KR20190062709A - The fabrication method of fine particle of biodegradable polymer, the fabrication method of injection including the same, and reactor for manufacturing fine particle of biodegradable polymer - Google Patents

Abstract

A production method of biodegradable polymeric microparticles comprises the steps of injecting a dispersion solution in which biodegradable polymers are dispersed in a continuous reactor; injecting an emulsified solution into the continuous reactor to produce biodegradable polymeric microparticles in Taylor-Couette fluid flow; discharging a discharge liquid containing the biodegradable polymeric microparticles in the continuous reactor and stabilizing the biodegradable polymeric microparticles by injecting the discharged liquid into a reactor in which a stabilized liquid is stirred; and separating the biodegradable polymeric microparticles.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing biodegradable polymer microparticles using a continuous reaction, a method for preparing the same, and a reactor for preparing biodegradable polymer microparticles, AND REACTOR FOR MANUFACTURING FINE PARTICLE OF BIODEGRADABLE POLYMER}

More particularly, the present invention relates to a method for producing biodegradable polymer microparticles, a method for preparing the same, and a reactor for preparing biodegradable polymer microparticles. More particularly, the present invention relates to a method for producing biodegradable polymer microparticles, And to a reactor for preparing biodegradable polymeric microparticles. The present invention also relates to a biodegradable polymeric microparticle preparation method and a biodegradable polymeric microparticle reactor.

Currently, biodegradable polymer microparticles for injection are prepared by emulsification solvent evaporation method, spray drying method, mechanical milling method, and the like.

Emulsification-Solvent Evaporation Method is a method of forming fine particles by strongly stirring a dispersion solution in which an polymer is dissolved in an organic solvent and an emulsion solution containing a surfactant. Since the emulsion is in a thermodynamically unstable state, a strong agitating force is required because the aqueous phase and the organic phase are separated from each other through processes such as coalescence, fusion, and creaming. Therefore, There are difficult disadvantages.

Korean Patent No. 10-1418888 discloses a method for preparing a microcapsule comprising a double emulsification step of redispersing and emulsifying an aqueous solution containing a hydrophilic salt in an aqueous solution containing a hydrophilic surfactant dissolved in an organic phase in which an aliphatic polyester polymer is dissolved, However, the above particulate carrier has biodegradability and high porosity, but it has a weak mechanical strength and a strong agitating force, which makes it difficult to apply a mass production process using a batch reaction.

Korean Patent No. 10-1725279, a spray dry method is used as a method capable of industrial mass production. It is a method to prepare biodegradable polymer microparticles by dissolving a biodegradable polymer in DMSO (dimethyl sulfoxide), injecting it into a low temperature hydrocarbon solution, freezing the DMSO and the polymer solution, and then removing DMSO from the low temperature salt aqueous solution. However, the biodegradable polymer microparticles have a high porosity and excellent mechanical strength, but they have a problem in that the production cost is very high using an excessive amount of organic solvent and the particle size distribution has a wide particle size distribution, making it difficult to control the particle size.

Accordingly, there has been a demand for development of a mass synthesis process which can easily and inexpensively produce polymer fine particles having excellent biocompatibility, biodegradability, particle shape, particle size, and mechanical strength.

Until now, biodegradable polymer microparticles have been produced mainly by a batch process, which has a limitation in producing monodisperse polymer particles having a desired size, degree of crosslinking and structure.

For example, U.S. Pat. No. 5,863,996 discloses a batch process for preparing polymeric particles. In order to obtain a desired product in such a batch process of polymer particles, a step of supplying a reactant containing a monomer or a monomer into a batch reactor and performing a polymerization reaction, followed by a step of cooling, removing and washing the polymer, . Thus, in the batch process, it takes a long time to produce the polymer particles, and the manufacturing cost is also greatly increased.

In order for the polymer particles to be effectively applied to various uses, it is necessary that the physical properties such as monodispersity are excellent. However, in the conventional process, it is difficult to uniformly maintain the physical properties of the produced particles such as polydisperse particles.

In addition, it has a disadvantage in that it is difficult to produce by a general stirring method of the batch reactor in the emulsification step of determining particles of a desired shape and size technically. The main cause of this problem is the polymer solution dissolved in the organic solvent and the emulsified solution dissolved in the water can not maintain the uniform state, and the main cause can be found. This is because the organic solvent and water can not be quickly mixed and separated, and some of them can not be emulsified to generate particles or distort their shape.

