KR102072968B1 - The fabrication method of fine particle of biodegradable polymer and a biodegradable material for recovering tissues - Google Patents

Abstract

A method for producing biodegradable polymer fine particles includes: a step of freezing biodegradable polymer particles and pulverizing the same by air blow or high-speed emulsification to form pulverized particles; and a step of washing the pulverized particles to form biodegradable polymer fine particles. The biodegradable polymer particles include at least one of first biodegradable polymer particles of a single component and second biodegradable polymer particles including a block copolymer of heterogeneous components.

Description

Method for manufacturing biodegradable polymer microparticles and biodegradable material for tissue repair {THE FABRICATION METHOD OF FINE PARTICLE OF BIODEGRADABLE POLYMER AND A BIODEGRADABLE MATERIAL FOR RECOVERING TISSUES}

The present invention relates to a method for preparing biodegradable polymer microparticles and a biodegradable material for tissue repair, and more particularly, to a method for producing biodegradable polymer microparticles and easily controlling the size and shape of the biodegradable polymer microparticles. A biodegradable material for tissue repair comprising biodegradable polymeric microparticles of size and shape.

As a method for producing biodegradable polymer microparticles, various methods have been proposed. First, a method of preparing biodegradable polymer microparticles is obtained by dissolving the biodegradable polymer in a toxic solvent and simultaneously adding a surfactant to obtain fine particles through recrystallization, followed by washing and drying followed by sterilization. have.

In addition, a method for producing biodegradable polymer microparticles by melting the biodegradable polymer through a high-speed spinning process, a method of producing biodegradable polymer microparticles by freeze drying and freeze grinding or mechanical milling of the biodegradable polymer is known.

However, the conventional biodegradable polymer microparticle manufacturing method has a problem that it is difficult to control the size and shape of the biodegradable polymer microparticles.
Prior art literature is as follows.
Korean Registered Patent No. 10-0840394 (Announcement of June 3, 2008)
Korean Registered Patent No. 10-1501217 (announced on March 3, 2015)

It is an object of the present invention to provide a method for producing biodegradable polymer microparticles, which is easy to control the size and shape of the biodegradable polymer microparticles.

Another object of the present invention is to provide a biodegradable material for tissue repair comprising biodegradable polymer microparticles having a certain size and shape.

According to an embodiment of the present invention, a method for preparing biodegradable polymer microparticles may include freezing and grinding biodegradable polymer particles to form pulverized particles, and washing the pulverized particles to form biodegradable polymer microparticles. It includes. The biodegradable polymer particles include at least one of first biodegradable polymer particles of a single component and second biodegradable polymer particles including a block copolymer of heterogeneous components.

The frozen biodegradable polymer particles may be ground through air blow or high speed emulsification.

The first biodegradable polymer particles are polydioxanone, polylactic acid, polyglycolic acid, poly (D, L-lactic acid-co-glycolic acid) (poly (D, L -lactic-coglycolic acid)), or polycaprolactone. The average molecular weight of the first biodegradable polymer particles may be from 10,000 to 300,000 Da.

The second biodegradable polymer particles are PLGA (poly (lactic acid-co-glycolic acid)), PLCL (poly (lactic acid-co-ε-caprolactone)), PDLGA (poly (dl-lactic acid-co-glycolide acid) )), PLLA-PDLLA (poly (l-lactic acid-co-dl-lactic acid)), GA-TMC (poly (glycolic acid-co-trimethylene carbonate)), or PDO-PGA-TMC (poly (glycolic acid) -co-trimethylene carbonate-co-dioxanone)).

The forming of the pulverized particles may include emulsifying the biodegradable polymer particles to form an emulsion solution including biodegradable polymer intermediate particles, and freezing the emulsion solution and pulverizing by air injection to form the pulverized particles. It includes a step. In the forming of the emulsion solution, the emulsion solution may include an organic solvent, the biodegradable polymer particles may be included in the 0.5 to 1.5% by weight based on the emulsion solution.

