WO2020122268A1 - Method for manufacturing biodegradable polymeric microparticles by using continuous reaction, method for manufacturing injection comprising same, and reactor for manufacturing biodegradable polymeric microparticles - Google Patents

Abstract

A method for manufacturing biodegradable polymeric microparticles 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 generate biodegradable polymeric microparticles through Couette-Taylor fluid flow; discharging a discharge liquid containing the biodegradable polymeric microparticles from the continuous reactor, and injecting the discharge liquid into a reactor, in which a stabilization liquid is stirred, to stabilize the biodegradable polymeric microparticles; and separating the biodegradable polymeric microparticles.

Description

Method for producing biodegradable polymer microparticles using a continuous reaction, method for preparing an injection containing the same, and reactor for producing biodegradable polymer microparticles

The present invention relates to a method for producing biodegradable polymer microparticles, a method for preparing an injection containing the same, and a reactor for producing biodegradable polymer microparticles, more specifically, mass production is easy, and the size of biodegradable polymer microparticles The present invention relates to a method for manufacturing biodegradable polymer fine particles, which is easy to control and shape, a method for manufacturing an injection containing the same, and a reactor for producing biodegradable polymer fine particles.

Currently used methods of manufacturing biodegradable polymer microparticles for injection include an emulsion solvent evaporation method, a spray drying method, and a mechanical milling method.

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

With reference to Korean Patent No. 10-1418888, a particulate carrier is prepared comprising a double emulsification step of re-dispersing and emulsifying an aqueous solution containing a hydrophilic surfactant by adding an aqueous solution in which an effervescent salt is dissolved in an organic phase in which an aliphatic polyester polymer is dissolved. A method is also known. However, the particulate carrier has biodegradability and high porosity, but has low mechanical strength and requires strong stirring force, making it difficult to apply a mass production process using a batch reaction.

Referring to Korean Patent No. 10-1725279, a spray dry method is used as a method capable of industrial mass production. It is a method of producing biodegradable polymer fine particles by dissolving the biodegradable polymer in DMSO (Dimethyl Sulfoxide) and spraying it in a low-temperature hydrocarbon solution to freeze the DMSO and the polymer solution and then remove the DMSO from the low-temperature salt aqueous solution. However, the biodegradable polymer fine particles have a high porosity and excellent mechanical strength, but have a problem in that it is difficult to control the particle size because the manufacturing cost is very high and a wide particle size distribution is used using an excessive amount of organic solvent.

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

To date, biodegradable polymer microparticles are mainly produced in a batch process, which has great limitations in producing monodisperse polymer particles having a desired size, degree of crosslinking, and structure.

For example, U.S. Patent No. 5863996 discloses a batch production process of polymer particles. In the batch production process of such polymer particles, in order to obtain a target product, a monomer or a reactant containing a monomer is supplied into a batch reactor, followed by a process of performing a polymerization reaction, followed by a process of cooling, removing and washing the polymer, etc. Process is required. Accordingly, in the batch process, not only does it take a long time to manufacture the polymer particles, but also the manufacturing cost increases significantly.

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

In addition, it has the disadvantage that it is difficult to manufacture with the general stirring method of the batch reactor in the emulsification step to determine the particles of the desired shape and size technically. The main cause of this problem can be found in the phenomenon that the polymer solution dissolved in the organic solvent and the emulsion solution dissolved in water do not maintain a uniform state and are separated. This is because the organic solvent and water do not mix quickly and are separated, and some of them cannot be emulsified to form particles or to distort the shape.

An object of the present invention is to provide a method for producing biodegradable polymer microparticles which is easy to mass-produce biodegradable polymer microparticles, and can easily control the size and shape of the biodegradable polymer microparticles.

An object of the present invention is to provide a method for preparing an injection containing biodegradable polymer microparticles that is easy to mass-produce and is easy to control the size and shape of biodegradable polymer microparticles.

An object of the present invention is to provide a reactor for the production of biodegradable polymer microparticles capable of producing biodegradable polymer microparticles that is easy to mass-produce and easy to control the size and shape of biodegradable polymer microparticles.

