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

Method for manufacturing biodegradable polymeric microparticles by using continuous reaction, method for manufacturing injection comprising same, and reactor for manufacturing biodegradable polymeric microparticles Download PDF

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Publication number
WO2020122268A1
WO2020122268A1 PCT/KR2018/015668 KR2018015668W WO2020122268A1 WO 2020122268 A1 WO2020122268 A1 WO 2020122268A1 KR 2018015668 W KR2018015668 W KR 2018015668W WO 2020122268 A1 WO2020122268 A1 WO 2020122268A1
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biodegradable polymer
fine particles
solution
polymer fine
reactor
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PCT/KR2018/015668
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French (fr)
Korean (ko)
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권한진
문호상
정민욱
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주식회사 울트라브이
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Priority to PCT/KR2018/015668 priority Critical patent/WO2020122268A1/en
Publication of WO2020122268A1 publication Critical patent/WO2020122268A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • DMSO Dimethyl Sulfoxide
  • 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.
  • 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.
  • U.S. Patent No. 5863996 discloses a batch production process of polymer particles.
  • 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.
  • 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 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.
  • the biodegradable polymer is selected from polydioxanone (PDO), polylactic acid (PLA) and its isomers and polycaprolactone (PCL), and the biodegradable
  • PDO polydioxanone
  • PLA polylactic acid
  • PCL polycaprolactone
  • the average molecular weight of the sex polymer may be 50,000 to 300,000.
  • 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.
  • 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.
  • the size of the biodegradable polymer microparticles may be 1 to 300 ⁇ m.
  • the biodegradable polymer fine particles may be used for facial molding fillers, male implants, or urinary incontinence treatments.
  • the emulsifying solution includes at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salts thereof, soybean lecithin, and monoglyceride. It may be.
  • 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 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.
  • the biodegradable polymer fine particles may be contained 10 to 80% by weight based on 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 ⁇ m.
  • 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 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.
  • biodegradable polymer microparticles 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.
  • 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.
  • biodegradable polymer microparticles 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.
  • FIG. 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.
  • FIG 3 is a cross-sectional view schematically showing a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention.
  • 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.
  • Example 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.
  • Example 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.
  • Example 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.
  • Example 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • variable includes all values within the described range including the described endpoints of the range.
  • 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.
  • 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.
  • FIG. 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.
  • the preparation method of the injection 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.
  • 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).
  • a dispersion solution in which a biodegradable polymer is dispersed is injected into a continuous reactor (S100).
  • the biodegradable polymer is selected from polydioxanone (PDO), polylactic acid (PLA) and its isomers and polycaprolactone (Polycarprolactone, PCL).
  • PDO polydioxanone
  • PLA polylactic acid
  • PCL polycaprolactone
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • a 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).
  • the emulsifying solution 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • biodegradable polymer microparticles can be classified by size using a size sieving machine, either dry or wet.
  • 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 ⁇ m.
  • the size of the biodegradable polymer microparticles may be, for example, a particle size of the biodegradable polymer microparticles.
  • the size of the biodegradable polymer microparticles is less than 1 ⁇ m, when manufacturing the biodegradable polymer microparticles, it is difficult to control the size, and when the size of the biodegradable polymer microparticles exceeds 300 ⁇ m, it is not suitable for use as an injection. .
  • 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).
  • 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.
  • 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.
  • 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 ⁇ m.
  • the size of the biodegradable polymer microparticles used in the treatment of male implants or urinary incontinence may be 100 to 300 ⁇ m.
  • FIG 3 is a cross-sectional view schematically showing a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention.
  • 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.
  • 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 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.
  • 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.
  • biodegradable polymer particles were prepared while changing the flow rates of the continuous reactors to 500 rpm, 1500 rpm, and 2000 rpm.
  • 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.
  • FIG. 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.
  • 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.
  • 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.
  • 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.
  • 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. .

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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

연속반응을 이용한 생분해성 고분자 미세 입자의 제조 방법, 이를 포함하는 주사제의 제조 방법, 및 생분해성 고분자 미세 입자의 제조용 반응기Method for producing biodegradable polymer microparticles using a continuous reaction, method for preparing an injection containing the same, and reactor for producing biodegradable polymer microparticles
본 발명은 생분해성 고분자 미세 입자의 제조 방법, 이를 포함하는 주사제의 제조 방법, 및 생분해성 고분자 미세 입자의 제조용 반응기에 관한 것으로, 더욱 상세하게는 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이한 생분해성 고분자 미세 입자의 제조 방법, 이를 포함하는 주사제의 제조 방법, 및 생분해성 고분자 미세 입자의 제조용 반응기에 관한 것이다.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.