Korean Patent No. 10-1418888 Korean Patent No. 10-1725279 United States Patent No. 5863996

M. Kanouni, H. L. Rosano, N. Naouli, Adv. Colloid Interface Sci. 99 (2002) 229-254; A. J. Webster, M. E. Cates, Langmuir, 14 (1998) 2068-2079

An object of the present invention is to provide a method for producing biodegradable polymer microparticles, which facilitates mass production of biodegradable polymer microparticles and facilitates the control of size and shape of the biodegradable polymer microparticles.

It is an object of the present invention to provide a method for producing an injection comprising biodegradable polymer microparticles which are easy to mass-produce and which can easily control the size and shape of biodegradable polymer microparticles.

An object of the present invention is to provide a reactor for producing biodegradable polymer microparticles which can easily produce mass-produced biodegradable polymer microparticles with ease in size and shape of biodegradable polymer microparticles.

A method for producing biodegradable polymer microparticles according to an embodiment of the present invention includes injecting a dispersion solution in which a biodegradable polymer is dispersed into a continuous reactor, injecting an emulsion solution into the continuous reactor, Generating biodegradable polymer microparticles, discharging the biodegradable polymer microparticles in the continuous reactor, injecting the biodegradable polymer microparticles into the reactor in which the stabilizing liquid has been stirred, And separating the biodegradable polymer microparticles.

In the step of injecting the dispersion solution, the biodegradable polymer is selected from among polydioxanone (PDO), polylactic acid (PLA) and its isomers and polycarprolactone (PCL) The average molecular weight of the macromolecular polymer may be from 50,000 to 300,000.

In the step of injecting the dispersion solution, the dispersion solution includes a solvent. The solvent includes at least one of perfluoro alcohol, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), chlorinated hydrocarbons, hydrocarbons and alkyl alcohols. The content of the biodegradable polymer may be 1 to 20% by weight based on the dispersion solution.

In the step of injecting the dispersion solution, the dispersion solution further comprises a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer. The average molecular weight of the terpolymer may be 7,000 to 15,000, and the content of the terpolymer may be 1 to 20% by weight based on the dispersion solution.

In the step of producing the biodegradable polymer microparticles, the size of the biodegradable polymer microparticles may be 1 to 300 μm.

The biodegradable polymer microparticles may be used for a facial forming filler, a male implant, or a therapeutic agent for urinary incontinence.

In the step of producing the biodegradable polymer microparticles, the emulsifying solution may contain at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salts thereof, soybean lecithin, and monoglyceride .

In the step of stabilizing the biodegradable polymer microparticles, the stabilizing liquid may contain at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salt thereof, soybean lecithin, and monoglyceride To do

A method for preparing an injectable preparation according to an embodiment of the present invention includes the steps of preparing an aqueous solution containing biodegradable polymer microparticles, adding an aqueous solution containing alginic acid and its salt, hyaluronic acid and its salt, Providing at least one of Carboxylmethyl cellulose and its salt, Dextran and its salts, collagen, Gelatin, and Elastin, and lyophilizing it. Preparing the aqueous solution comprises the steps of injecting a dispersion solution in which a biodegradable polymer is dispersed into a continuous reactor, injecting an emulsion solution into the continuous reactor to produce biodegradable polymer microparticles in a Kuett Taylor fluid flow, Discharging a discharged liquid containing the biodegradable polymer microparticles in the continuous reactor and injecting the discharged liquid into a reactor in which the stabilized liquid is stirred to stabilize the biodegradable polymer microparticles, And separating the particles.

In preparing the aqueous solution, the biodegradable polymer microparticles may be contained in an amount of 10 to 80% by weight based on the aqueous solution.

When the carboxymethylcellulose is provided to the aqueous solution, the biodegradable polymer microparticles may be contained in an amount of 30 to 60% by weight based on the aqueous solution containing the carboxymethylcellulose.

The size of the biodegradable polymer fine particles may be 10 to 300 탆.

And sterilizing the lyophilized biodegradable polymer microparticles. The sterilization may be performed by gamma sterilization, ethylene oxide sterilization, or vacuum sterilization.

The injection may be a facial forming filler, a male implant, or a therapeutic agent for urinary incontinence.

The reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention includes a continuous reactor in which biodegradable polymer microparticles are formed by a Kuett Taylor fluid flow, a first inlet for injecting an emulsified solution into the continuous reactor, a biodegradable polymer A second inlet for introducing the dispersion solution into the continuous reactor, a reaction solution discharging part for discharging the reaction solution containing the biodegradable polymer microparticles produced in the continuous reactor, and a second solution inlet for discharging the biodegradable polymer fine And a continuous centrifuge separating the particles.

The continuous reactor includes a reaction part generating the biodegradable polymer microparticles, a stirring motor disposed on one side of the cylinder, and a stirring rod spaced apart from the reaction part and driven by the stirring motor.

The stirring motor may have a rotation speed of 10 to 2000 rpm.

The first inlet may be disposed at a quarter of the reaction part.

According to the method for producing biodegradable polymer microparticles according to an embodiment of the present invention, mass production of biodegradable polymer microparticles is easy, and the size and shape of the biodegradable polymer microparticles can be easily controlled.

According to the method of manufacturing an injection according to an embodiment of the present invention, the biodegradable polymer microparticles can be easily mass-produced and easily controlled in size and shape of the biodegradable polymer microparticles.

According to the reactor for manufacturing biodegradable polymer microparticles according to an embodiment of the present invention, it is easy to mass-produce biodegradable polymer microparticles, and it is easy to control the size and shape of the biodegradable polymer microparticles.

1 is a flowchart schematically showing a method of manufacturing an injection according to an embodiment of the present invention.
2 is a flowchart schematically showing a method of producing biodegradable polymer microparticles according to an embodiment of the present invention.
3 is a cross-sectional view schematically showing a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention.
4 is an electron micrograph of the biodegradable polymer microparticles of Examples 1 to 3. FIG.
5 is an electron micrograph of biodegradable polymer microparticles according to the residence time in a continuous reactor.
FIG. 6 is a photograph of the biodegradable polymer fine particles according to the stirring speed.
FIG. 7 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention by an electron microscope at x200 magnification.
FIG. 8 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention by an electron microscope at an x1,000 magnification.
9 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention by an electron microscope at an x5,000 magnification.
10 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention by an electron microscope at x10,000 magnification.

BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects, features, and advantages of the present invention will become more readily apparent from the following description of preferred embodiments with reference to the accompanying drawings. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the embodiments disclosed herein are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.

Like reference numerals are used for like elements in describing each drawing. In the accompanying drawings, the dimensions of the structures are shown enlarged from the actual for the sake of clarity of the present invention. The terms first, second, etc. 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 a second component, and similarly, the second component may also be referred to as a first component. The singular expressions include plural expressions unless the context clearly dictates otherwise.

In the present application, the terms "comprises" or "having" and the like are used to specify that there is a feature, a number, a step, an operation, an element, a component or a combination thereof described in the specification, But do not preclude the presence or addition of one or more other features, integers, steps, operations, components, parts, or combinations thereof. Also, where a portion such as a layer, film, region, plate, or the like is referred to as being "on" another portion, this includes not only the case where it is "directly on" another portion, but also the case where there is another portion in between. On the contrary, when a part such as a layer, film, region, plate or the like is referred to as being "under" another part, it includes not only the case where it is "directly underneath" another part but also another part in the middle.

Unless otherwise specified, all numbers, values, and / or representations that express the amounts of components, reaction conditions, polymer compositions, and combinations used herein are intended to include those numbers It should be understood that in all cases the term " about " is to be construed as an approximation reflecting the various uncertainties of the measurement. Also, where a numerical range is disclosed in this specification, such a range is contiguous and includes all values from the minimum value of this range to the maximum value including the maximum value, unless otherwise indicated. Further, when such a range refers to an integer, all integers including the minimum value to the maximum value including the maximum value are included unless otherwise indicated.

In the present specification, when a range is described for a variable, it will be understood that the variable includes all values within the stated range including the end points described in the range. For example, a range of " 5 to 10 " may include any subrange, such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc., as well as values of 5, 6, 7, 8, 9, And will also be understood to include any value between integers that are reasonable within the scope of the stated ranges such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and so on. Also, for example, a range of " 10% to 30% " may range from 10% to 15%, 12% to 12%, as well as all integers including values of 10%, 11%, 12%, 13% And any arbitrary integer within the range of ranges described, such as 10.5%, 15.5%, 25.5%, and the like, including any subranges such as 18%, 20%

First, a method for producing biodegradable polymer microparticles and a method for producing an injection containing the same will be described.