Method for producing biodegradable polymer fine particles according to an embodiment of the present invention is a step of injecting a dispersion solution in which a biodegradable polymer is dispersed in a continuous reactor, an emulsion solution is injected into the continuous reactor, and a Kuet Taylor fluid flow Generating biodegradable polymer microparticles, discharging a discharge liquid containing the biodegradable polymer microparticles from the continuous reactor, and injecting the discharge liquid into a reactor in which a stabilizing liquid is stirred, to obtain the biodegradable polymer microparticles Stabilizing, and separating the biodegradable polymer fine particles.

In the step of injecting the dispersion solution, the biodegradable polymer is selected from polydioxanone (PDO), polylactic acid (PLA) and its isomers and polycaprolactone (PCL), and the biodegradable The average molecular weight of the sex polymer may be 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 perfluorine alcohol, DMF (N,N-Dimethylforamide), DMSO (Dimethyl sulfoxide), chlorinated hydrocarbons, hydrocarbons and alkyl alcohols. The content of the biodegradable polymer, based on the dispersion solution, may be 1 to 20% by weight.

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 ternary copolymer is 7,000 to 15,000, and the content of the ternary copolymer may be 1 to 20% by weight based on the dispersion solution.

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

The biodegradable polymer fine particles may be used for facial molding fillers, male implants, or urinary incontinence treatments.

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

In the step of stabilizing the biodegradable polymer microparticles, the stabilizing solution includes at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salts thereof, soybean lecithin, and monoglyceride Doing

Preparation method of the injection according to an embodiment of the present invention comprises the steps of preparing an aqueous solution containing biodegradable polymer microparticles, and alginic acid and its salt, hyaluronic acid and its salt in the aqueous solution, And providing at least one of carboxymethyl cellulose and its salt, dextran and its salt, collagen, gelatin, and elastin, and freeze-drying. The step of preparing the aqueous solution includes injecting a dispersion solution in which a biodegradable polymer is dispersed into a continuous reactor, injecting an emulsifying solution into the continuous reactor, and generating biodegradable polymer fine particles through a Kuet Taylor fluid flow, Stabilizing the biodegradable polymer fine particles by discharging the discharge liquid containing the biodegradable polymer fine particles in the continuous reactor, and injecting the discharge liquid into a reactor in which the stabilizing solution is stirred, and the biodegradable polymer fine particles And separating the particles.

In the step of preparing the aqueous solution, the biodegradable polymer fine particles may be contained 10 to 80% by weight based on the aqueous solution.

When providing carboxymethyl cellulose to the aqueous solution, the biodegradable polymer fine particles may be 30 to 60% by weight based on the aqueous solution containing the carboxymethyl cellulose.

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

Further comprising sterilizing the freeze-dried biodegradable polymer fine particles. The sterilizing step may be performed by gamma ray sterilization, ethylene oxide sterilization, or reduced pressure sterilization.

The injection may be used as a facelift filler, a male implant, or a treatment for incontinence.

The reactor for preparing biodegradable polymer microparticles according to an embodiment of the present invention is a continuous reactor in which biodegradable polymer microparticles are formed by Kuet Taylor fluid flow, a first inlet for introducing an emulsifying solution into the continuous reactor, biodegradable polymer A second inlet for dispersing the dispersed solution into the continuous reactor, a reaction liquid discharge part for discharging a reaction solution containing biodegradable polymer fine particles generated in the continuous reactor, and the biodegradable polymer fine from the reaction solution And a continuous centrifuge to separate the particles.

The continuous reactor includes a reaction unit where the biodegradable polymer fine particles are generated, a stirring motor disposed on one side of the cylinder, and a stirring rod spaced apart from the reaction unit and driven by the stirring motor.

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

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

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

According to the method of manufacturing an injection according to an embodiment of the present invention, biodegradable polymer microparticles which are easy to mass-produce and easy to control the size and shape of biodegradable polymer microparticles can be used for injection.

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

1 is a flow chart schematically showing a method of manufacturing an injection according to an embodiment of the present invention.

Figure 2 is a flow chart schematically showing a method for producing biodegradable polymer fine particles 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 fine particles of Examples 1 to 3.

5 is an electron micrograph of biodegradable polymer fine particles according to the residence time in a continuous reactor.

Figure 6 is a photograph of the biodegradable polymer fine particles according to the stirring speed.

7 is a photograph taken with an electron microscope of x200 magnification of the biodegradable polymer fine particles prepared according to Example 1 of the present invention.