The organic solvent may include at least one of tetrahydrofuran, hexafluoroisopropanol, ethanol, methanol, acetone, and dichloromethane.

The emulsion solution may further include polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer (polyethylene oxide-polypropylene oxide-polyethylene oxidtriblock copolymer), and polyvinyl alcohol.

The polyethylene oxa-polypropylene oxide-polyethylene oxide terpolymer is included in the 1.5 to 2.5% by weight based on the emulsion solution. The polyvinyl alcohol may be included 2.5 to 4.0% by weight based on the emulsion solution.

The forming of the pulverized particles may be to freeze the biodegradable polymer particles at -150 ° C to -20 ° C, preferably at -150 ° C to -80 ° C, and to grind at 2,000 rpm to 30,000 rpm. .

The forming of the pulverized particles may further include drying the biodegradable polymer particles under conditions of 0 ° C. to 40 ° C. and −0.2 MPa to −0.01 MPa.

The step of forming the biodegradable polymer microparticles is the first washing with sterile water having a weight of 100 to 200 times the weight of the crushed particles, having a weight of 5 to 10 times the weight of the crushed particles, 70 Second washing with ethanol having a concentration of from 80 percent to 80 percent, and drying the second washed milled particles to form biodegradable polymeric microparticles.

As the average molecular weight of the biodegradable polymer particles increases, the size of the biodegradable polymer intermediate particles may be increased.

As the average molecular weight of the biodegradable polymer particles increases, the biodegradable polymer intermediate particles may have a sphere in an amorphous form.

When the first biodegradable polymer particles are polydioxanone, as the average molecular weight of the first biodegradable polymer particles decreases, the size of the biodegradable polymer intermediate particles may increase.

When the first biodegradable polymer particles are polydioxanone, as the average molecular weight of the first biodegradable polymer particles decreases, the biodegradable polymer intermediate particles may have a spherical shape in an amorphous form.

The average particle diameter of the biodegradable polymer microparticles may be from 1 to 200 ㎛.

The biodegradable material for tissue repair according to an embodiment of the present invention includes biodegradable polymer fine particles. The biodegradable polymer microparticles may be prepared by freezing the biodegradable polymer particles, pulverizing to form pulverized particles, and washing the pulverized particles to form biodegradable polymer microparticles. It is manufactured by the method. The biodegradable polymer particles frozen here are pulverized by air blow or high speed emulsification. The biodegradable polymer particles include first biodegradable polymer particles of a single component and second biodegradable polymer particles including a block copolymer of heterogeneous components.

The biodegradable material for tissue repair may be a shaped prosthesis, bone filler, or support for tissue engineering.

According to the method for preparing biodegradable polymer microparticles according to an embodiment of the present invention, it is easy to control the size and shape of the biodegradable polymer microparticles.

According to the biodegradable material for tissue repair according to an embodiment of the present invention may include biodegradable polymer microparticles having a predetermined size and shape.

1 is a schematic flowchart of a method for preparing biodegradable polymer microparticles according to an embodiment of the present invention.
FIG. 2 is an electron micrograph of the biodegradable polymer intermediate particles formed by emulsifying polydioxanone having an average molecular weight of 300 kDa in Example 1. FIG.
3 is a graph showing the average molecular weight and the size of the biodegradable polymer microparticles in Examples 1 to 4.
4 is a photograph taken with an electron microscope of biodegradable polymer microparticles when formed using polydioxanone having an average molecular weight of 10 kDa in Example 1. FIG.
FIG. 5 is a photograph taken with an electron microscope of biodegradable polymer microparticles when formed using polydioxanone having an average molecular weight of 100 kDa in Example 1. FIG.
FIG. 6 is a photograph taken with an electron microscope of biodegradable polymer microparticles when formed using polydioxanone having an average molecular weight of 200 kDa in Example 1. FIG.
7 is a photograph taken with an electron microscope of biodegradable polymer microparticles when formed using polydioxanone having an average molecular weight of 300 kDa in Example 1. FIG.