1 is a flowchart schematically showing a method of manufacturing an injection according to an embodiment of the present invention. 2 is a flowchart schematically showing a method of producing biodegradable polymer microparticles according to an embodiment of the present invention.

Referring to FIG. 1, a method for preparing an injectable preparation according to an embodiment of the present invention includes preparing an aqueous solution containing biodegradable polymer microparticles (S10), adding an aqueous solution containing alginic acid and its salt, hyaluronic acid The present invention provides at least one of Hyalurinic acid and its salts, Carboxylmethyl cellulose and salts thereof, Dextran and its salts, collagen, Gelatin, and Elastin, And lyophilization (S20). Step S10 of preparing an aqueous solution includes preparing biodegradable polymer microparticles. 1 and 2, the preparation of the biodegradable polymer microparticles comprises the steps of injecting a dispersion solution in which a biodegradable polymer is dispersed into a continuous reactor (S100), injecting an emulsion solution into a continuous reactor, (S200) of producing biodegradable polymer microparticles by Taylor fluid flow, discharging a discharge containing biodegradable polymer microparticles in a continuous reactor, injecting a discharge liquid into a reactor in which the stabilized liquid is stirred, Stabilizing the fine particles (S300), and separating the biodegradable polymer fine particles (S400).

First, a dispersion solution in which a biodegradable polymer is dispersed is injected into a continuous reactor (S100).

In step S100 of injecting the dispersion solution, the biodegradable polymer is selected from polydioxanone (PDO), polylactic acid (PLA) and its isomers and polycarprolactone (PCL). Polydioxanone can be dissolved in perfluoroalcohols. The perfluoroalcohol is an alcohol compound having 1 to 6 carbon atoms substituted with 3 to 13 fluorine atoms, for example, 1,1,1,3,3,3-hexafluoro-2-propanol.

The average molecular weight of the biodegradable polymer may be from 50,000 to 300,000. When the average molecular weight of the biodegradable polymer is less than 50,000, the biodegradable polymer has a low degradation rate and the biodegradable polymer has an average molecular weight of more than 300,000, which is difficult to process due to high viscoelasticity. It is difficult to make.

The content of the biodegradable polymer may be 1 to 20% by weight based on the dispersion solution. Outside of this range, it is difficult to form a quartetail fluid stream during stirring with the emulsified solution due to its high viscosity or to form particles when the emulsification concentration is low.

In the step (S100) of injecting the dispersion solution, the dispersion solution includes a solvent. The solvent includes at least one of perfluoro alcohol, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), chlorinated hydrocarbons, hydrocarbons and alkyl alcohols.

In the step (S100) of injecting the dispersion solution, the dispersion solution further comprises a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer. The average molecular weight of the terpolymer may be from 7,000 to 15,000. When the average molecular weight of the terpolymer is less than 7,000, the surfaces of the particles are uneven, and when the average molecular weight of the terpolymer is more than 15,000, it is difficult to produce spherical fine particles because of high viscosity. The content of the terpolymer may be 1 to 20% by weight, based on the dispersion solution. It is difficult to control the shape of the biodegradable polymer microparticles generated due to the difference in permeability and viscosity in the particles outside the above range.

The terpolymer can determine the shape of biodegradable microparticles. The terpolymer is adsorbed on the surface of the produced biodegradable fine particle to form an adsorbed film between the particles to prevent coagulation between particles.

Next, the emulsified solution is injected into a continuous reactor to produce biodegradable polymer microparticles in a Kuett Taylor fluid flow (S200).

The emulsifying solution may contain at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salts thereof, soybean lecithin, and monoglyceride.

When the emulsifying solution contains polyvinyl alcohol, the emulsifying solution can be used by dissolving the polyvinyl alcohol in water or a mixture of water and an alkyl alcohol. At this time, the content of polyvinyl alcohol may be 1 to 10 wt% based on the emulsified solution. Outside of the above range, the emulsifying action of the PVA serving as a surfactant is weakened, making it difficult to form fine particles.

The polyvinyl alcohol may have an average molecular weight of 50,000 to 200,000. If the average molecular weight of the terpolymer is less than 50,000, the emulsification action is very poor. If the average molecular weight of the terpolymer exceeds 200,000, it is difficult to smoothly form the Taylor flow due to the high concentration.