8 is a photograph taken with an electron microscope at a magnification of x1,000 of biodegradable polymer microparticles prepared according to Example 1 of the present invention.

9 is a photograph taken with an electron microscope of x5,000 magnification of the biodegradable polymer fine particles prepared according to Example 1 of the present invention.

10 is a photograph taken with an electron microscope of x10,000 magnification of the biodegradable polymer fine particles prepared according to Example 1 of the present invention.

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 to ensure that the disclosed contents are thorough and complete and that the spirit of the present invention is sufficiently conveyed to those skilled in the art.

In describing each drawing, similar reference numerals are used for similar components. In the accompanying drawings, the dimensions of the structures are shown to be enlarged than the actual for clarity of the present 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 other components. For example, the first component may be referred to as a second component without departing from the scope of the present invention, and similarly, the second component may be referred to as a first component. Singular expressions include plural expressions unless the context clearly indicates otherwise.

In this application, the terms "include" or "have" are intended to indicate the presence of features, numbers, steps, actions, components, parts or combinations thereof described in the specification, one or more other features. It should be understood that the existence or addition possibilities of fields or numbers, steps, actions, components, parts or combinations thereof are not excluded in advance. In addition, when a part such as a layer, film, region, plate, etc. is said to be "on" another part, this includes not only the case of being "directly above" another part but also another part in the middle. Conversely, when a portion of a layer, film, region, plate, or the like is said to be “under” another portion, this includes not only the case “underneath” another portion, but also another portion in the middle.

Unless otherwise specified, all numbers, values, and/or expressions expressing the amounts of ingredients, reaction conditions, polymer compositions, and blends used herein are those numbers that occur in obtaining these values, among others. As these are approximations that reflect the various uncertainties of the measurement, it should be understood that in all cases they are modified by the term "about". In addition, when numerical ranges are disclosed in this description, these ranges are continuous, and include all values from the minimum value in 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 described range including the described endpoints of the range. For example, a range of “5 to 10” includes values of 5, 6, 7, 8, 9, and 10, as well as any subrange of 6 to 10, 7 to 10, 6 to 9, 7 to 9, and the like. It will be understood to include, and include any value between integers pertinent to the stated range of ranges such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also, for example, the range of “10% to 30%” is 10% to 15%, 12% to 10%, 11%, 12%, 13%, etc., and all integers including up to 30%. It will be understood that it includes any subranges such as 18%, 20% to 30%, etc., and also includes any value between valid integers within the scope of the stated range, such as 10.5%, 15.5%, 25.5%, and the like.

First, a method of manufacturing biodegradable polymer fine particles and a method of manufacturing an injection containing the same will be described.

1 is a flow chart schematically showing a method of manufacturing an injection according to an embodiment of the present invention. Figure 2 is a flow chart schematically showing a method for producing biodegradable polymer fine particles according to an embodiment of the present invention.

Referring to Figure 1, the preparation method of the injection according to an embodiment of the present invention comprises the steps of preparing an aqueous solution containing biodegradable polymer fine particles (S10), and alginic acid and its salt in the aqueous solution, hyaluronic acid (Hyalurinic acid) and a salt thereof, carboxymethyl cellulose (Carboxylmethyl cellulose) and a salt thereof, Dextran (Dextran) and a salt thereof, collagen (collagen), gelatin (Gelatin), and at least one of elastin (Elastin) is provided, Freeze-drying step (S20). Preparing the aqueous solution (S10) includes preparing biodegradable polymer fine particles. 1 and 2, the step of preparing the biodegradable polymer fine particles is a step of injecting a dispersion solution in which a biodegradable polymer is dispersed in a continuous reactor (S100), and injecting an emulsifying solution into a continuous reactor, a cue Step (S200) of generating biodegradable polymer microparticles through a Taylor fluid flow, discharging a discharge liquid containing biodegradable polymer microparticles from a continuous reactor, and injecting a discharge liquid into a reactor in which the stabilizing liquid is stirred, thereby biodegradable polymer 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 the step of injecting the dispersion solution (S100), the biodegradable polymer is selected from polydioxanone (PDO), polylactic acid (PLA) and its isomers and polycaprolactone (Polycarprolactone, PCL). Polydioxanone can be dissolved in perfluorine alcohol. Perfluorinated alcohol is an alcohol compound having 1 to 6 carbon atoms with 3 to 13 fluorine atoms substituted, for example, 1,1,1,3,3,3-hexafluoro-2-propanol.