현재 이용되는 주사제용 생분해성 고분자 미세 입자의 제조방법은 유화 용매 증발법(Emulsification Solvent Evaporation Method), 스프레이 건조법(Spray dry Method), 기계적 분쇄 방법(Mechanical milling Method) 등이 있다.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.
유화 용매 증발법(Emulsification-Solvent Evaporation Method)은 유기 용매에 고분자를 녹인 분산 용액과 계면활성제가 포함된 유화 용액을 강하게 교반시켜 미세 입자를 형성하는 방법이다. 에멀젼은 열역학적으로 불안정한 상태이기 때문에 뭉침(Coalescence), 융합(Fusion), 상분리(Creaming) 등의 과정을 거쳐 수상과 유기상이 서로 분리되려고 하기 때문에 강력한 교반력이 필요하기 때문에 회분식 반응으로는 대량합성이 어려운 단점이 있다.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.
한국 특허 번호 제10-1418888호를 참조하면, 지방족 폴리에스테르 고분자를 녹인 유기상에 발포성 염을 녹인 수용액을 첨가하여 친수성 계면활성제를 포함하는 수용액에 재분산, 유화시키는 이중 유화단계를 포함하는 미립 담체 제조방법도 알려져 있다 다만, 상기 미립 담체는 생분해성, 높은 공극율을 가지고 있으나 기계적 강도가 약하고, 강력한 교반력이 필요하여 회분식반응(Batch reaction)을 이용한 양산 공정의 적용에 어려움이 있다.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.
한국 특허 번호 제10-1725279를 참조하면, 공업적으로 대량 생산이 가능한 방법으로 스프레이 드라이(Spray dry) 방법이 이용되고 있다. 생분해성 고분자를 DMSO(Dimethyl Sulfoxide)에 용해시킨 후 저온의 탄화수소 용액에 분사시켜 DMSO 및고분자 용액을 냉동시킨 후 저온의 염 수용액에서 DMSO를 제거함으로서 생분해성 고분자 미세 입자를 제조하는 방법이다. 다만 상기 생분해성 고분자 미세 입자는 높은 공극율, 우수한 기계적 강도를 가지고 있으나 과량의 유기 용매를 사용하여 제조 원가가 매우 높고 넓은 입도분포를 가지고 있어 입자 크기의 제어가 어렵다는 문제를 가지고 있다.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.
따라서, 생체 적합성, 생분해성, 입자모양, 입자크기, 기계적 강도가 우수한 고분자 미세 입자를 보다 쉽고 저렴하게 제조할 수 있는 대량합성 공정개발이 요구되어 왔다.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.
현재까지 생분해성 고분자 미세 입자들은 주로 회분식 공정(batch process)으로 제조되고 있고 있는데, 이는 목적하는 크기, 가교도 및 구조를 가지는 단분산 고분자 입자를 제조하기에는 제약이 크다.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.
예를 들면, 미국 등록 특허 제5863996호는 고분자 입자의 회분식 제조 공정을 개시하고 있다. 이와 같은 고분자 입자의 회분식 제조 공정에서는 목적물을 얻기 위하여, 단량체 또는 단량체를 포함하는 반응물을 회분식 반응기 내로 공급하고, 중합 반응을 수행하는 공정에 이어서, 중합체의 냉각, 제거 및 세척 공정 등의 등의 다수의 공정이 필요하다. 이에 따라, 회분식 공정에서는 고분자 입자를 제조하는 데에 장시간이 소요될 뿐만 아니라, 제조 단가도 크게 상승한다.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.
고분자 입자가 각종 용도에 효과적으로 적용되기 위해서는 단분산성(monodispersity) 등의 물성이 우수할 필요가 있다. 그러나, 종래 공정에서는 다분산 입자가 생성되는 등 제조된 입자의 물성을 균일하게 유지하는 것이 곤란하다.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.
또한 기술적으로 원하는 모양과 크기의 입자를 결정하는 유화 단계에서 회분식반응기의 일반적인 교반 방법으로는 제조하기 어렵다는 단점을 가진다. 이러한 문제를 일으키는 가장 큰 원인은 유기 용제에 용해된 고분자 용액과 물에 녹여진 유화 용액이 균일한 상태를 유지하지 못하고 분리되는 현상에서 주 원인을 찾을 수 있다. 이는 유기용매와 물이 빠르게 섞이지 못하고 분리되며, 일부가 유화되지 못해 입자를 생성하지 못하거나 모양이 일그러지기 때문이다.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.
