Preparation method of poly (p-dioxanone) polymer and other high polymer material blank microspheres

Abstract

The invention discloses a poly (p-dioxanone) polymer and other polymer material blank microspheres, and belongs to the technical field of biological medicines. The process is as follows: polydioxanone is dissolved in hexafluoroisopropanol, and the proportion of polydioxanone to hexafluoroisopropanol is 1%-10%; the polyvinyl alcohol is dissolved in water, the proportion of the polyvinyl alcohol to the water is 1%-10%, and the proportion of the polydioxanone solution to the polyvinyl alcohol solution is 0.1%-10%; dispersing the two solutions at the rotating speed of 5000 to 15000 for 0.5 to 5 minutes; stirring the suspension until the organic solvent is completely volatilized, standing and layering the suspension, and decanting supernate; adding water to wash the precipitate, carrying out centrifugal filtration, repeating for three times, removing the supernatant, and then carrying out vacuum drying; the prepared biodegradable material has the particle size of 10-100 microns, is used for human body injection filling, is simple to operate, good in repeatability, low in cost, high in safety in the preparation process, easy to industrialize, good in hydrolyzability, excellent in biocompatibility and bioabsorbable, and is used for human body injection filling.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to a method for preparing blank microspheres of polydioxanone polymer and other polymer materials. Background Art

[0002] With the continuous development of science and technology, people's requirements for pharmaceutical preparations are gradually increasing. Microspheres, as a new type of controlled-release and sustained-release drug delivery system (DDS), are gaining more and more attention and are widely used. After being microspheroidized and microencapsulated, drugs can be prevented from oxidation and decomposition in the air, reducing stimulation to human organs. Through sustained release, drug dosage can be reduced and drug efficacy can be prolonged.

[0003] After searching, the Chinese patent "A core-shell double-layer microsphere with polydioxanone as the core and its preparation method and application" has a patent number of CN106727422A. The patent discloses a preparation method. The double-layer microspheres prepared by this method have a large particle size. This method uses negative pressure distillation treatment, which is complicated to operate and not easy to industrialize.

[0004] After searching, the Chinese patent "A polydioxanone polymer microsphere and its preparation method and application" has a patent number of CN116589710A. This method uses all flammable and explosive organic solvents, which can easily cause safety hazards.

[0005] Therefore, it is urgent to invent a method for preparing blank microspheres of polydioxanone polymers and other polymer materials to solve the above problems. Summary of the invention

[0006] The present invention mainly solves the technical problems existing in the above-mentioned prior art and provides a method for preparing blank microspheres of polydioxanone polymer and other polymer materials.

[0007] The above technical problem of the present invention is mainly solved by the following technical solution: A method for preparing blank microspheres of polydioxanone polymer and other polymer materials, comprising the following process steps:

[0008] Step A, oil phase: dissolving polydioxanone in hexafluoroisopropanol, wherein the ratio of polydioxanone to hexafluoroisopropanol is 1%-10%;

[0009] Step B, aqueous phase: dissolving polyvinyl alcohol in water, wherein the ratio of polyvinyl alcohol to water is 1%-10%, and the ratio of polydioxanone solution to polyvinyl alcohol solution is 0.1%-10%;

[0010] Step C, dispersion: disperse the above two solutions at a rotation speed of 5000-15000 for 0.5-5 minutes;

[0011] Step D, volatilization: stirring the suspension until the organic solvent is completely volatilized, allowing the suspension to stand for stratification, and decanting the supernatant;

[0012] Step E, washing: adding water to wash the precipitate, centrifuging and filtering, repeating three times, removing the supernatant, and then drying by vacuum drying;

[0013] The intrinsic viscosity of the polydioxanone in step A is 0.5-3 dl / g;

[0014] The number average molecular weight of the polyvinyl alcohol in step B is between 50,000 Daltons and 200,000 Daltons.

[0015] Preferably, the alternatives to polydioxanone in step A are: polylactic acid, poly-L-lactic acid, poly-D-lactic acid, polycaprolactone or polyglycolic acid.

