative Example 5. DETAILED DESCRIPTION

[0036] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0037] Unless otherwise specified, the raw materials involved in the following examples and comparative examples are conventional materials in the art and can be purchased commercially.

[0038] In particular, the information of some raw materials and instruments involved is as follows:

[0039] (1) Polycaprolactone: purchased from Jinan Daigang Bioengineering Co., Ltd., with a weight average molecular weight of 40,000;

[0040] (2) Formic acid: purchased from Sinopharm Group;

[0041] (3) Acetic acid: purchased from Sinopharm Group;

[0042] (4) Electrostatic sprayer: purchased from Beijing Yongkang Leye, model BT-1334H;

[0043] (5) Electronic balance: Sartorius BSA124S-CW, Germany;

[0044] (6) Magnetic stirrer: purchased from Beijing Dalong Xingchuang Experimental Instrument Co., Ltd., model number MS-HS;

[0045] (7) Scanning electron microscope: JEOL Ltd., model: JEM-7001F.

[0046] Example 1

[0047] A method for preparing polycaprolactone microspheres, comprising the following steps:

[0048] (1) using an electronic balance to precisely measure acetic acid and formic acid in a volume ratio of 2:1 to prepare a mixed solvent A, and then mixing the mixed solvent A and water in a volume ratio of 1:0.2 to prepare a mixed solvent B;

[0049] (2) Accurately weigh 0.3 g of polycaprolactone and 0.2 g of sodium dodecyl sulfate using an electronic balance, dissolve them in 10 mL of the mixed solvent B obtained in step (1), and stir evenly in a magnetic stirrer to obtain a mixed solution;

[0050] (3) Load the mixed solution obtained in step (2) into a 10 mL syringe, then install the syringe on an electrostatic sprayer, set the flow rate to 0.3 mm / min, the working voltage to 20 kV, the inner diameter of the needle to 1.6 mm, and the receiving distance to 15 cm, and perform electrostatic spraying. Collect the dried white powder on the collection plate, which is the polycaprolactone microspheres.

[0051] Example 2

[0052] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the working voltage of the electrostatic sprayer is set to 15 kV, and other substances, dosages, and steps are the same as those in Example 1.

[0053] Example 3

[0054] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the inner diameter of the needle of the syringe is 0.69 mm, and other substances, dosages, and steps are the same as those in Example 1.

[0055] Example 4

[0056] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the flow rate of the electrostatic sprayer is 0.2 mm / min, and other substances, dosages, and steps are the same as those in Example 1.

[0057] Example 5

[0058] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the flow rate of the electrostatic sprayer is 0.4 mm / min, and other substances, dosages, and steps are the same as those in Example 1.

[0059] Example 6

[0060] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the volume ratio of mixed solvent A to water is 1:0.15, and other substances, dosages, and steps are the same as those in Example 1.

[0061] Example 7

[0062] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the volume ratio of mixed solvent A to water is 1:0.3, and other substances, dosages, and steps are the same as those in Example 1.

[0063] Example 8

[0064] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the volume ratio of mixed solvent A to water is 1:0.05, and other substances, dosages and steps are the same as those in Example 1.

[0065] Example 9

[0066] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the volume ratio of mixed solvent A to water is 1:0.4, and other substances, dosages and steps are the same as those in Example 1.

[0067] Example 10

[0068] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the dosage of polycaprolactone is 0.5 g, and other substances, dosages and steps are the same as those in Example 1.

[0069] Example 11

[0070] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the dosage of polycaprolactone is 0.1 g, and other substances, dosages and steps are the same as those in Example 1.

[0071] Example 12

[0072] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the dosage of sodium dodecyl sulfate is 0.1 g, and other substances, dosages and steps are the same as those in Example 1.

[0073] Example 13

[0074] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that the dosage of sodium dodecyl sulfate is 0.05 g, and other substances, dosages and steps are the same as those in Example 1.