본 발명의 목적은 생분해성 고분자 미세 입자의 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이한 생분해성 고분자 미세 입자의 제조 방법을 제공하는 것이다.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.
본 발명의 목적은 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이한 생분해성 고분자 미세 입자를 포함하는 주사제의 제조 방법을 제공하는 것이다.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.
본 발명의 목적은 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이한 생분해성 고분자 미세 입자를 제조할 수 있는 생분해성 고분자 미세 입자의 제조용 반응기를 제공하는 것이다.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.
본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조 방법은 연속 반응기에, 생분해성 고분자가 분산된 분산 용액을 주입하는 단계, 유화 용액을 상기 연속 반응기에 주입하여, 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자를 생성하는 단계, 상기 연속 반응기에서 상기 생분해성 고분자 미세 입자를 포함하는 토출액을 토출하고, 안정화액이 교반된 반응기에 상기 토출액을 주입하여, 상기 생분해성 고분자 미세 입자를 안정화하는 단계, 및 상기 생분해성 고분자 미세 입자를 분리하는 단계를 포함한다.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.
상기 분산 용액을 주입하는 단계에서, 상기 생분해성 고분자는 폴리디옥사논(Polydioxanone, PDO), 폴리락트산(Polylactic acid, PLA) 및 그 이성질체 및 폴리카프로락톤(Polycarprolactone, PCL) 중에서 선택되고, 상기 생분해성 고분자의 평균 분자량은 50,000 내지 300,000인 것일 수 있다.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.
상기 분산 용액을 주입하는 단계에서, 상기 분산 용액은 용매를 포함한다. 상기 용매는 과불소알콜, DMF (N,N-Dimethylforamide), DMSO (Dimethyl sulfoxide), 염소화탄화수소, 탄화수소 및 알킬알콜 중 적어도 하나를 포함한다. 상기 생분해성 고분자의 함량은, 상기 분산 용액을 기준으로, 1 내지 20 중량%인 것일 수 있다.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.
상기 분산 용액을 주입하는 단계에서, 상기 분산 용액은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 더 포함한다. 상기 삼원 공중합체의의 평균분자량은 7,000 내지 15,000이고, 상기 삼원 공중합체의 함량은, 상기 분산 용액을 기준으로, 1 내지 20 중량%인 것일 수 있다.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.
상기 생분해성 고분자 미세 입자를 생성하는 단계에서, 상기 생분해성 고분자 미세 입자의 크기는 1 내지 300㎛인 것일 수 있다.In the step of generating the biodegradable polymer microparticles, the size of the biodegradable polymer microparticles may be 1 to 300 μm.
상기 생분해성 고분자 미세 입자는 안면 성형 필러, 남성 보형물, 또는 요실금 치료제에 사용되는 것일 수 있다.The biodegradable polymer fine particles may be used for facial molding fillers, male implants, or urinary incontinence treatments.
상기 생분해성 고분자 미세 입자를 생성하는 단계에서, 상기 유화 용액은 폴리비닐알콜(Polyvinyl alcohol), 폴리옥시에틸렌 솔비탄 및 그 염, 대두 레시틴(soybean Lecithin), 및 모노글리세리드(monoglyceride 중 적어도 하나를 포함하는 것일 수 있다.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.
상기 생분해성 고분자 미세 입자를 안정화하는 단계에서, 상기 안정화액은 폴리비닐알콜(Polyvinyl alcohol), 폴리옥시에틸렌 솔비탄 및 그 염, 대두 레시틴(soybean Lecithin), 및 모노글리세리드(monoglyceride 중 적어도 하나를 포함하는 것In 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
본 발명의 일 실시예에 따른 주사제의 제조 방법은 생분해성 고분자 미세 입자를 포함하는 수용액을 준비하는 단계, 및 상기 수용액에 알긴산(Alginic acid) 및 그 염, 히알루론산(Hyalurinic acid) 및 그 염, 카르복시메틸 셀룰로오스(Carboxylmethyl cellulose) 및 그 염, 덱스트란(Dextran) 및 그 염, 콜라겐(collagen), 젤라틴(Gelatin), 및 엘라스틴(Elastin) 중 적어도 하나를 제공하고, 동결 건조하는 단계를 포함한다. 상기 수용액을 준비하는 단계는 연속 반응기에, 생분해성 고분자가 분산된 분산 용액을 주입하는 단계, 유화 용액을 상기 연속 반응기에 주입하여, 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자를 생성하는 단계, 상기 연속 반응기에서 상기 생분해성 고분자 미세 입자를 포함하는 토출액을 토출하고, 안정화액이 교반된 반응기에 상기 토출액을 주입하여, 상기 생분해성 고분자 미세 입자를 안정화하는 단계, 및 상기 생분해성 고분자 미세 입자를 분리하는 단계를 포함한다.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.