[0016] Preferably, the substitutes for hexafluoroisopropanol in step A are: acetone, acetonitrile, acetic acid, dioxane, tetrahydrofuran or pentane.

[0017] Preferably, the alternatives to polyvinyl alcohol in step B are: poloxamer, polyoxyethylene sorbitan and their salts.

[0018] Preferably, in step C, the two solutions are dispersed at a rotation speed of 10,000 rpm for five minutes.

[0019] Preferably, in step D, the suspension is stirred at 400 rpm for five days, and the suspension is allowed to stand for one day, and the supernatant is decanted.

[0020] Preferably, the amount of water used in step E is 100 ml, stirring is performed at a speed of 400 rpm for one hour, and the suspension is allowed to stand for one day.

[0021] Preferably, in step E, the polyvinyl alcohol is removed and then filtered, and the product is vacuum dried for two days.

[0022] The polydioxanone polymer microspheres are prepared by the preparation method of the polydioxanone polymer microspheres.

[0023] The present invention has the beneficial effects:

[0024] The invention prepares blank microspheres of polydioxanone polymer and other macromolecular materials with a particle size of 10-100 μm, which are used for human body injection filling.

[0025] The technical advantages of the present invention are simple operation, good repeatability, low cost, less use of organic solvents, high safety in the preparation process, and easy industrialization.

[0026] The product advantages of the present invention are: good hydrolysis, excellent biocompatibility, and bioabsorbable and biodegradable material. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a scanning electron microscope image of the product of the present invention. DETAILED DESCRIPTION

[0028] The following are examples and the attached Figure 1 , the technical solution of the present invention is further specifically described.

[0029] Example 1: A method for preparing blank microspheres of polydioxanone polymer and other polymer materials, comprising the following process steps:

[0030] Step A, oil phase: dissolving polydioxanone in hexafluoroisopropanol, wherein the ratio of polydioxanone to hexafluoroisopropanol is 1%-10%;

[0031] Step B, aqueous phase: dissolving polyvinyl alcohol in water, the ratio of polyvinyl alcohol to water being 1%-10%, and the ratio of polydioxanone solution to polyvinyl alcohol solution being 0.1%-10%;

[0032] Step C, dispersion: disperse the above two solutions at a rotation speed of 5000-15000 for 0.5-5 minutes;

[0033] Step D, volatilization: stirring the suspension until the organic solvent is completely volatilized, allowing the suspension to stand for stratification, and decanting the supernatant;

[0034] Step E, washing: adding water to wash the precipitate, centrifuging and filtering, repeating three times, removing the supernatant, and then drying by vacuum drying;

[0035] The intrinsic viscosity of the polydioxanone in step A is 0.5-3 dl / g;

[0036] The number average molecular weight of the polyvinyl alcohol in step B is between 50,000 Daltons and 200,000 Daltons.

[0037] The specific implementation method is:

[0038] Step A, adding polydioxanone to hexafluoroisopropanol at a mass volume ratio (g / ml) of 3.3:100 until the polydioxanone is completely dissolved;

[0039] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 3.3:100 until the polyvinyl alcohol is completely dissolved;

[0040] Step C, dispersing the solutions of step A and step B uniformly;

[0041] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0042] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0043] The particle size D50 obtained in this embodiment is 30um

[0044] like Figure 1 The following is a scanning electron microscope image of this product.

[0045] Embodiment 2:

[0046] Based on Example 1, this example further defines that the alternatives to polydioxanone in step A are: polylactic acid;

[0047] Step A, adding polylactic acid to hexafluoroisopropanol at a mass volume ratio (g / ml) of 2:100 until polydioxanone is completely dissolved;

[0048] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 5:100 until the polyvinyl alcohol is completely dissolved;

[0049] Step C, dispersing the solutions of step A and step B uniformly;

[0050] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0051] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0052] The obtained particle size D50 is 25 um.