The emulsifying solution may contain a surfactant. As the surfactant, any of anionic, cationic or amphoteric surfactants can be used. Surfactants include, for example, polyoxyethylene sorbitan monolaurate (Tween 20 product), polyoxyethylene sorbitan monopalmitate (Tween 40 product), polyoxyethylene sorbitan monostearate (Tween 60 product), poly Oxyethylene sorbitan monooleate (Tween 80 product), and polyoxyethylene sorbitan trioleate (Tween 85 product).

When an emulsified solution is supplied to a continuous reactor into which a dispersion solution is injected, emulsification occurs. In this case, the emulsion may be emulsified for 1 to 30 minutes. When the emulsification is carried out for less than 1 minute, biodegradable polymer microparticles are not sufficiently produced, and when emulsification proceeds for more than 30 minutes, productivity of the biodegradable polymer microparticles decreases compared to the external force.

At this time, biodegradable polymer microparticles are produced, which can be obtained by a general mechanical stirring method, for example, a stirring method using a magnetic bar, a stirring method using a mechanical stirrer or a homogenizer, a method using a Kuett Taylor fluid flow to be. Unlike the batchwise agitation method, the quettiell fluid flow has a strong agitating force and has an advantage in that it is proportional to the reaction time and the time passing through the continuous reactor, unlike the batch reaction.

The biodegradable polymer microparticles are stabilized by injecting the effluent into the reactor in which the stabilizing liquid is stirred (S300). The stabilizing liquid may be prepared by dissolving polyvinyl alcohol or a surfactant in water or a mixed solution of water and an alkyl alcohol. When the stabilizing liquid contains polyvinyl alcohol, the content of polyvinyl alcohol may be 0.1 to 5% by weight based on the stabilizing liquid.

The stabilizing liquid may comprise polyvinyl alcohol having an average molecular weight of 10,000 to 100,000. If the average molecular weight of the polyvinyl alcohol is less than 10,000, it is difficult to maintain the shape of the particles. If the average molecular weight of the polyvinyl alcohol is more than 100,000, the removal is difficult in the washing process. The stabilizing liquid may contain a single component aqueous solution or a mixed solution of a surfactant and an alkyl alcohol.

The effluent which has passed through the continuous reactor is continuously injected into the reactor in which the stabilizing solution already prepared is stirred and stabilized. The effluent contains biodegradable polymer microparticles. The continuous reactor may include a decompression device, and the organic solvent may be removed by the decompression device.

The biodegradable polymer microparticles are separated (S400). The biodegradable polymer microparticles and the solution are separated using a continuous centrifuge or a high-speed stirring centrifuge. The alkyl alcohol and water or water alone can be used to wash biodegradable polymer microparticles. Alkyl alcohols can be, for example, ethanol.

Biodegradable polymer microparticles may be classified by size. The biodegradable polymer microparticles separated from the solution can be classified by size using a powder mill. For example, biodegradable polymer microparticles can be sized by dry or wet using size sieving machines.

When wet-pulverized, freeze-drying may be additionally performed to remove water and then be classified.

The size of the biodegradable polymer fine particles may be 1 to 300 탆. The size of the biodegradable polymer microparticles may be, for example, the particle size of the biodegradable polymer microparticles.

If the size of the biodegradable polymer microparticles is less than 1 탆, it is difficult to control the size when the biodegradable polymer microparticles are prepared, and if the size of the biodegradable polymer microparticles is more than 300 탆, the biodegradable polymer microparticles are not suitable for injection .

As described above, the method for preparing an injection according to an embodiment of the present invention includes the step of providing an excipient to an aqueous solution containing biodegradable polymer microparticles. The excipient may be, for example, alginic acid and salts thereof, hyaluronic acid and salts thereof, carboxymethyl cellulose and salts thereof, dextran and its salts, collagen, Gelatin, and elastin. ≪ Desc / Clms Page number 7 > The method for preparing an injection according to an embodiment of the present invention includes providing an excipient to an aqueous solution containing biodegradable polymer microparticles and lyophilizing (S20).

In step S10 of preparing an aqueous solution, the biodegradable polymer microparticles may be contained in an amount of 10 to 80% by weight based on the aqueous solution. When the content of the biodegradable polymer fine particles is less than 10% by weight, the concentration is low and it is difficult to disperse evenly. When the biodegradable polymer fine particles are more than 80% by weight, it is difficult to freeze-dry and mix with the excipient.