The above objects, other objects, features and advantages of the present invention will be readily understood through the following preferred embodiments associated with the accompanying drawings. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the embodiments introduced herein are provided so that the disclosure may be made thorough and complete, and to fully convey the spirit of the invention to those skilled in the art.

In describing the drawings, similar reference numerals are used for similar elements. In the accompanying drawings, the dimensions of the structures are shown in an enlarged scale than actual for clarity of the invention. Terms such as first and second may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, the first component may be referred to as the second component, and similarly, the second component may also be referred to as the first component. Singular expressions include plural expressions unless the context clearly indicates otherwise.

In this application, the terms "comprise" or "have" are intended to indicate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, and one or more other features. It is to be understood that the present invention does not exclude the possibility of the presence or the addition of numbers, steps, operations, components, parts, or combinations thereof. In addition, when a part of a layer, film, region, plate, etc. is said to be "on" another part, this includes not only the case where the other part is "right on" but also another part in the middle. Conversely, when a part of a layer, film, region, plate, etc. is said to be "below" another part, this includes not only the other part "below" but also another part in the middle.

Hereinafter, a method for preparing biodegradable polymer microparticles and a biodegradable material for tissue repair according to an embodiment of the present invention will be described.

1 is a schematic flowchart of a method for preparing biodegradable polymer microparticles according to an embodiment of the present invention.

Referring to FIG. 1, the method for preparing biodegradable polymer microparticles according to an embodiment of the present invention freezes and grinds the biodegradable polymer particles to form pulverized particles (S100), and washes the pulverized particles to biodegrade. Forming the polymer polymer fine particles (S200). The biodegradable polymer particles include at least one of the first biodegradable polymer particles of a single component and the second biodegradable polymer particles comprising a block copolymer of heterogeneous components.

The first biodegradable polymer particles are polydioxanone, polylactic acid, polyglycolic acid, poly (D, L-lactic acid-co-glycolic acid) (poly (D, L- lactic-coglycolic acid)), or polycaprolactone. The average molecular weight of the first biodegradable polymer particles may be from 10,000 to 300,000 Da.

The second biodegradable polymer particles include PLGA (poly (lactic acid-co-glycolic acid)), PLCL (poly (lactic acid-co-ε-caprolactone)), PDLGA (poly (dl-lactic acid-co-glycolide acid) ), PLLA-PDLLA (poly (l-lactic acid-co-dl-lactic acid)), GA-TMC (poly (glycolic acid-co-trimethylene carbonate)), or PDO-PGA-TMC (poly (glycolic acid- co-trimethylene carbonate-co-dioxanone)).

First, the biodegradable polymer particles are frozen. Forming the pulverized particles (S100) may freeze the biodegradable polymer particles at -150 ℃ to -20 ℃. If frozen below -150 ℃, it is below the temperature of liquid nitrogen, so mass production and fine click on the surface of the polymer particles may occur, and if frozen above -20 ℃, biodegradable polymer particles may not freeze sufficiently inside have. Forming the pulverized particles (S100) may be to rapidly freeze the biodegradable polymer particles at -150 ℃ to -20 ℃ preferably 1 to 3 hours at -150 ℃ to -80 ℃.

The frozen biodegradable polymer particles may be ground through air blow or high speed emulsification under conditions of 2,000 rpm to 30,000 rpm.

The air injection is not limited to a particular method, but should be interpreted as including all means and methods for injecting air to crush the particles. For example, it should be interpreted as encompassing all methods, such as forming a swirl flow by injecting material and air together in a chamber of a predetermined shape, or injecting compressed air into the chamber.

In addition, the high speed emulsification is not limited to a particular method, but should be interpreted to include all methods using a high speed emulsifier.

If the grinding conditions are less than 2,000 rpm, the biodegradable polymer particles may not be sufficiently pulverized. If the grinding conditions exceed 30,000 rpm, defects may occur in the biodegradable polymer particles or the pulverized particles. In particular, when the biodegradable polymer particles are pulverized by a high-speed emulsification method, when the grinding conditions exceed 30,000 rpm, 70% or more of the average particle diameter of the biodegradable polymer particles is 1 μm or less, which is contrary to the object to be achieved in the present invention. Can be.