[0053] Embodiment 3:

[0054] This embodiment further defines the embodiment in which polydioxanone is replaced with poly-L-lactic acid in step A on the basis of embodiment 1 as follows:

[0055] Step A, adding poly-L-lactic acid to hexafluoroisopropanol at a mass volume ratio (g / ml) of 2:100 until polydioxanone is completely dissolved;

[0056] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 5:100 until the polyvinyl alcohol is completely dissolved;

[0057] Step C, dispersing the solutions of step A and step B uniformly;

[0058] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0059] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0060] The obtained particle size D50 is 22 um.

[0061] Embodiment 4:

[0062] This embodiment further defines the embodiment in which polydioxanone is replaced by poly (d-lactic acid) in step A on the basis of embodiment 1 as follows:

[0063] Step A, adding poly (d-lactic acid) to hexafluoroisopropanol at a mass volume ratio (g / ml) of 2:100 until poly (p-dioxanone) is completely dissolved;

[0064] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 5:100 until the polyvinyl alcohol is completely dissolved;

[0065] Step C, dispersing the solutions of step A and step B uniformly;

[0066] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0067] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0068] The obtained particle size D50 is 25 um.

[0069] Embodiment 5:

[0070] This embodiment further defines the embodiment in which polydioxanone is replaced by polycaprolactone in step A on the basis of embodiment 1 as follows:

[0071] Step A, adding polycaprolactone to hexafluoroisopropanol at a mass volume ratio (g / ml) of 2:100 until polydioxanone is completely dissolved;

[0072] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 5:100 until the polyvinyl alcohol is completely dissolved;

[0073] Step C, dispersing the solutions of step A and step B uniformly;

[0074] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0075] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0076] The obtained particle size D50 is 30 um.

[0077] Embodiment 6:

[0078] This embodiment further defines the example in which polydioxanone replaces polyglycolic acid in step A on the basis of embodiment 1 as follows:

[0079] Step A, adding polyglycolic acid to hexafluoroisopropanol at a mass volume ratio (g / ml) of 2:100 until polydioxanone is completely dissolved;

[0080] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 5:100 until the polyvinyl alcohol is completely dissolved;

[0081] Step C, dispersing the solutions of step A and step B uniformly;

[0082] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0083] Step E, washing the precipitate obtained in step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate; the obtained particle size D50 is 25 um.

[0084] Embodiment 7:

[0085] This embodiment further defines the embodiment in which hexafluoroisopropanol is replaced by acetone in step A on the basis of embodiment 1 as follows:

[0086] Step A, adding polydioxanone to acetone at a mass volume ratio (g / ml) of 1:100 until the polydioxanone is completely dissolved;

[0087] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 1:100 until the polyvinyl alcohol is completely dissolved;

[0088] Step C, dispersing the solutions of step A and step B uniformly;

[0089] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0090] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0091] The obtained particle size D50 is 50 um.

[0092] Embodiment 8:

[0093] This embodiment further defines the embodiment in which hexafluoroisopropanol in step A is replaced by acetonitrile on the basis of embodiment 1 as follows:

[0094] Step A, adding polydioxanone to acetonitrile at a mass volume ratio (g / ml) of 1:100 until the polydioxanone is completely dissolved;

[0095] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 1:100 until the polyvinyl alcohol is completely dissolved;

[0096] Step C, dispersing the solutions of step A and step B uniformly;

[0097] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0098] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0099] The obtained particle size D50 is 80 um.

[0100] Embodiment 9:

[0101] This embodiment further defines the embodiment in which hexafluoroisopropanol replaces acetic acid in step A on the basis of embodiment 1 as follows:

[0102] Step A, adding polydioxanone to acetic acid at a mass volume ratio (g / ml) of 1:100 until the polydioxanone is completely dissolved;

[0103] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 1:100 until the polyvinyl alcohol is completely dissolved;

[0104] Step C, dispersing the solutions of step A and step B uniformly;

[0105] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0106] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0107] The obtained particle size D50 is 62 um.