[0075] Comparative Example 1

[0076] A method for preparing polycaprolactone microspheres specifically includes the following steps:

[0077] (1) Use an electronic balance to accurately measure acetic acid and formic acid with a volume ratio of 2:1 to prepare mixed solvent A;

[0078] (2) Use an electronic balance to accurately weigh 0.3 g of polycaprolactone and 0.2 g of sodium dodecyl sulfate and dissolve them in 10 mL of the mixed solvent A obtained in step (1) to obtain a mixed solution;

[0079] (3) Load the mixture obtained in step (2) into a 10 mL syringe, then install the syringe on an electrostatic sprayer. Set the flow rate to 0.3 mm / min, the working voltage to 20 kV, the inner diameter of the needle to 1.6 mm, and the receiving distance to 15 cm. Conduct electrostatic spraying, and collect the dry white powder on the collection plate, which is the polycaprolactone microspheres.

[0080] Comparative Example 2

[0081] A method for preparing polycaprolactone microspheres specifically includes the following steps:

[0082] (1) Accurately measure acetic acid and water with a volume ratio of 1:0.2 to prepare a mixed solvent A;

[0083] (2) Use an electronic balance to accurately weigh 0.3 g of polycaprolactone and 0.2 g of sodium dodecyl sulfate and dissolve them in 10 mL of the mixed solvent A obtained in step (1) to obtain a mixture;

[0084] (3) Load the mixture obtained in step (2) into a 10 mL syringe, then install the syringe on an electrostatic sprayer. Set the flow rate to 0.3 mm / min, the working voltage to 20 kV, the inner diameter of the needle to 1.6 mm, and the receiving distance to 15 cm. Conduct electrostatic spraying, and collect the dry white powder on the collection plate, which is the polycaprolactone microspheres.

[0085] Comparative Example 3

[0086] A method for preparing polycaprolactone microspheres specifically includes the following steps:

[0087] (1) Accurately measure formic acid and water with a volume ratio of 1:0.2 to prepare a mixed solvent A;

[0088] (2) Use an electronic balance to accurately weigh 0.3 g of polycaprolactone and 0.2 g of sodium dodecyl sulfate and dissolve them in 10 mL of the mixed solvent A obtained in step (1) to obtain a mixture;

[0089] (3) Load the mixture obtained in step (2) into a 10 mL syringe, then install the syringe on an electrostatic sprayer. Set the flow rate to 0.3 mm / min, the working voltage to 20 kV, the inner diameter of the needle to 1.6 mm, and the receiving distance to 15 cm. Conduct electrostatic spraying, and collect the dry white powder on the collection plate, which is the polycaprolactone microspheres.

[0090] Comparative Example 4

[0091] A method for preparing polycaprolactone microspheres, which is different from Example 1 in that sodium dodecyl sulfate is not added, and other substances, dosages, and steps are the same as those in Example 1.

[0092] Comparative Example 5

[0093] A method for preparing polycaprolactone microspheres, the specific method being: weighing 1 g of polycaprolactone, dissolving it in 10 mL of dichloromethane solvent, adding 1 mL of purified water containing 2% PVA1788 and vortexing for 5 min, then adding 100 mL of purified water containing 0.2% PVA1788 and mixing at a shear speed of 14000 rpm for 3 min, continuing to stir at a speed of 1500 rpm for 3 h, after stirring is completed, centrifuging at 15000 rpm for 10 min, discarding the supernatant, adding purified water to wash the microspheres and centrifuging at 15000 rpm for 10 min, washing three times repeatedly and then freeze-drying to obtain the polycaprolactone microspheres.

[0094] Performance testing:

[0095] (1) Physical observation: Observe the appearance of the dry white powder collected on the collection plate in the preparation method provided in Example 3, and obtain the physical diagram of the polycaprolactone microspheres provided in Example 3 as Figure 1 shown;

[0096] From Figure 1 it can be seen that: The polycaprolactone microspheres prepared by the preparation method provided in Example 3 are white oval solids and can be gently scraped off with a spatula.

[0097] (2) Electron microscopy morphology: Use a scanning electron microscope to observe the morphology of the polycaprolactone microspheres prepared by the preparation methods provided in Example 3 and Comparative Example 5, and obtain the scanning electron microscope diagram of the polycaprolactone microspheres provided in Example 3 as Figure 2 shown, and obtain the scanning electron microscope diagram of the polycaprolactone microspheres provided in Comparative Example 5 as Figure 3 shown;

[0098] From Figure 2 and Figure 3 it can be seen that: The polycaprolactone microspheres prepared by the preparation method provided in Example 3 are all regular spherical particles, in the shape of microspheres, evenly distributed, with a smaller particle size, about 10 - 15 μm; while the particle size of the polycaprolactone microspheres prepared by the preparation method provided in Comparative Example 2 is uneven, with a particle size in the range of 10 - 50 μm and a wider particle size distribution.