Forming the crushed particles (S100) may further comprise the step of drying the biodegradable polymer particles in the conditions of 0 ℃ to 40 ℃, -0.2 Mpa to -0.01 MPa. Condensation between the pulverized particles can be prevented under the above conditions. If the step (S100) of forming the pulverized particles to be described later further comprises the step of forming an emulsion solution, it is possible to remove the organic solvent, the emulsifier under the above conditions, to prevent condensation between the biodegradable polymer intermediate particles.

Forming the pulverized particles (S100) comprises emulsifying the biodegradable polymer particles to form an emulsion solution comprising the biodegradable polymer intermediate particles, and freezing the emulsion solution, pulverized to form the pulverized particles can do. In forming the emulsion solution, the size and shape of the biodegradable polymer particles may be controlled.

The emulsion solution may comprise biodegradable polymer particles, an organic solvent, and an emulsifier. The emulsion solution may be, for example, formed by mixing the biodegradable polymer particles, the organic solvent, and the emulsifier with a vibration, an emulsifier, a stirrer, and the like.

However, the morphology of the particles during emulsification by ultrasonic vibration is amorphous similar to that of FIG. 4 regardless of the molecular weight of the biodegradable polymer and at the same time a layer is generated inside the particles may cause a bottleneck upon injection.

Biodegradable polymer particles may be included from 0.5 to 1.5% by weight based on the emulsion solution. Outside of this range, the biodegradable polymer particles may not be emulsified.

The organic solvent may include at least one of tetrahydrofuran, hexafluoroispropanol, ethanol, methanol, acetone, and dichloromethane.

The emulsifier may be included from 4.0 to 6.5% by weight based on the emulsion solution. If the emulsifier is outside the above range, it is not easy to control the shape of the biodegradable polymer particles. For example, the biodegradable polymer particles are in a fibrous state, so that it may be difficult to implement a sphere or the like.

Emulsifiers include emulsifiers and stabilizers. The emulsifier may be, for example, polyethyleneoxa-polypropyleneoxide-polyethylene oxide terpolymer (polyethylene oxide-polypropylene oxide-polyethylene oxidtriblock copolymer). The polyethyleneoxa-polypropyleneoxide-polyethyleneoxide terpolymer is included 1.5 to 2.5% by weight based on the emulsion solution. Outside the above range, it is not easy to control the shape of the biodegradable polymer intermediate particles.

The terpolymer forms a skeleton of the micro particles in a uniform state together with the biodegradable polymer during emulsification, and then dissolves into a polyvinyl alcohol solution within a certain time during the hardening process. At this time, the inner and outer surfaces of the biodegradable polymer particles are determined by the amount of the terpolymer released.

Stabilizers can be, for example, polyvinyl alcohol. Polyvinyl alcohol may be included 2.5 to 4.0% by weight based on the emulsion solution. Outside the above range, it is difficult to stabilize the biodegradable polymer intermediate particles.

As the average molecular weight of the biodegradable polymer particles increases, the size of the biodegradable polymer intermediate particles may increase. When the first biodegradable polymer particles are polydioxanone, as the average molecular weight of the first biodegradable polymer particles decreases, the size of the biodegradable polymer intermediate particles may increase.

As the average molecular weight of the biodegradable polymer particles increases, the biodegradable polymer intermediate particles may be from amorphous to spherical. When the first biodegradable polymer particles are polydioxanone, as the average molecular weight of the first biodegradable polymer particles decreases, the biodegradable polymer intermediate particles may have an amorphous to spherical shape.

As the molecular weight of the biodegradable polymers excluding polydioxanone increases, the degree of intermixing and fusion with the terpolymers decreases with increasing hydrophobicity with the increase, so that the terpolymers do not penetrate into the biodegradable polymers. It acts only on the surface, forming a sphere, and at the same time increasing the size of the biodegradable polymer intermediate particles.