[0108] Embodiment 10:

[0109] This embodiment further defines the example in which hexafluoroisopropanol replaces dioxane in step A on the basis of embodiment 1 as follows:

[0110] Step A, adding polydioxanone to dioxane at a mass volume ratio (g / ml) of 1:100 until the polydioxanone is completely dissolved;

[0111] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 1:100 until the polyvinyl alcohol is completely dissolved;

[0112] Step C, dispersing the solutions of step A and step B uniformly;

[0113] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0114] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0115] The obtained particle size D50 is 55 um.

[0116] Embodiment 11:

[0117] This embodiment further defines the example in which hexafluoroisopropanol replaces tetrahydrofuran in step A on the basis of embodiment 1 as follows:

[0118] Step A, adding polydioxanone to tetrahydrofuran at a mass volume ratio (g / ml) of 1:100 until the polydioxanone is completely dissolved;

[0119] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 1:100 until the polyvinyl alcohol is completely dissolved;

[0120] Step C, dispersing the solutions of step A and step B uniformly;

[0121] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0122] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0123] The obtained particle size D50 is 82 um.

[0124] Embodiment 12:

[0125] This embodiment further defines the example in which hexafluoroisopropanol replaces pentane in step A on the basis of embodiment 1 as follows:

[0126] Step A, adding polydioxanone to pentane at a mass volume ratio (g / ml) of 1:100 until the polydioxanone is completely dissolved;

[0127] Step B, adding polyvinyl alcohol to water at a mass volume ratio (g / ml) of 1:100 until the polyvinyl alcohol is completely dissolved;

[0128] Step C, dispersing the solutions of step A and step B uniformly;

[0129] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0130] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0131] The obtained particle size D50 is 66 um.

[0132] Embodiment 13:

[0133] This embodiment further defines the embodiment in which polyvinyl alcohol replaces polyoxyethylene sorbitan in step B on the basis of embodiment 1 as follows:

[0134] Step A, adding polydioxanone to hexafluoroisopropanol at a mass volume ratio (g / ml) of 6:100 until the polydioxanone is completely dissolved;

[0135] Step B, adding polyoxyethylene sorbitan to water at a mass volume ratio (g / ml) of 3:100 until the polyoxyethylene sorbitan is completely dissolved;

[0136] Step C, dispersing the solutions of step A and step B uniformly;

[0137] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0138] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0139] The obtained particle size D50 is 50 um.

[0140] Embodiment 14:

[0141] This embodiment further defines the embodiment in which polyvinyl alcohol replaces poloxamer in step B on the basis of embodiment 1 as follows:

[0142] Step A, adding polydioxanone to hexafluoroisopropanol at a mass volume ratio (g / ml) of 6:100 until the polydioxanone is completely dissolved;

[0143] Step B, adding poloxamer to water at a mass volume ratio (g / ml) of 3:100 until the poloxamer is completely dissolved;

[0144] Step C, dispersing the solutions of step A and step B uniformly;

[0145] Step D, stirring the suspension at 400 r / min for 3 hours, letting it stand and discarding the supernatant;

[0146] Step E, washing the precipitate from step D with water, discarding the supernatant after standing, and then freeze-drying the precipitate;

[0147] The obtained particle size D50 is 58 um.

[0148] Embodiment 15:

[0149] Based on Example 1, this example further defines that in step C, the two solutions are dispersed at a rotation speed of 10,000 rpm for five minutes.

[0150] The other parts of this embodiment are the same as those of the above-mentioned embodiment 1 and will not be described in detail.

[0151] Embodiment 16:

[0152] This embodiment further defines, on the basis of embodiment 1, that in step D, the suspension is stirred at a rotation speed of 400 rpm for five days, and the suspension is allowed to stand for one day, and the supernatant is decanted.

[0153] The other parts of this embodiment are the same as those of the above-mentioned embodiment 1 and will not be described in detail.

[0154] Embodiment 17:

[0155] Based on Example 1, this example further limits the amount of water used in step E to 100 ml, stirs at a speed of 400 rpm for one hour, and leaves the suspension to stand for one day.