The biodegradable polymer may have an average molecular weight of 50,000 to 300,000. If the average molecular weight of the biodegradable polymer is less than 50,000, the decomposition rate is fast, and the value as a biomaterial for the filler decreases. Difficult to make

The content of the biodegradable polymer, based on the dispersion solution, may be 1 to 20% by weight. Outside the above range, due to the high viscosity, it is difficult to form a Kuet Taylor fluid flow upon stirring with the emulsifying solution or when the emulsifying concentration is low, particles cannot be formed.

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

In the step (S100) of injecting the dispersion solution, the dispersion solution further includes a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer. The average molecular weight of the terpolymer may be 7,000 to 15,000. If the average molecular weight of the ternary copolymer is less than 7,000, the surface of the particles is uneven, and if the average molecular weight of the ternary copolymer is more than 15,000, it is difficult to manufacture spherical fine particles due to high viscosity. The content of the terpolymer may be 1 to 20% by weight based on the dispersion solution. If it is outside the above range, it is difficult to control the shape of the biodegradable polymer fine particles generated due to the difference in permeability and viscosity in the particles.

Terpolymers can determine the shape of biodegradable microparticles. The ternary copolymer is adsorbed on the surface of the resulting biodegradable fine particles to create an adsorption film between particles to prevent aggregation between particles.

Next, the emulsion solution is injected into a continuous reactor to generate biodegradable polymer fine particles through a Kuet Taylor fluid flow (S200).

The emulsion solution may include 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 polyvinyl alcohol in water or a mixed solution of water and alkyl alcohol. At this time, the content of polyvinyl alcohol may be included 1 to 10% by weight based on the emulsion solution. Outside the above range, the emulsification of PVA acting as a surfactant is weakened, making it difficult to make fine particles.

The polyvinyl alcohol may have an average molecular weight of 50,000 to 200,000. If the average molecular weight of the ternary copolymer is less than 50,000, emulsification is very poor, and if the average molecular weight of the ternary copolymer is more than 200,000, it is difficult to form a Taylor flow smoothly due to high concentration.

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

When the emulsifying solution is provided to a continuous reactor in which a dispersion solution is injected, emulsification occurs. At this time, the emulsification may be to emulsify for 1 to 30 minutes. When the emulsification is performed in less than 1 minute, the biodegradable polymer fine particles are not sufficiently generated, and when the emulsification is performed for more than 30 minutes, the productivity of the biodegradable polymer fine particles is reduced compared to the external force provided.

At this time, biodegradable polymer fine particles are generated, which is a method of applying a Kuet Taylor fluid flow, not a general mechanical stirring method, for example, a stirring method using a magnetic bar, or a stirring method using a mechanical stirrer or a homogenizer. to be. Compared to the batch agitation method, the cue tail fluid flow has a strong agitation power and, unlike a batch reaction, has an advantage of being proportional to the reaction time and the time passing through the continuous reactor.

The discharge solution is injected into the reactor in which the stabilizer is stirred to stabilize the biodegradable polymer fine particles (S300). The stabilizing solution may be prepared by dissolving polyvinyl alcohol or surfactant in water or a mixed solution of water and alkyl alcohol. When the stabilizing solution contains polyvinyl alcohol, the content of polyvinyl alcohol may be 0.1 to 5% by weight based on the stabilizing solution.

The stabilizer may include 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, and if the average molecular weight of the polyvinyl alcohol is more than 100,000, there is a problem that it is difficult to remove in the washing process. The stabilizing solution may include a single component aqueous solution or a mixed solution of a surfactant and an alkyl alcohol.

The discharge liquid that has passed through the continuous reactor is continuously injected into the reactor in which the previously prepared stabilization solution is being stirred, and then undergoes a stabilization process. The discharge liquid contains fine particles of biodegradable polymer. The continuous reactor may include a pressure reducing device and organic solvent may be removed by the pressure reducing device.

The biodegradable polymer fine particles are separated (S400). The biodegradable polymer fine particles and the solution are separated using a continuous centrifuge or a high-speed stirred centrifuge. The biodegradable polymer fine particles can be washed with alkyl alcohol and water or water alone. As the alkyl alcohol, ethanol may be used.