As the polydioxanone increases in molecular weight, the interaction with the terpolymer is reversed, resulting in a spherical shape, and the size of the biodegradable polymer intermediate particles decreases.

As the molecular weight of the biodegradable polymer decreases, it is easier to penetrate into the emulsion solution in which the terpolymer is dissolved, and thus the biodegradable polymer intermediate particles are determined to be amorphous rather than spherical due to interaction with polyvinyl alcohol.

Due to the influence of polyethylene oxide of the terpolymer, the terpolymer penetrates into the emulsion solution and phase separation occurs, thereby preventing the biodegradable polymer intermediate particles from forming a sphere. During the phase separation progression, the terpolymer absorbed at the interface stabilizes the macrostructure to retard the phase separation progression, thereby changing the shape of the biodegradable polymer intermediate particles.

Next, washing the pulverized particles to form a biodegradable polymer fine particles (S200). Biodegradable polymeric microparticles can be used as biodegradable materials for tissue repair. The biodegradable material for tissue repair may be a shaped prosthesis, bone filler or a tissue engineering support.

The average particle diameter of the biodegradable polymer fine particles may be 1 to 200 ㎛. Outside of this range, it is not easy to use as a biodegradable material for tissue repair.

Forming the biodegradable polymer fine particles (S200) is the first step of washing with phosphate-buffered saline (PBS) having a weight of 5 to 10 times the weight of the crushed particles, compared to the weight of the crushed particles A second wash with sterile water having a weight of 100 to 200 times, a third wash with ethanol having a weight of 5 to 10 times the weight of the ground particles, a concentration of 70 to 80 percent, and a third wash Drying the ground particles to form biodegradable polymeric microparticles.

When the step of forming the pulverized particles (S100) further comprises the step of forming an emulsion solution, the second washing step is to remove the terpolymer and polyvinyl alcohol to 100 to 200 times the weight of the pulverized particles Proceed with sterile water with weight. Outside the above range, the terpolymer and polyvinyl alcohol may not be sufficiently removed.

The temperature of the sterilized water during washing may be 30 to 40 ℃. If the temperature of the sterilized water is less than 30 ℃ prolongs the dissolution time of polyvinyl alcohol, if it is above 40 ℃ may deform the biodegradable polymer microparticles near the glass transition temperature of the biodegradable polymer microparticles.

Next, a third wash may be performed with ethanol having a weight of 5 to 10 times the weight of the ground particles and having a concentration of 70 to 80 percent. This is to remove the remaining organic solvent and terpolymer.

In addition, it may be dried to form biodegradable polymer fine particles.

Method for producing biodegradable polymer microparticles according to an embodiment of the present invention comprises the step of pulverizing the frozen particles by air injection or high-speed emulsification, and optionally emulsifying, the size and shape of the biodegradable polymer microparticles Easy to adjust

Hereinafter, the present invention will be described in more detail with reference to specific examples. The following examples are merely examples to help understanding of the present invention, but the scope of the present invention is not limited thereto.

Example 1

After dissolving 100 g of polydioxanone having a weight average molecular weight of 10 kDa, 100 kDa, 200 kDa, and 300 kDa in 1800 g of hexafluoroispropanol, 200 g of polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer was added thereto for 12 hours or more. Dissolved. Thereafter, an aqueous solution having a polyvinyl alcohol content of 300 g was emulsified by adding 3.0 wt% of the total weight of the emulsion solution by high speed stirring.

An electron micrograph of the emulsified polydioxanone of 300 kDa is shown in FIG. 2, and it was confirmed that the biodegradable polymer intermediate particles were spherical and had a constant size.

The microparticles in the emulsified solution state were rapidly frozen at −147 ° C. for 1 hour and ground at 2,000 rpm or more in the grinder. Internal conditions during the grinding were dried at a pressure of -0.05 MPa at a temperature of 40 ° C. 600 g of the dried ground particles were washed with 3,000 g of phosphate buffered saline (PBS). Subsequently, 600 g of the divided particles were washed with 60,000 g of sterile water maintained at 30 to 40 ° C. The biodegradable polymer fine particles were prepared by washing and drying 100 g of the washed particles using 500 g of 70 to 80 wt% ethanol.