상기 수용액을 준비하는 단계에서, 상기 생분해성 고분자 미세 입자는 상기 수용액을 기준으로 10 내지 80 중량% 포함되는 것일 수 있다.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.
상기 수용액에 카르복시메틸 셀룰로오스를 제공할 때, 상기 생분해성 고분자 미세 입자는 상기 카르복시메틸 셀룰로오스가 포함된 상기 수용액을 기준으로, 30 내지 60 중량% 포함되는 것일 수 있다.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.
상기 생분해성 고분자 미세 입자의 크기는 10 내지 300㎛인 것일 수 있다.The size of the biodegradable polymer fine particles may be 10 to 300㎛.
상기 동결 건조한 생분해성 고분자 미세 입자를 멸균하는 단계를 더 포함한다. 상기 멸균하는 단계는 감마선 멸균, 에틸렌옥사이드 멸균, 또는 감압 멸균으로 수행되는 것일 수 있다.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.
상기 주사제는 안면 성형 필러, 남성 보형물, 또는 요실금 치료제로 사용되는 것일 수 있다.The injection may be used as a facelift filler, a male implant, or a treatment for incontinence.
본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기는 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자가 형성되는 연속 반응기, 유화 용액을 상기 연속 반응기에 투입하는 제1 투입구, 생분해성 고분자가 분산된 분산 용액을 상기 연속 반응기에 투입하는 제2 투입구, 상기 연속 반응기에서 생성된 생분해성 고분자 미세 입자를 포함하는 반응액을 토출하는 반응액 토출부, 및 상기 반응액에서 상기 생분해성 고분자 미세 입자를 분리하는 연속 원심 분리기를 포함한다.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.
상기 연속 반응기는 상기 생분해성 고분자 미세 입자가 생성되는 반응부, 상기 실린더의 일측에 배치되는 교반 모터, 및 상기 반응부와 이격되고, 상기 교반 모터에 의해 구동되는 교반봉을 포함한다.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.
상기 교반 모터는 10 내지 2000rpm의 회전 속도를 갖는 것일 수 있다.The stirring motor may have a rotation speed of 10 to 2000rpm.
상기 제1 투입구는 상기 반응부의 1/4 지점에 배치되는 것일 수 있다.The first inlet may be disposed at a quarter of the reaction unit.
본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조 방법에 의하면, 생분해성 고분자 미세 입자의 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이하다.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.
본 발명의 일 실시예에 따른 주사제의 제조 방법에 의하면 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이한 생분해성 고분자 미세 입자를 주사제에 활용할 수 있다.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.
본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기에 의하면 생분해성 고분자 미세 입자의 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이하다.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.
도 1은 본 발명의 일 실시예에 따른 주사제의 제조 방법을 개략적으로 나타낸 순서도이다.1 is a flow chart schematically showing a method of manufacturing an injection according to an embodiment of the present invention.
도 2는 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조 방법을 개략적으로 나타낸 순서도이다.Figure 2 is a flow chart schematically showing a method for producing biodegradable polymer fine particles according to an embodiment of the present invention.
도 3은 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기를 개략적으로 나타낸 단면도이다.3 is a cross-sectional view schematically showing a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention.
도 4는 실시예 1 내지 3의 생분해성 고분자 미세 입자를 촬영한 전자 현미경 사진이다.4 is an electron micrograph of the biodegradable polymer fine particles of Examples 1 to 3.
도 5는 연속 반응기 내에서의 체류 시간에 따른 생분해성 고분자 미세 입자를 촬영한 전자 현미경 사진이다.5 is an electron micrograph of biodegradable polymer fine particles according to the residence time in a continuous reactor.
도 6은 교반 속도에 따른 생분해성 고분자 미세 입자를 촬영한 사진이다.Figure 6 is a photograph of the biodegradable polymer fine particles according to the stirring speed.