The biodegradable polymer fine particles can also be classified by size. The biodegradable polymer fine particles separated from the solution can be classified by size using a powder group. For example, biodegradable polymer microparticles can be classified by size using a size sieving machine, either dry or wet.

In the case of wet powder, freeze-drying may be additionally performed to remove water, and then classified.

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

When the size of the biodegradable polymer microparticles is less than 1 μm, when manufacturing the biodegradable polymer microparticles, it is difficult to control the size, and when the size of the biodegradable polymer microparticles exceeds 300 μm, it is not suitable for use as an injection. .

As mentioned above, the method for preparing an injection according to an embodiment of the present invention includes providing an excipient in an aqueous solution containing biodegradable polymer microparticles. Excipients include, for example, alginic acid and its salts, hyaluronic acid and its salts, Carboxylmethyl cellulose and its salts, dextran and its salts, collagen, It may include at least one of gelatin (Gelatin), and elastin (Elastin). The preparation method of the injection according to an embodiment of the present invention includes the step of providing an excipient in an aqueous solution containing biodegradable polymer microparticles and freeze-drying (S20).

In the step (S10) of preparing an aqueous solution, the biodegradable polymer fine particles may be contained 10 to 80% by weight based on the aqueous solution. If 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. If it exceeds 80% by weight, it is difficult to freeze-dry and mix with excipients with a low moisture content.

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

At this time, using a three-roll mill (Three roll mill) it is possible to uniformly disperse the mixed solution of a high viscosity.

The method for preparing an injection according to an embodiment of the present invention may further include sterilizing the lyophilized biodegradable polymer fine particles. The sterilizing step may be, for example, gamma ray sterilization, ethylene oxide sterilization, or pressure sterilization.

The injection may be used as a facelift filler, a male implant, or a therapeutic agent for incontinence. The size of the biodegradable polymer fine particles used in the face molding filler may be 10 to 100 μm. The size of the biodegradable polymer microparticles used in the treatment of male implants or urinary incontinence may be 100 to 300 μm.

Manufacturing method of the injection according to an embodiment of the present invention and the method of manufacturing the biodegradable polymer fine particles according to an embodiment of the present invention, using the Kuet Taylor fluid flow, mass production of biodegradable polymer fine particles is easy , It is easy to control the size and shape of the biodegradable polymer fine particles.

Hereinafter, a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention will be described. Hereinafter, a description will be given of differences between a method for manufacturing an injection according to an embodiment of the present invention and a method for producing biodegradable polymer microparticles according to an embodiment of the present invention, and the same or similar ones are 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, the 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, and a reaction liquid discharge unit (11), and a continuous centrifuge (12). The reactor 100 for producing biodegradable polymer microparticles according to an embodiment of the present invention includes an emulsified solution storage (1), a dispersion solution storage (2), a waste solution outlet (13), and a biodegradable polymer fine particle recovery unit (14). It further includes.

In the continuous reactor 100, biodegradable polymer fine particles are formed by the Kuet 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 solution containing the biodegradable polymer fine particles generated in the continuous reactor 100 is discharged to the reaction solution discharge unit 11. The reaction liquid discharged to the reaction liquid discharge unit 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 outlet (13). The biodegradable polymer fine particles are recovered from the biodegradable polymer fine particle recovery unit 14.

The continuous reactor 100 includes an inner cylinder 5, a temperature control unit, an outer cylinder 7, and a reaction unit 8. The inner cylinder 5 rotates at high speed to serve to stir the reaction solution. The outer cylinder 7 is equipped with an inlet outlet, etc., and serves to protect the reaction interior. The temperature control unit 6 is connected to a cooling device between the reaction unit 8 and the outer cylinder 7 to control the temperature. The reaction unit 8 is an empty space in which the reaction solution is filled, whereby biodegradable polymer fine particles are formed by the Coet Taylor fluid flow.

The continuous reactor 100 further includes a stirring motor 3, a drive shaft 4, and a stirring rod. The stirring motor 3 may be to 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 stirring rod is driven by receiving an external force from the stirring motor 3 around the driving shaft 4. The stirring rod is separated 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 emulsion solution and the dispersion solution are not sufficiently stirred, and if it is more than 2000 rpm, the stirring efficiency is not high compared to the external force provided.

