Polycaprolactone microspheres prepared based on electrostatic spraying method as well as preparation method and application of polycaprolactone microspheres

Abstract

The invention provides polycaprolactone microspheres prepared on the basis of an electrostatic spraying method and a preparation method and application thereof.The preparation method comprises the steps that polycaprolactone, a compound solvent and a surfactant are mixed and subjected to electrostatic spraying, the polycaprolactone microspheres are obtained, and the compound solvent comprises formic acid, acetic acid and water; the preparation method is simple to operate, and formic acid, acetic acid and water are matched to serve as a compound solvent, so that the prepared polycaprolactone microspheres have the characteristics of narrow particle size distribution, good microsphere shape, high roundness and the like; the problems of wide particle size distribution, poor microsphere form and the like of the polycaprolactone microspheres prepared by a traditional method such as an emulsified solvent evaporation method are solved; meanwhile, the polycaprolactone microspheres with controllable particle sizes and forms can be prepared by adjusting the technological parameters of the electrostatic spraying process, such as voltage, the inner diameter of a needle head and the flow velocity of a solution.

Description

Technical Field

[0001] The invention belongs to the technical field of microspheres, and particularly relates to polycaprolactone microspheres prepared based on an electrostatic spraying method, and a preparation method and application thereof. Background Art

[0002] Microspheres are tiny spherical entities that are dispersed and embedded in a polymer matrix through microencapsulation technology. Through drug-loaded microsphere intervention, a variety of chemotherapy drugs can be loaded to achieve a combined effect of embolization and local high-concentration chemotherapy. Commonly used synthetic materials are mainly polyester materials, including polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA) and polycaprolactone (PCL).

[0003] PCL is a biodegradable synthetic polymer material formed by ring-opening polymerization of ε-caprolactone under the catalysis of 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. The degradation products can be absorbed or excreted by the body. Its good biocompatibility makes it widely used in drug controlled release. It is also an ideal material for tissue engineering because of its cell compatibility with some tissues of the human body. However, PCL itself has limitations such as long degradation cycle and poor hydrophilicity.

[0004] The conventional preparation method of PCL microspheres is the emulsification method, which is to dissolve PCL in an organic solvent, then add it dropwise to the aqueous phase, form microspheres by high-speed shear stirring, wash with water, centrifuge and dry. For example, CN113769164A discloses a polycaprolactone microsphere and its preparation method and use, the preparation method of the polycaprolactone microspheres comprising: contacting a hydroxypropylmethylcellulose aqueous solution and a dichloromethane solution of polycaprolactone and simultaneously shearing and emulsifying to form a shear emulsified mixed solution; contacting and mixing a polyvinyl alcohol aqueous solution with the shear emulsified mixed solution and heating until the dichloromethane is completely volatilized; filtering to obtain microspheres of 28 to 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, it is urgent to develop a preparation method for preparing polycaprolactone microspheres with uniform particle size distribution, good morphology and high roundness. Summary of the invention

[0006] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a polycaprolactone microsphere prepared by electrostatic spraying, and a preparation method and application thereof. The preparation method is simple to operate, and the prepared polycaprolactone microspheres have the advantages of narrow particle size distribution, good microsphere morphology and high roundness. They can be mixed in a gel for preparing an injectable filler, and have broad application prospects.

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

[0008] In a first aspect, the present invention provides a method for preparing polycaprolactone microspheres based on an electrostatic spray method, the preparation method comprising: mixing polycaprolactone, a compound solvent and a surfactant, and obtaining the polycaprolactone microspheres by electrostatic spraying;

[0009] The compound solvent comprises formic acid, acetic acid and water.

[0010] Electrospray Technology refers to the process of using electrohydrodynamic technology to make polymer carrier solution into micron, nanoparticles or fibers. It has the advantages of simple operation, full shape, smooth appearance and uniform particle size of the prepared products.

[0011] Based on the above content, the preparation method of polycaprolactone microspheres provided by the present invention uses a mixed solution of polycaprolactone and a surfactant as a raw material, uses formic acid, acetic acid and water as a compound solvent, and utilizes an electrostatic spray method. By adjusting the process parameters of the electrostatic spray, such as voltage, needle inner diameter, solution flow rate, etc., white dry powder polycaprolactone microspheres are directly prepared in a one-step method, eliminating the cumbersome process steps of mixing, shearing, curing, washing, etc. required by the conventional emulsified solvent volatilization method. It is observed that the polycaprolactone microspheres prepared by the preparation method provided by the present invention have the characteristics of narrow particle size distribution, good microsphere morphology and high roundness, and solves the problems of wide particle size distribution and poor microsphere morphology of the polycaprolactone microspheres prepared by the traditional method such as the emulsified solvent volatilization method.