Depending on the aqueous solution, the ratio of the biodegradable polymer microparticles to the excipient in the mixture may be in a weight ratio of 2: 8 to 8: 2. If it is out of the above range, it is difficult to disperse the biodegradable polymer microparticles evenly at an appropriate concentration, out of the range in which the content of the excipient can be controlled.

At this time, the mixed liquid having a high viscosity can be evenly dispersed by using a three roll mill.

The method for preparing an injection according to an embodiment of the present invention may further comprise sterilizing the lyophilized biodegradable polymer microparticles. The step of sterilizing may be performed, for example, by gamma sterilization, ethylene oxide sterilization, or vacuum sterilization.

Injection may be used as a facelift filler, a male implant, or a treatment for urinary incontinence. The size of the biodegradable polymeric microparticles used in the face-forming filler may be 10 to 100 mu m. The size of the biodegradable polymer microparticles used for male implant or urinary incontinence treatment agent may be 100 to 300 탆.

The method of producing an injectable agent according to an embodiment of the present invention and the method of producing biodegradable polymer microparticles according to an embodiment of the present invention can easily mass-produce biodegradable polymer microparticles using a Kuett Taylor fluid flow , It is easy to control the size and shape of biodegradable polymer microparticles.

Hereinafter, a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention will be described. Hereinafter, the difference between the method of manufacturing an injection according to an embodiment of the present invention and the method of producing biodegradable polymer microparticles according to an embodiment of the present invention will be described, and the same or similar features will be omitted.

3 is a cross-sectional view schematically showing a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention.

Referring to FIG. 3, a reactor 100 for producing biodegradable polymer microparticles according to an embodiment of the present invention includes a first inlet 9, a second inlet 10, a continuous reactor 100, (11), and a continuous centrifuge (12). The reactor 100 for producing biodegradable polymer microparticles according to an embodiment of the present invention includes an emulsion solution storage 1, a dispersion solution storage 2, a waste solution outlet 13, a biodegradable polymer microparticle recovery unit 14, .

In the continuous reactor (100), biodegradable polymer microparticles are formed by the Kuett Taylor fluid flow. The Coet Taylor fluid flow is formed by stirring the emulsion solution provided from the first inlet 9 and the dispersion solution in which the biodegradable polymer provided from the second inlet 10 is dispersed. The first inlet 9 is connected to the emulsion solution storage 1. The second inlet (10) is connected to the dispersion solution storage (2).

The reaction liquid containing the biodegradable polymer microparticles produced in the continuous reactor (100) is discharged to the reaction liquid discharge portion (11). The reaction liquid discharged to the reaction liquid discharge portion 11 is separated into waste liquid and biodegradable polymer fine particles in a continuous centrifuge (12). The waste liquid is discharged to the waste liquid discharge port (13). The biodegradable polymer microparticles are recovered in the biodegradable polymer microparticle retrieval section (14).

The continuous reactor 100 includes an inner cylinder 5, a temperature regulating portion, an outer cylinder 7, and a reaction portion 8. The inner cylinder 5 is rotated at a high speed to stir the reaction liquid. The outer cylinder 7 is equipped with an injection orifice and serves to protect the inside of the reaction. The temperature regulating part 6 can control the temperature by connecting a cooling device between the reaction part 8 and the outer cylinder 7. The reaction part (8) is an empty space filled with the reaction liquid, and the biodegradable polymer fine particle is formed by the Koet Taylor fluid flow.

The continuous reactor (100) further includes a stirring motor (3), a driving shaft (4), and a stirring rod. The stirring motor 3 may rotate the stirring rod. The stirring rod is driven by the stirring motor 3. The stirring rod stirs the emulsion solution and dispersion solution provided in the inner cylinder (5). The agitating rod is driven by receiving an external force from the agitating motor 3 at the center of the drive shaft 4. [ The stir rod is spaced apart from the reaction part 8.

The stirring motor 3 may have a rotation speed of 10 to 2000 rpm. If it is less than 10 rpm, the emulsified solution and the dispersion solution are not sufficiently stirred, and if it exceeds 2000 rpm, the stirring efficiency of the external force is not high.