Example 2

The same procedure as in Example 1 was carried out except that polylactic acid was used instead of polydioxanone.

Example 3

The same procedure as in Example 1 was carried out except that polyglycolic acid was used instead of polydioxanone.

Example 4

The procedure was the same as in Example 1 except that poly (D, L-lactic acid-co-glycolic acid) was used instead of polydioxanone.

Example 5

The same procedure as in Example 1 was carried out except that polycaprolactone was used instead of polydioxanone.

Comparative Example 1

Centrifugal force of 2,000 rpm after freezing at -147 ° C for 1 hour by adding 10% by weight of water to polydioxanone based on the total weight of polydioxanone to polydioxanone having a weight average molecular weight of 10kDa, 100kDa, 200kDa and 300kDa, respectively The particles were prepared by pulverizing in a pulverizer using the same and drying at a pressure of −0.05 MPa at a temperature of 40 ° C.

Comparative Example 2

The same procedure as in Comparative Example 1 was conducted except that polylactic acid was used instead of polydioxanone.

Comparative Example 3

The same procedure as in Comparative Example 1 was conducted except that polyglycolic acid was used instead of polydioxanone.

Comparative Example 4

The same procedure as in Comparative Example 1 was conducted except that poly (D, L-lactic acid-co-glycolic acid) was used instead of polydioxanone.

Comparative Example 5

The same procedure as in Comparative Example 1 was conducted except that polycaprolactone was used instead of polydioxanone.

The size of the biodegradable polymer microparticles prepared in Comparative Examples 1 to 5 was measured by a particle size analyzer and was constantly measured by the apparatus inside the mill regardless of the weight average molecular weight. In addition, the particle shape was not spherical but had a thin plate-shaped amorphous shape. When the particles that do not contain water are pulverized, they are much thinner than the particles that contain water.

Experimental Example 1: Change in particle size according to the weight average molecular weight of the biodegradable polymer

Table 1 shows the data obtained by measuring particle size of the biodegradable microparticles prepared in Examples 1 to 5. Figure 3 is a graph showing the average molecular weight and the size of the biodegradable polymer microparticles in Examples 1 to 4.

Referring to Table 1 and FIG. 3, each biodegradable polymer except polydioxanone showed a tendency to increase the average size of the particles as the weight average molecular weight was increased, but polydioxanone decreased the weight of the particles as the weight average molecular weight decreased. It can be seen that the average size increases.

Experimental Example 2: Change in the Shape of Particles According to Weight-average Molecular Weight of Biodegradable Polymers

The shape of each biodegradable microparticles prepared in Examples 1 to 5 was measured by scanning electron microscopy. 4 is a photograph taken with an electron microscope of biodegradable polymer microparticles when formed using polydioxanone having an average molecular weight of 10 kDa in Example 1. FIG. FIG. 5 is a photograph taken with an electron microscope of biodegradable polymer microparticles when formed using polydioxanone having an average molecular weight of 100 kDa in Example 1. FIG. FIG. 6 is a photograph taken with an electron microscope of biodegradable polymer microparticles when formed using polydioxanone having an average molecular weight of 200 kDa in Example 1. FIG. FIG. 7 is a photograph taken with an electron microscope of biodegradable polymer fine particles when formed using polydioxanone having an average molecular weight of 300 kDa in Example 1. FIG.

It can be seen that the particles of FIG. 4 have a three-dimensional amorphous shape, the particles of FIG. 5 have a plate-shaped amorphous shape, the particles of FIG. 6 have a partial spherical shape, and the particles of FIG. 7 have a spherical shape. That is, as the molecular weight decreases, the polydioxanone changes its shape from spherical to amorphous.