도 7은 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x200 배율의 전자현미경으로 촬영한 사진이다.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.
도 8은 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x1,000 배율의 전자현미경으로 촬영한 사진이다.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.
도 9는 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x5,000 배율의 전자현미경으로 촬영한 사진이다.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.
도 10은 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x10,000 배율의 전자현미경으로 촬영한 사진이다.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.
이상의 본 발명의 목적들, 다른 목적들, 특징들 및 이점들은 첨부된 도면과 관련된 이하의 바람직한 실시예들을 통해서 쉽게 이해될 것이다. 그러나 본 발명은 여기서 설명되는 실시예들에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 실시예들은 개시된 내용이 철저하고 완전해질 수 있도록 그리고 통상의 기술자에게 본 발명의 사상이 충분히 전달될 수 있도록 하기 위해 제공되는 것이다.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.
각 도면을 설명하면서 유사한 참조부호를 유사한 구성요소에 대해 사용하였다. 첨부된 도면에 있어서, 구조물들의 치수는 본 발명의 명확성을 위하여 실제보다 확대하여 도시한 것이다. 제1, 제2 등의 용어는 다양한 구성요소들을 설명하는데 사용될 수 있지만, 상기 구성요소들은 상기 용어들에 의해 한정되어서는 안 된다. 상기 용어들은 하나의 구성요소를 다른 구성요소로부터 구별하는 목적으로만 사용된다. 예를 들어, 본 발명의 권리 범위를 벗어나지 않으면서 제1 구성요소는 제2 구성요소로 명명될 수 있고, 유사하게 제2 구성요소도 제1 구성요소로 명명될 수 있다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다.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.
본 출원에서, "포함하다" 또는 "가지다" 등의 용어는 명세서 상에 기재된 특징, 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 숫자, 단계, 동작, 구성요소, 부분품 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다. 또한, 층, 막, 영역, 판 등의 부분이 다른 부분 "상에" 있다고 할 경우, 이는 다른 부분 "바로 위에" 있는 경우뿐만 아니라 그 중간에 또 다른 부분이 있는 경우도 포함한다. 반대로 층, 막, 영역, 판 등의 부분이 다른 부분 "하부에" 있다고 할 경우, 이는 다른 부분 "바로 아래에" 있는 경우뿐만 아니라 그 중간에 또 다른 부분이 있는 경우도 포함한다.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.
달리 명시되지 않는 한, 본 명세서에서 사용된 성분, 반응 조건, 폴리머 조성물 및 배합물의 양을 표현하는 모든 숫자, 값 및/또는 표현은, 이러한 숫자들이 본질적으로 다른 것들 중에서 이러한 값을 얻는 데 발생하는 측정의 다양한 불확실성이 반영된 근사치들이므로, 모든 경우 "약"이라는 용어에 의해 수식되는 것으로 이해되어야 한다. 또한, 본 기재에서 수치범위가 개시되는 경우, 이러한 범위는 연속적이며, 달리 지적되지 않는 한 이러한 범 위의 최소값으로부터 최대값이 포함된 상기 최대값까지의 모든 값을 포함한다. 더 나아가, 이러한 범위가 정수를 지칭하는 경우, 달리 지적되지 않는 한 최소값으로부터 최대값이 포함된 상기 최대값까지를 포함하는 모든 정수가 포함된다.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.
본 명세서에 있어서, 범위가 변수에 대해 기재되는 경우, 상기 변수는 상기 범위의 기재된 종료점들을 포함하는 기재된 범위 내의 모든 값들을 포함하는 것으로 이해될 것이다. 예를 들면, "5 내지 10"의 범위는 5, 6, 7, 8, 9, 및 10의 값들뿐만 아니라 6 내지 10, 7 내지 10, 6 내지 9, 7 내지 9 등의 임의의 하위 범위를 포함하고, 5.5, 6.5, 7.5, 5.5 내지 8.5 및 6.5 내지 9 등과 같은 기재된 범위의 범주에 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다. 또한 예를 들면, "10% 내지 30%"의 범위는 10%, 11%, 12%, 13% 등의 값들과 30%까지를 포함하는 모든 정수들뿐만 아니라 10% 내지 15%, 12% 내지 18%, 20% 내지 30% 등의 임의의 하위 범위를 포함하고, 10.5%, 15.5%, 25.5% 등과 같이 기재된 범위의 범주 내의 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다.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.