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

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

Hereinafter, the present invention will be described in more detail through specific examples. The following examples are only examples for helping the 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 ternary copolymer F-127 (manufactured by BASF, average molecular weight 12,600), and 60 g of ternary copolymer F-68 (manufactured by BASF, average molecular weight 8,400) It was added to 1500 mL of isopropanol (Hexafluoroisopropanol) and stirred to mix.

While the polydioxanone dispersion solution was introduced into a continuous reactor using a Kuet Taylor fluid flow at a rate of 10 mL/min, 7,500 mL of a 5% PVA (average molecular weight 130,000) solution was simultaneously introduced at a rate of 50 mL/mL. The residence time in the reactor was adjusted so that the reaction solution could be discharged after maintaining 10 minutes.

The discharged reaction solution was stirred while putting in a 7,500 mL solution of 1% PVA (average molecular weight 93,500). After all the discharged liquid was added, hexafluoroisopropanol was removed while stirring for 24 hours under reduced pressure to stabilize the resulting biodegradable polymer fine particles.

The reaction solution containing the biodegradable polymer microparticles was subjected to solid-liquid separation by centrifugation to obtain polydioxanone microparticles from which impurities were removed. This was again washed 5 times with 900 mL distilled water, followed by centrifugation to completely remove residual impurities and freeze-drying to complete polydioxanone fine particles, biodegradable polymer fine particles.

At this time, biodegradable polymer particles were prepared while changing the flow rates of the continuous reactors to 500 rpm, 1500 rpm, and 2000 rpm.

In addition, biodegradable polymer particles were prepared while varying the residence time in the reactor of the polymer dispersion solution and the emulsifying solution input to the continuous reactor from 1 to 10 minutes.

Example 2: Preparation of polylactic acid fine particles

It was carried out in the same manner as in Example 1, except that polylactic acid (Polylactic acid) instead of polydioxanone and Dichloromethane instead of hexafluoroisopropanol were used.

Example 3: Preparation of polylactic acid fine particles

It was carried out in the same manner as in Example 1, except that dichloromethane was used instead of polycaprolactone and hexafluoroisopropanol instead of polydioxanone.

Property measurement

1. Figure 4 is an electron micrograph of the biodegradable polymer fine particles of Examples 1 to 3. Referring to FIG. 4, when the biodegradable polymer microparticles were produced by the production method of the present invention, it was confirmed that the biodegradable polymer microparticles of the same type could be formed regardless of the type of biodegradable polymer.

2. FIG. 5 is an electron micrograph of biodegradable polymer fine particles according to the residence time in a continuous reactor. It was confirmed that the longer the residence time, the smoother the production of biodegradable polymer fine particles.

3. Figure 6 is a photograph of the biodegradable polymer fine particles according to the stirring speed. It was confirmed that the faster the stirring speed, the smoother the biodegradable polymer fine particles could be produced.

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

Referring to Figures 7 to 10, it can be seen that the biodegradable polymer microparticles produced by the method for producing biodegradable polymer microparticles of one embodiment of the present invention are easy to control in size and shape even when produced in large quantities. .

The embodiments of the present invention have been described above with reference to the accompanying drawings, but those of ordinary skill in the art to which the present invention pertains may be implemented in other specific forms without changing the present invention to its technical spirit or essential features. You will understand that there is. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (18)

1. Injecting a dispersion solution in which a biodegradable polymer is dispersed in a continuous reactor;

   Injecting an emulsifying solution into the continuous reactor to produce biodegradable polymer microparticles with a Kuet Taylor fluid flow;

   Stabilizing the biodegradable polymer microparticles by discharging a discharge liquid containing the biodegradable polymer microparticles from the continuous reactor and injecting the discharge liquid into a reactor in which a stabilizing liquid is stirred; And

   Separating the biodegradable polymer fine particles; Method for producing biodegradable polymer fine particles comprising a.
2. According to claim 1,

   In the step of injecting the dispersion solution,

   The biodegradable polymer is polydioxanone (PDO), polylactic acid (PLA) and its isomers, polyglycolic acid (PGA) and its isomers, and polycaprolactone (Polycarprolactone, PCL) Is selected,