The first inlet 9 may be disposed at a quarter of the reaction part 8, and may be injected at a point receiving a sufficient rotational force to form spherical fine particles by a strong agitating force.

The reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention uses a Kuett Taylor fluid flow to facilitate the mass production of biodegradable polymer microparticles and to control the size and shape of the biodegradable polymer microparticles It is easy.

Hereinafter, the present invention will be described more specifically by way of specific examples. The following examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of polydioxanone fine particles

90 g of polydioxanone having an average molecular weight of 100,000 and 60 g of a terpolymer F-127 (product of BASF, average molecular weight 12,600) and a terpolymer F-68 (product of BASF, average molecular weight 8,400) were dissolved in hexafluoro Was added to 1500 mL of isopropanol (Hexafluoroisopropanol), followed by stirring and mixing.

7,500 mL of 5% PVA (average molecular weight 130,000) solution was simultaneously added at a rate of 50 mL / mL while the dispersion solution of polydioxanone was fed into a continuous reactor using a Kuett Taylor fluid flow at a rate of 10 mL / min. The residence time in the reactor was maintained for 10 minutes and the reaction solution was adjusted to be discharged.

The reaction solution to be discharged was stirred while being added to a 7,500 mL solution of 1% PVA (average molecular weight: 93,500). After the completion of the discharge, hexafluoroisopropanol was removed under reduced pressure with stirring for 24 hours to stabilize the resulting biodegradable polymer microparticles.

The reaction liquid containing the biodegradable polymer microparticles was separated by solid - liquid separation using a centrifuge to obtain polydioxanone fine particles from which the impurity was removed. This was washed five times with 900 mL of distilled water and centrifuged to remove residual impurities completely and lyophilized to complete polydioxanone microparticles as biodegradable polymer microparticles.

At this time, the biodegradable polymer particles were produced by changing the flow rates of the continuous reactor at 500 rpm, 1500 rpm, and 2000 rpm.

Also, biodegradable polymer particles were prepared by changing the residence time of the polymer dispersion solution and the emulsion solution in the reactor to 1 to 10 minutes.

Example 2: Preparation of polylactic acid microparticles

The procedure of Example 1 was repeated except that polylactic acid was used in place of polydioxanone and dichloromethane was used in place of hexafluoroisopropanol.

Example 3: Preparation of polylactic acid microparticles

The procedure of Example 1 was repeated except that poly caprolactone was used instead of polydioxanone and dichloromethane was used instead of hexafluoroisopropanol.

Property measurement

1. Fig. 4 is an electron micrograph of the biodegradable polymer microparticles of Examples 1 to 3. Fig. Referring to FIG. 4, when the biodegradable polymer microparticles were prepared by the production method of the present invention, biodegradable polymer microparticles of the same type could be formed regardless of the type of the biodegradable polymer.

2. FIG. 5 is an electron micrograph of biodegradable polymer microparticles according to the residence time in a continuous reactor. It was confirmed that the biodegradable polymer fine particles can be produced smoothly as the retention time becomes longer.

3. FIG. 6 is a photograph of the biodegradable polymer fine particles according to the stirring speed. It was confirmed that the biodegradable polymer fine particles can be produced smoothly as the stirring speed is increased.

4. FIG. 7 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention, taken at an electron microscope of x200 magnification. FIG. 8 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention by an electron microscope at an x1,000 magnification. 9 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention by an electron microscope at an x5,000 magnification. 10 is a photograph of a biodegradable polymer fine particle prepared according to Example 1 of the present invention by an electron microscope at x10,000 magnification.

7 to 10, it can be confirmed that the biodegradable polymer microparticles prepared by the method for producing biodegradable polymer microparticles according to an embodiment of the present invention can be easily controlled in size and shape even if they are produced in a large amount .

While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, It will be understood. It is therefore to be understood that the above-described embodiments are illustrative and non-restrictive in every respect.