먼저, 생분해성 고분자 미세 입자의 제조 방법, 이를 포함하는 주사제의 제조 방법에 대하여 설명한다.First, a method of manufacturing biodegradable polymer fine particles and a method of manufacturing an injection containing the same will be described.
도 1은 본 발명의 일 실시예에 따른 주사제의 제조 방법을 개략적으로 나타낸 순서도이다. 도 2는 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조 방법을 개략적으로 나타낸 순서도이다.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.
도 1을 참조하면, 본 발명의 일 실시예에 따른 주사제의 제조 방법은 생분해성 고분자 미세 입자를 포함하는 수용액을 준비하는 단계(S10), 및 수용액에 알긴산(Alginic acid) 및 그 염, 히알루론산(Hyalurinic acid) 및 그 염, 카르복시메틸 셀룰로오스(Carboxylmethyl cellulose) 및 그 염, 덱스트란(Dextran) 및 그 염, 콜라겐(collagen), 젤라틴(Gelatin), 및 엘라스틴(Elastin) 중 적어도 하나를 제공하고, 동결 건조하는 단계(S20)를 포함한다. 수용액을 준비하는 단계(S10)는 생분해성 고분자 미세 입자를 준비하는 단계를 포함한다. 도 1 및 도 2를 참조하면, 생분해성 고분자 미세 입자를 준비하는 단계는 연속 반응기에, 생분해성 고분자가 분산된 분산 용액을 주입하는 단계(S100), 유화 용액을 연속 반응기에 주입하여, 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자를 생성하는 단계(S200), 연속 반응기에서 생분해성 고분자 미세 입자를 포함하는 토출액을 토출하고, 안정화액이 교반된 반응기에 토출액을 주입하여, 생분해성 고분자 미세 입자를 안정화하는 단계(S300), 및 생분해성 고분자 미세 입자를 분리하는 단계(S400)를 포함한다.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).
먼저, 연속 반응기에, 생분해성 고분자가 분산된 분산 용액을 주입한다(S100).First, a dispersion solution in which a biodegradable polymer is dispersed is injected into a continuous reactor (S100).
분산 용액을 주입하는 단계(S100)에서, 생분해성 고분자는 폴리디옥사논(Polydioxanone, PDO), 폴리락트산(Polylactic acid, PLA) 및 그 이성질체 및 폴리카프로락톤(Polycarprolactone, PCL) 중에서 선택된다. 폴리디옥사논(Polydioxanone)은 과불소알콜류에 녹일 수 있다. 과불소알콜은 불소원자가 3 내지 13개 치환된 탄소수 1 내지 6의 알콜화합물로, 예를 들면 1,1,1,3,3,3-헥사플루오로-2-프로판올이 포함될 수 있다.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.
생분해성 고분자의 평균 분자량은 50,000 내지 300,000인 것일 수 있다. 생분해성 고분자의 평균 분자량은 50,000 미만이면 분해 속도가 빨라 필러용 생체소재로서의 가치가 떨어지고, 생분해성 고분자의 평균 분자량은 300,000 초과이면 높은 점탄성으로 인해 가공이 어려운 관계로 균일한 크기와 품질의 입자를 만들기 어렵다.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
생분해성 고분자의 함량은, 분산 용액을 기준으로, 1 내지 20 중량%인 것일 수 있다. 상기 범위를 벗어나면, 높은 점도로 인해 유화 용액과 교반시 쿠에트 테일러 유체 흐름을 만들기 어렵거나 유화 농도가 낮을 경우 입자를 형성하지 못한다.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.
분산 용액을 주입하는 단계(S100)에서, 분산 용액은 용매를 포함한다. 용매는 과불소알콜, DMF (N,N-Dimethylforamide), DMSO (Dimethyl sulfoxide), 염소화탄화수소, 탄화수소 및 알킬알콜 중 적어도 하나를 포함한다.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.
분산 용액을 주입하는 단계(S100)에서, 분산 용액은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 더 포함한다. 삼원 공중합체의의 평균 분자량은 7,000 내지 15,000일 수 있다. 삼원 공중합체의 평균 분자량은 7,000 미만이면 입자의 표면이 고르지 않고, 삼원 공중합체의 평균 분자량은 15,000 초과이면 높은 점도로 인해 구형의 미세입자 제조가 어렵다. 삼원 공중합체의 함량은, 분산 용액을 기준으로, 1 내지 20 중량%인 것일 수 있다. 상기 범위를 벗어나면, 입자내의 침투성과 점도의 차이로 인해 생성되는 생분해성 고분자 미세 입자의 형상을 제어하기 어렵다.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.