   The biodegradable polymer has an average molecular weight of 50,000 to 300,000.
3. According to claim 1,

   In the step of injecting the dispersion solution,

   The dispersion solution contains a solvent,

   The solvent

   Perfluorinated alcohol, DMF (N,N-Dimethylforamide), DMSO (Dimethyl sulfoxide), at least one of chlorinated hydrocarbons, hydrocarbons and alkyl alcohols,

   The content of the biodegradable polymer, based on the dispersion solution, 1 to 20% by weight of the method for producing biodegradable polymer fine particles.
4. According to claim 1,

   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 ternary copolymer is 7,000 to 15,000,

   The content of the ternary copolymer, based on the dispersion solution, 1 to 20% by weight of the method for producing biodegradable polymer fine particles.
5. According to claim 1,

   In the step of generating the biodegradable polymer fine particles,

   The size of the biodegradable polymer microparticles is 1 to 300㎛ the method for producing biodegradable polymer microparticles.
6. According to claim 1,

   The biodegradable polymer fine particles

   A method for producing biodegradable polymer microparticles that is used in facial cosmetic fillers, male implants, or incontinence treatments.
7. According to claim 1,

   In the step of generating the biodegradable polymer fine particles,

   The emulsifying solution is polyvinyl alcohol (Polyvinyl alcohol), polyoxyethylene sorbitan and its salt, soybean lecithin (soybean Lecithin), and monoglyceride (monoglyceride) at least one of the manufacturing method of the fine particles of the polymer.
8. According to claim 1,

   In the step of stabilizing the biodegradable polymer fine particles,

   The stabilizing solution is a polyvinyl alcohol (Polyvinyl alcohol), polyoxyethylene sorbitan and its salt, soybean lecithin (soybean Lecithin), and monoglyceride (monoglyceride) at least one of the method of manufacturing fine particles of the polymer.
9. Preparing an aqueous solution containing the biodegradable polymer fine particles prepared by claim 1; And

   Alginic acid and its salt, hyaluronic acid and its salt, Carboxylmethyl cellulose and its salt, Dextran and its salt, collagen, gelatin in the aqueous solution ), and at least one of elastin, and freeze-dried.
10. The method of claim 9,

    In the step of preparing the aqueous solution,

    The biodegradable polymer fine particles are 10 to 80% by weight based on the aqueous solution, the method of manufacturing an injection.
11. The method of claim 9,

    When providing carboxymethyl cellulose to the aqueous solution,

    The biodegradable polymer microparticles, 30 to 60% by weight based on the aqueous solution containing the carboxymethyl cellulose, the injection method of the injection.
12. The method of claim 9,

    The size of the biodegradable polymer microparticles is 10 to 300㎛ injection method.
13. The method of claim 9,

    Further comprising the step of sterilizing the lyophilized biodegradable polymer fine particles,

    The sterilizing step

    Gamma-ray sterilization, ethylene oxide sterilization, or a method for producing an injection that is performed by sterilization under reduced pressure.
14. The method of claim 9,

    The injection is a method of manufacturing an injection that is used as a facial cosmetic filler, male implant, or incontinence treatment.
15. A continuous reactor in which biodegradable polymer fine particles are formed by a Kuet Taylor fluid flow;

    A first inlet for introducing an emulsifying solution into the continuous reactor;

    A second inlet for introducing a dispersion solution in which a biodegradable polymer is dispersed into the continuous reactor;

    A reaction solution discharge unit for discharging a reaction solution containing biodegradable polymer fine particles generated in the continuous reactor; And

    A continuous reactor for separating the biodegradable polymer microparticles from the reaction solution; Reactor for the production of biodegradable polymer microparticles comprising a.
16. The method of claim 15,

    The continuous reactor

    A reaction unit in which the biodegradable polymer fine particles are generated;

    A stirring motor disposed on one side of the cylinder; And

    A reactor for producing biodegradable polymer fine particles that is spaced apart from the reaction unit and includes a stirring rod driven by the stirring motor.
17. The method of claim 16,

    The stirring motor

    A reactor for producing biodegradable polymer microparticles having a rotational speed of 10 to 2000 rpm.
18. The method of claim 16,

    The first inlet is a reactor for producing biodegradable polymer fine particles that are arranged at a quarter of the reaction part.

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