[0012] Specifically, formic acid, acetic acid and water are used as a composite solvent, especially adding water to the acid can change the solubility state of polycaprolactone. Theoretically, the introduction of a small amount of water will reduce the solubility 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 utilizing the wetting and emulsification effects of surfactants, polycaprolactone within a certain concentration range can not only achieve a better solubility state in the system, but also the addition of water changes the dielectric constant of the solvent system, which is more conducive to subsequent electrostatic spraying, so that the electrostatic spray can better utilize the electric potential to volatilize the solvent due to the change in the dielectric constant of the new solvent system, 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, for example, 5000, 6000, 7000, 8000, 9000, 10000, 20000, 40000, 60000, 80000 or 100000.

[0014] Preferably, the volume ratio of acid to water in the composite solvent is 1:(0.1-0.3), for example, 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), for example, 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 monododecyl phosphate, sodium laurate, sodium dodecyl sulfate, dodecylamine or sodium dodecylbenzene sulfonate.

[0017] Preferably, the concentration of polycaprolactone in the mixed solution obtained by mixing is 0.01-0.05 g / mL, for example, 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.

[0018] Preferably, the concentration of the surfactant in the mixed solution obtained by mixing is 0.01-0.03 g / mL, for example, 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 sprayer.

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

[0021] Preferably, the receiving distance of the electrostatic sprayer is 10 to 20 cm, for example, 10 cm, 12 cm, 14 cm, 16 cm, 18 cm or 20 cm.

[0022] Preferably, the inner diameter of the needle of the syringe in the electrostatic sprayer is 0.69 to 1.6 mm, for example, 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.

[0023] Preferably, the flow rate of the electrostatic sprayer is 0.2-0.4 mm / min, for example, 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.

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

[0025] (1) mixing polycaprolactone in a composite solvent including formic acid, acetic acid and water, and then adding a surfactant and mixing them to obtain a mixed solution;

[0026] (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 14-19G, the working voltage is 15-20kV, the inner diameter of the needle is 0.69-1.6mm, the flow rate is 0.2-0.4mm / min, and the receiving distance is 10-20cm to obtain the polycaprolactone microspheres.

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

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

[0029] In a third aspect, the present invention provides a use of the polycaprolactone microspheres prepared by the electrostatic spraying method as described in the second aspect in the preparation of an injectable filler.

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

[0031] (1) The preparation method of polycaprolactone based on electrostatic spraying provided by the present invention comprises the steps of mixing polycaprolactone, a solvent and a surfactant, and obtaining the polycaprolactone microspheres by electrostatic spraying. The preparation method is simple to operate, and by selecting formic acid, acetic acid and water as solvents, the prepared caprolactone microspheres have the characteristics of narrow particle size distribution, good microsphere morphology and high roundness, thereby solving the problems of wide particle size distribution and poor microsphere morphology of polycaprolactone microspheres prepared by traditional methods such as emulsified solvent volatilization method;

[0032] (2) The preparation method of polycaprolactone provided by the present invention uses an electrostatic spraying method to spray a mixed solution of a surfactant and polycaprolactone. By adjusting the process parameters of the electrostatic spraying, such as voltage, needle inner diameter, solution flow rate, etc., polycaprolactone microspheres with controllable particle size and morphology can be prepared. BRIEF 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) using an electronic balance to accurately weigh 0.3 g of polycaprolactone and 0.2 g of sodium dodecyl sulfate, dissolving them in 10 mL of the mixed solvent B obtained in step (1), and stirring them evenly in a magnetic stirrer to obtain a mixed solution;

[0050] (3) The mixed solution obtained in step (2) is loaded into a 10 mL syringe, and the syringe is then installed on an electrostatic sprayer, and the flow rate is set to 0.3 mm / min, the working voltage is 20 kV, the inner diameter of the needle is 1.6 mm, and the receiving distance is 15 cm. Electrostatic spraying is performed and a dry white powder is collected on a collecting plate, which is polycaprolactone microspheres.

[0051] Example 2

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

[0053] Example 3

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

[0055] Example 4

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

[0057] Example 5

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

[0059] Example 6

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

[0061] Example 7

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

[0063] Example 8

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

[0065] Example 9

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

[0067] Example 10

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

[0069] Embodiment 11

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

[0071] Example 12

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

[0073] Example 13

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

[0075] Comparative Example 1

[0076] A method for preparing polycaprolactone microspheres, comprising the following steps:

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

[0078] (2) using 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) The mixed solution obtained in step (2) is loaded into a 10 mL syringe, and the syringe is then installed on an electrostatic sprayer, and the flow rate is set to 0.3 mm / min, the working voltage is 20 kV, the inner diameter of the needle is 1.6 mm, and the receiving distance is 15 cm. Electrostatic spraying is performed and a dry white powder is collected on a collecting plate, which is polycaprolactone microspheres.