삼원 공중합체는 생분해성 미세 입자의 형태를 결정할 수 있다. 삼원 공중합체는 생성되는 생분해성 미세 입자의 표면에 흡착되어 입자 사이에서 흡착막을 생성하여 입자간의 응집을 막아준다.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.
다음으로, 유화 용액을 연속 반응기에 주입하여, 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자를 생성한다(S200).Next, the emulsion solution is injected into a continuous reactor to generate biodegradable polymer fine particles through a Kuet Taylor fluid flow (S200).
유화 용액은 폴리비닐알콜(Polyvinyl alcohol), 폴리옥시에틸렌 솔비탄 및 그 염, 대두 레시틴(soybean Lecithin), 및 모노글리세리드(monoglyceride 중 적어도 하나를 포함하는 것일 수 있다.The emulsion solution may include at least one of polyvinyl alcohol, polyoxyethylene sorbitan and salts thereof, soybean lecithin, and monoglyceride.
유화 용액이 폴리비닐알콜을 포함할 때, 유화 용액은 폴리비닐알콜을 물 또는 물과 알킬알콜 혼합 용액에 용해하여 사용할 수 있다. 이 때 폴리비닐알콜의 함량은 유화 용액을 기준으로 1 내지 10 중량% 포함될 수 있다. 상기 범위를 벗어나면, 계면활성제로 작용하는 PVA의 유화작용이 약화되어 미세입자를 만들기 어렵다. 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.
폴리비닐알콜은 50,000 내지 200,000의 평균 분자량을 갖는 것일 수 있다. 삼원 공중합체의 평균 분자량은 50,000 미만이면 유화작용이 매우 떨어지며, 삼원 공중합체의 평균 분자량이 200,000 초과이면 높은 농도로 인해 테일러 흐름을 원활히 형성하기 어렵다. 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.
유화 용액은 계면 활성제를 포함할 수 있다. 계면 활성제로는 음이온성, 양이온성 또는 양쪽성의 계면 활성제를 모두 사용할 수 있다. 계면 활성제는 예를 들어, 폴리옥시에틸렌 솔비탄모노라우레이트 (트윈 20 상품), 폴리옥시에틸렌 솔비탄 모노팔미테이트 (트윈 40 상품), 폴리옥시에틸렌 솔비탄 모노스테아레이트(트윈 60 상품), 폴리옥시에틸렌 솔비탄 모노올레에이트 (트윈 80 상품), 및 폴리옥시에틸렌 솔비탄 트리올레에이트(트윈 85 상품) 중 적어도 하나를 포함할 수 있다.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).
유화 용액을 분산 용액이 주입된 연속 반응기에 제공되면, 유화가 일어난다. 이 때 유화는 1 내지 30 분간 유화하는 것일 수 있다. 1분 미만으로 유화가 진행되면 생분해성 고분자 미세 입자가 충분히 생성되지 않고, 30분 초과로 유화가 진행되면 제공되는 외력 대비 생분해성 고분자 미세 입자의 생산성이 떨어진다.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.
이 때, 생분해성 고분자 미세 입자가 생성되고, 이는 일반적인 기계적 교반법, 예를 들어 마그네틱 바를 이용한 교반법, 기계적 시트어(mechanical stirrer) 또는 균질기를 사용한 교반법이 아닌 쿠에트 테일러 유체 흐름을 적용한 방법이다. 쿠에트 테일르 유체 흐름은 회분식 교반법에 비하여, 강력한 교반력을 갖고, 회분식 반응과는 다르게 반응시간과 연속 반응기 내부를 통과하는 시간과 비례한다는 장점을 가지고 있다.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.
안정화액이 교반된 반응기에 토출액을 주입하여, 생분해성 고분자 미세 입자를 안정화한다(S300). 안정화액은 폴리비닐알콜(Polyvinyl alcohol) 또는 계면 활성제를 물 또는 물과 알킬알콜 혼합용액에 용해하여 제조할 수 있다. 안정화액이 폴리비닐알콜을 포함할 때, 폴리비닐알콜의 함량은 안정화액을 기준으로 0.1 내지 5 중량%의 포함되는 것일 수 있다.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.