1: emulsion solution storage 2: dispersion solution storage
3: Stirring motor 4: Drive shaft
5: inner cylinder 6: temperature control unit
7: outer cylinder 8: reaction part
9: First inlet 10: Second inlet
11: reaction liquid discharging part 12: continuous centrifugal separator
13: waste liquid outlet 14: biodegradable polymer fine particle collecting part

Claims (18)

Injecting a dispersion solution in which a biodegradable polymer is dispersed into a continuous reactor;
Injecting an emulsified solution into the continuous reactor to produce biodegradable polymer microparticles in a Kuett Taylor fluid flow;
Discharging a discharged liquid containing the biodegradable polymer microparticles in the continuous reactor and injecting the discharged liquid into a reactor in which the stabilized liquid is stirred to stabilize the biodegradable polymer microparticles; And
And separating the biodegradable polymer microparticles from the biodegradable polymer microparticles. The method according to claim 1,
In the step of injecting the dispersion solution,
The biodegradable polymer may be selected from the group consisting of polydioxanone (PDO), polylactic acid (PLA) and its isomers, polyglycolic acid (PGA) and its isomers, and polycarprolactone Selected,
Wherein the biodegradable polymer has an average molecular weight of 50,000 to 300,000. The method according to claim 1,
In the step of injecting the dispersion solution,
Wherein the dispersion solution comprises a solvent,
The solvent
At least one of perfluoro alcohol, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), chlorinated hydrocarbons, hydrocarbons and alkyl alcohols,
Wherein the content of the biodegradable polymer is 1 to 20% by weight based on the dispersion solution. The method according to claim 1,
In the step of injecting the dispersion solution,
Wherein the dispersion solution further comprises a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer,
The average molecular weight of the terpolymer is 7,000 to 15,000,
Wherein the content of the terpolymer is 1 to 20% by weight based on the dispersion solution. The method according to claim 1,
In the step of producing the biodegradable polymer microparticles,
Wherein the biodegradable polymer microparticles have a size of 1 to 300 mu m. The method according to claim 1,
The biodegradable polymer microparticles
Wherein the biodegradable polymeric microparticles are used for facial forming fillers, male implants, or urinary incontinence treatments. The method according to claim 1,
In the step of producing the biodegradable polymer microparticles,
Wherein the emulsifying solution contains at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salt thereof, soybean lecithin, and monoglyceride. The method according to claim 1,
In stabilizing the biodegradable polymer microparticles,
Wherein the stabilizing liquid comprises at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salt thereof, soybean lecithin, and monoglyceride. The method for producing biodegradable polymer microparticles according to claim 1, wherein the stabilizing liquid comprises at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salts thereof, soybean lecithin, and monoglyceride. Preparing an aqueous solution containing biodegradable polymer microparticles prepared according to claim 1; And
Alginic acid and salts thereof, hyaluronic acid and salts thereof, carboxymethyl cellulose and salts thereof, dextran and salts thereof, collagen, gelatin, ), And elastin (Elastin), followed by lyophilization. 10. The method of claim 9,
In preparing the aqueous solution,
Wherein the biodegradable polymer microparticles are contained in an amount of 10 to 80% by weight based on the aqueous solution. 10. The method of claim 9,
When carboxymethylcellulose is provided in the aqueous solution,
Wherein the biodegradable polymer microparticles are contained in an amount of 30 to 60% by weight based on the aqueous solution containing the carboxymethyl cellulose. 10. The method of claim 9,
Wherein the size of the biodegradable polymer microparticles is 10 to 300 mu m. 10. The method of claim 9,
Further comprising the step of sterilizing the lyophilized biodegradable polymer microparticles,
The sterilizing step
Gamma-ray sterilization, ethylene oxide sterilization, or vacuum sterilization. 10. The method of claim 9,
Wherein the injection is used as a facial forming filler, a male implant, or a treatment for urinary incontinence. A continuous reactor in which biodegradable polymer microparticles are formed by a Kuett Taylor fluid flow;
A first inlet for introducing the emulsified solution into the continuous reactor;
A second inlet through which the dispersion solution in which the biodegradable polymer is dispersed is injected into the continuous reactor;
A reaction solution discharging part for discharging a reaction solution containing the biodegradable polymer microparticles produced in the continuous reactor; And
And a continuous centrifugal separator for separating the biodegradable polymer microparticles from the reaction solution. 16. The method of claim 15,
The continuous reactor
A reaction part generating the biodegradable polymer fine particles;
A stirring motor disposed on one side of the cylinder; And
And a stirring rod spaced from the reaction part and driven by the stirring motor. The reactor for producing biodegradable polymer microparticles according to claim 1, 17. The method of claim 16,
The stirring motor
And having a rotation speed of 10 to 2000 rpm. 17. The method of claim 16,
Wherein the first inlet is disposed at a quarter point of the reaction part.

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