[0099] (3) In addition, use a scanning electron microscope to detect the shape, distribution, particle size and sphericity of the polycaprolactone microspheres provided in other examples and comparative examples. Among them, if the sphericity ≥ 0.98, it is excellent; if the sphericity ≥ 0.95, it is good; if the sphericity ≥ 0.8, it is qualified; if the sphericity < 0.8, it is unqualified and the results are tabulated in Table 1;

[0100] Table 1

[0101]

[0102]

[0103] It can be seen from the data in Table 1 that:

[0104] By selecting formic acid, acetic acid and water in combination as solvents, adding surfactants, and controlling parameters such as flow rate, needle size, voltage, etc. in the process, the present invention can obtain polycaprolactone microspheres with better sphericity and narrower particle size distribution.

[0105] The applicant declares that the present invention illustrates a polycaprolactone microsphere and its preparation method and application through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement to the present invention, equivalent substitution of each raw material of the product of the present invention, addition of auxiliary components, selection of specific methods, etc. all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing polycaprolactone microspheres based on electrostatic spraying, characterized in that: The preparation method comprises: mixing polycaprolactone, a compound solvent and a surfactant, and obtaining the polycaprolactone microspheres by electrostatic spraying; The composite solvent comprises formic acid, acetic acid and water; the volume ratio of formic acid to acetic acid is 1:(1-3); The volume ratio of acid to water in the composite solvent is 1:(0.1-0.3); The surfactant includes any one or a combination of at least two of potassium monododecyl phosphate, sodium laurate, sodium dodecyl sulfate, dodecylamine or sodium dodecylbenzene sulfonate; The concentration of polycaprolactone in the mixed solution obtained by mixing is 0.01-0.05 g / mL; The concentration of the surfactant in the mixed solution obtained by mixing is 0.01-0.03 g / mL; The particle size distribution of the polycaprolactone microspheres prepared by the preparation method is 10-40 μm.

2. The preparation method according to claim 1, characterized in that: The weight average molecular weight of the polycaprolactone is 5000-100000.

3. The preparation method according to claim 1, characterized in that: The electrostatic spraying is carried out in an electrostatic sprayer.

4. The preparation method according to claim 3, characterized in that: The working voltage of the electrostatic sprayer is 15-20 kV.

5. The preparation method according to claim 3, characterized in that: The receiving distance of the electrostatic sprayer is 10-20 cm.

6. The preparation method according to claim 3, characterized in that: The inner diameter of the needle of the syringe in the electrostatic sprayer is 0.69-1.6 mm.

7. The preparation method according to claim 3, characterized in that: The flow rate of the electrostatic sprayer is 0.2-0.4 mm / min.

8. The preparation method according to claim 1, characterized in that: The preparation method specifically comprises the following steps: (1) mixing polycaprolactone in a composite solvent including formic acid, acetic acid and water, and then adding a surfactant to mix to obtain a mixed solution; (2) Add the mixed solution obtained in step (1) into a syringe, load it into an electrostatic sprayer, and perform electrostatic spraying, wherein the spray needle is selected to be 14-19 G, the working voltage is 15-20 kV, the inner diameter of the needle is 0.69-1.6 mm, the flow rate is 0.2-0.4 mm / min, and the receiving distance is 10-20 cm to obtain the polycaprolactone microspheres.

9. A polycaprolactone microsphere prepared by electrostatic spraying, characterized in that: The polycaprolactone microspheres are prepared by the preparation method according to any one of claims 1 to 8; The particle size distribution of the polycaprolactone microspheres is 10-40 μm.

10. The polycaprolactone microspheres according to claim 9, characterized in that: The particle size distribution of the polycaprolactone microspheres is 10-25 μm.

11. Use of the polycaprolactone microspheres prepared by electrostatic spraying as claimed in claim 9 or 10 in preparing an injectable filler.

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