[0156] The other parts of this embodiment are the same as those of the above-mentioned embodiment 1 and will not be described in detail.

[0157] Embodiment 18:

[0158] This embodiment further defines the step E based on the embodiment 1, wherein the polyvinyl alcohol is removed and then filtered, and the product is vacuum dried for two days.

[0159] The other parts of this embodiment are the same as those of the above-mentioned embodiment 1 and will not be described in detail.

[0160] The invention prepares blank microspheres of polydioxanone polymer and other macromolecular materials with a particle size of 10-100 μm, which are used for human body injection filling.

[0161] The technical advantages of the present invention are simple operation, good repeatability, low cost, less use of organic solvents, high safety in the preparation process, and easy industrialization.

[0162] The product advantages of the present invention are: good hydrolysis, excellent biocompatibility, and bioabsorbable and biodegradable material.

[0163] Finally, it should be pointed out that the above embodiments are only representative examples of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. Any simple modification, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention should be considered to belong to the protection scope of the present invention.

Claims

1. A method for preparing blank microspheres of polydioxanone polymer and other polymer materials, characterized in that The process steps include: Step A, oil phase: dissolving polydioxanone in hexafluoroisopropanol, wherein the ratio of polydioxanone to hexafluoroisopropanol is 1%-10%; Step B, aqueous phase: dissolving polyvinyl alcohol in water, wherein the ratio of polyvinyl alcohol to water is 1%-10%, and the ratio of polydioxanone solution to polyvinyl alcohol solution is 0.1%-10%; Step C, dispersion: disperse the above two solutions at a rotation speed of 5000-15000 for 0.5-5 minutes; Step D, volatilization: stirring the suspension until the organic solvent is completely volatilized, allowing the suspension to stand for stratification, and decanting the supernatant; Step E, washing: adding water to wash the precipitate, centrifuging and filtering, repeating three times, removing the supernatant, and then drying by vacuum drying; The intrinsic viscosity of the polydioxanone in step A is 0.5-3 dl / g; The number average molecular weight of the polyvinyl alcohol in step B is between 50,000 Daltons and 200,000 Daltons.

2. The method for preparing polydioxanone polymer microspheres according to claim 1, characterized in that The alternatives to polydioxanone in step A are: polylactic acid, poly-L-lactic acid, poly-D-lactic acid, polycaprolactone or polyglycolic acid.

3. The method for preparing blank microspheres of polydioxanone polymer and other polymer materials according to claim 1, characterized in that The alternatives to hexafluoroisopropanol in step A are: acetone, acetonitrile, acetic acid, dioxane, tetrahydrofuran or pentane.

4. The method for preparing blank microspheres of polydioxanone polymer and other polymer materials according to claim 1, characterized in that The alternatives to polyvinyl alcohol in step B are: poloxamer, polyoxyethylene sorbitan and their salt compounds.

5. The method for preparing blank microspheres of polydioxanone polymer and other polymer materials according to claim 1, characterized in that In step C, the two solutions are dispersed at a rotation speed of 10,000 rpm for 5 minutes.

6. The method for preparing blank microspheres of polydioxanone polymer and other polymer materials according to claim 1, characterized in that In step D, the suspension is stirred at a speed of 400 rpm for five days, and the suspension is allowed to stand for one day, and the supernatant is decanted.

7. The method for preparing blank microspheres of polydioxanone polymer and other polymer materials according to claim 1, characterized in that In the step E, the amount of water used is 100 ml, the mixture is stirred at a speed of 400 rpm for one hour, and the suspension is left to stand for one day.

8. The method for preparing blank microspheres of polydioxanone polymer and other polymer materials according to claim 1, characterized in that In the step E, the polyvinyl alcohol is removed and then filtered, and the product is vacuum dried for two days.

9. Blank microspheres of polydioxanone polymer and other polymer materials prepared by the method according to any one of claims 1 to 8.

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