Polylactic acid, polyglycolic acid, poly (D, L-lactic acid-co-glycolic acid), and polycaprolactone have a morphology of particles from amorphous to spherical with increasing molecular weight. This increases the hydrophobicity with increasing molecular weight and decreases the degree of intermixing and fusion with the terpolymer, which affects the morphology of the microparticles. Is predicted

Although the embodiments of the present invention have been described above with reference to the accompanying drawings, those skilled in the art to which the present invention pertains may implement the present invention in other specific forms without changing the technical idea or essential features thereof. You will understand that there is. Therefore, it is to be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims (17)

Emulsifying the biodegradable polymer particles to form an emulsion solution comprising the biodegradable polymer intermediate particles;
Freezing and grinding the emulsion solution to form pulverized particles; And
And washing the ground particles to form biodegradable polymer fine particles.
The biodegradable polymer particles
A second biodegradable polymer particle comprising a single component of the first biodegradable polymer particles or a copolymer of heterogeneous components,
The emulsion solution includes biodegradable polymer particles, organic solvents, emulsifiers and stabilizers,
The biodegradable polymer particles based on the total weight of the emulsion solution is 0.5 to 1.5% by weight, the emulsifier is included 1.5 to 2.5% by weight and the stabilizer is 2.5 to 4.0% by weight,
The emulsifier is polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer,
The stabilizer is polyvinyl alcohol,
Method for producing biodegradable polymer fine particles. The method of claim 1,
The first biodegradable polymer particles are polydioxanone, polylactic acid, polyglycolic acid, poly (D, L-lactic acid-co-glycolic acid) (poly (D, L -lactic-coglycolic acid)), or polycaprolactone,
The average molecular weight of the first biodegradable polymer particles is a method for producing biodegradable polymer fine particles of 10,000 to 300,000 Da. The method of claim 1,
The second biodegradable polymer particles may include PLGA (poly (lactic acid-co-glycolic acid)), PLCL (poly (lactic acid-co-ε-caprolactone)) or PDLGA (poly (dl-lactic acid-co-glycolide acid) )) Is a method for producing biodegradable polymer fine particles. delete The method of claim 1,
The organic solvent is biodegradable, including at least one of tetrahydrofuran, hexafluoroisopropanol, ethanol, methanol, acetone, and dichloromethane. Method for producing polymer fine particles. delete delete The method of claim 1,
The forming of the pulverized particles is a method of producing biodegradable polymer microparticles, wherein the biodegradable polymer particles are frozen at -150 ° C to -20 ° C and pulverized at 2,000 rpm to 30,000 rpm. The method of claim 1,
Forming the pulverized particles further comprises the step of drying the biodegradable polymer particles under a temperature condition of 0 ℃ to 40 ℃, negative pressure conditions of -0.2 MPa to -0.01 MPa Way. The method of claim 1,
Forming the biodegradable polymer fine particles
First washing with phosphate-buffered saline (PBS) having a weight of 5 to 10 times the weight of the ground particles;
Second washing with sterile water having a weight of 100 to 200 times the weight of the ground particles;
Third washing with ethanol having a weight of 5 to 10 times the weight of the ground particles and having a concentration of 70 to 80 percent; And
Drying the third crushed particles to form a biodegradable polymer fine particles; Method of producing a biodegradable polymer fine particles comprising a. The method of claim 1,
Method of producing a biodegradable polymer microparticles that the size of the biodegradable polymer intermediate particles increases as the average molecular weight of the biodegradable polymer particles increases. The method of claim 1,
As the average molecular weight of the biodegradable polymer particles increases, the biodegradable polymer intermediate particles are amorphous, having a spherical shape, a method for producing biodegradable polymer microparticles. delete delete A biodegradable material for tissue repair comprising the biodegradable polymer microparticles prepared by claim 1. The method of claim 15,
The average particle diameter of the biodegradable polymer fine particles is 1 to 200 ㎛, biodegradable material for tissue repair. The method of claim 15,
The biodegradable material for tissue repair is a tissue implant, bone filler or tissue engineering support.

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