[0080] Comparative Example 2

[0081] A method for preparing polycaprolactone microspheres, comprising the following steps:

[0082] (1) accurately measuring acetic acid and water in a volume ratio of 1:0.2 to prepare a mixed solvent A;

[0083] (2) using 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;

[0084] (3) The mixed solution obtained in step (2) is loaded into a 10 mL syringe, and the syringe is then installed on an electrostatic sprayer, and the flow rate is set to 0.3 mm / min, the working voltage is 20 kV, the inner diameter of the needle is 1.6 mm, and the receiving distance is 15 cm. Electrostatic spraying is performed and a dry white powder is collected on a collecting plate, which is polycaprolactone microspheres.

[0085] Comparative Example 3

[0086] A method for preparing polycaprolactone microspheres, comprising the following steps:

[0087] (1) accurately measuring formic acid and water in a volume ratio of 1:0.2 to prepare a mixed solvent A;

[0088] (2) using 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;

[0089] (3) The mixed solution obtained in step (2) is loaded into a 10 mL syringe, and the syringe is then installed on an electrostatic sprayer, and the flow rate is set to 0.3 mm / min, the working voltage is 20 kV, the inner diameter of the needle is 1.6 mm, and the receiving distance is 15 cm. Electrostatic spraying is performed and a dry white powder is collected on a collecting plate, which is polycaprolactone microspheres.

[0090] Comparative Example 4

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

[0092] Comparative Example 5

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

[0094] Performance Test:

[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 image of the polycaprolactone microspheres provided in Example 3 as shown in the figure below: Figure 1 As 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 microscopic morphology: The morphology of the polycaprolactone microspheres prepared by the preparation methods provided in Example 3 and Comparative Example 5 was observed using a scanning electron microscope. The scanning electron microscopic image of the polycaprolactone microspheres provided in Example 3 was as follows: Figure 2 As shown, the scanning electron microscope image of the polycaprolactone microspheres provided in Comparative Example 5 is as shown Figure 3 As 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 small particle size of about 10 to 15 μm; while the polycaprolactone microspheres prepared by the preparation method provided in Comparative Example 2 have uneven particle sizes, with a particle size in the range of 10 to 50 μm, and a wide particle size distribution.

[0099] (3) In addition, the shape, distribution, particle size and sphericity of the polycaprolactone microspheres provided in other embodiments and comparative examples were detected by scanning electron microscopy, wherein if the sphericity is ≥0.98, it is excellent, if the sphericity is ≥0.95, it is good, if the sphericity is ≥0.8, it is qualified, and if the sphericity is <0.8, it is unqualified and the results are statistically summarized in Table 1;

[0100] Table 1

[0101]

[0102]

[0103] From the data in Table 1, we can see that:

[0104] The invention selects formic acid, acetic acid and water as solvents, adds a surfactant, and controls parameters such as flow rate, needle size, voltage, etc. in the process, so as to obtain polycaprolactone microspheres with good sphericity and narrow particle size distribution.

[0105] The applicant declares that the present invention illustrates a polycaprolactone microsphere and its preparation method and application through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials 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 compound solvent comprises formic acid, acetic acid and water.

2. The preparation method according to claim 1, characterized in that: The weight average molecular weight of the polycaprolactone is 5,000 to 100,000.

3. The preparation method according to claim 1 or 2, characterized in that: The volume ratio of acid to water in the composite solvent is 1:(0.1-0.3); Preferably, the volume ratio of formic acid to acetic acid is 1:(1-3).

4. The preparation method according to any one of claims 1 to 3, characterized in that: The surfactant includes any one of potassium monododecyl phosphate, sodium laurate, sodium dodecyl sulfate, dodecylamine or sodium dodecylbenzene sulfonate, or a combination of at least two thereof.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The concentration of polycaprolactone in the mixed solution obtained by mixing is 0.01 to 0.05 g / mL; Preferably, the concentration of the surfactant in the mixed solution obtained by mixing is 0.01 to 0.03 g / mL.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The electrostatic spraying is carried out in an electrostatic sprayer; Preferably, the working voltage of the electrostatic sprayer is 15-20 kV; Preferably, the receiving distance of the electrostatic sprayer is 10 to 20 cm; Preferably, the inner diameter of the needle of the syringe in the electrostatic sprayer is 0.69 to 1.6 mm; Preferably, the flow rate of the electrostatic sprayer is 0.2-0.4 mm / min.

7. The preparation method according to any one of claims 1 to 6, 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 14-19G, the working voltage is 15-20kV, the inner diameter of the needle is 0.69-1.6mm, the flow rate is 0.2-0.4mm / min, and the receiving distance is 10-20cm to obtain the polycaprolactone microspheres.

8. 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 7.

9. The polycaprolactone microspheres according to claim 8, characterized in that: The particle size distribution of the polycaprolactone microspheres is 10 to 40 μm, preferably 10 to 25 μm.

10. Use of polycaprolactone microspheres prepared by electrostatic spraying as described in 8 or 9 in the preparation of injectable fillers.

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