안정화액은 10,000 내지 100,000 의 평균 분자량을 갖는 폴리비닐알콜을 포함할 수 있다. 폴리비닐알콜의 평균 분자량이 10,000 미만이면 입자의 형태를 유지하기 어렵고, 폴리비닐알콜의 평균 분자량이 100,000 초과이면 세척과정에서 제거가 어려운 문제가 있다. 안정화액은 단일 성분의 수용액 또는 계면 활성제와 알킬알콜의 혼합 용액을 포함할 수도 있다.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.
연속 반응기를 통과한 토출액은 이미 제조된 안정화 용액이 교반되고 있는 반응기로 연속적으로 주입이 되어 안정화 과정을 거친다. 토출액은 생분해성 고분자 미세 입자를 포함한다. 연속 반응기는 감압 장치를 포함할 수 있고, 감압 장치에 의해 유기 용매를 제거할 수 있다.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.
생분해성 고분자 미세 입자를 분리한다(S400). 연속형 원심분리기 또는 고속 교반 원심분리기를 사용하여 생분해성 고분자 미세 입자와 용액을 분리한다. 알킬알콜과 물 또는 물 단독으로 생분해성 고분자 미세 입자를 세척할 수 있다. 알킬알콜은 예를 들어, 에탄올을 사용할 수 있다.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.
생분해성 고분자 미세 입자는 크기별로 분류할 수도 있다. 용액과 분리된 생분해성 고분자 미세 입자를 분체기를 사용하여 크기별로 분류할 수 있다. 예를 들어, 크기 체별(size sieving)기를 사용하여 건식 또는 습식으로 생분해성 고분자 미세 입자를 크기별로 분류할 수 있다.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.
습식으로 분체할 경우, 동결 건조를 추가적으로 시행하여, 수분을 제거한 후, 분류할 수도 있다.In the case of wet powder, freeze-drying may be additionally performed to remove water, and then classified.
생분해성 고분자 미세 입자의 크기는 1 내지 300㎛인 것일 수 있다. 생분해성 고분자 미세 입자의 크기란 예를 들어, 생분해성 고분자 미세 입자의 입경을 의미하는 것일 수 있다.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.
생분해성 고분자 미세 입자의 크기가 1㎛ 미만이면, 생분해성 고분자 미세 입자를 제조할 때, 크기를 제어하기 어렵고, 생분해성 고분자 미세 입자의 크기가 300㎛ 초과이면, 주사제용으로 사용되기 적합하지 않다.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. .
앞서 언급한 바와 같이, 본 발명의 일 실시예에 따른 주사제의 제조 방법은 생분해성 고분자 미세 입자를 포함하는 수용액에 부형제를 제공하는 단계를 포함한다. 부형제는 예를 들어, 알긴산(Alginic acid) 및 그 염, 히알루론산(Hyalurinic acid) 및 그 염, 카르복시메틸 셀룰로오스(Carboxylmethyl cellulose) 및 그 염, 덱스트란(Dextran) 및 그 염, 콜라겐(collagen), 젤라틴(Gelatin), 및 엘라스틴(Elastin) 중 적어도 하나를 포함할 수 있다. 본 발명의 일 실시예에 따른 주사제의 제조 방법은 생분해성 고분자 미세 입자를 포함하는 수용액에 부형제를 제공하고, 동결 건조하는 단계(S20)를 포함한다.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).
수용액을 준비하는 단계(S10)에서, 생분해성 고분자 미세 입자는 수용액을 기준으로 10 내지 80 중량% 포함되는 것일 수 있다. 생분해성 고분자 미세 입자의 함량이 10 중량% 미만이면 농도가 낮아 고르게 분산시키기 어렵고, 80 중량% 초과이면 낮은 수분 함량으로 동결 건조 및 부형제와의 혼합이 어렵다.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.
상기 수용액에 따라혼합액의 생분해성 고분자 미세 입자와 부형제의 비율은 2:8 내지 8:2의 중량비%일 수 있다. 상기 범위를 벗어나면 부형제의 함량을 조절할 수 있는 범위를 벗어나 생분해성 고분자 미세입자들을 적정 농도로 고르게 분산 시키기 어렵다.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.
이 때, 3롤밀(Three roll mill)을 사용하여 높은 점도의 혼합액을 고르게 분산시킬 수 있다.At this time, using a three-roll mill (Three roll mill) it is possible to uniformly disperse the mixed solution of a high viscosity.
본 발명의 일 실시예에 따른 주사제의 제조 방법은 동결 건조한 생분해성 고분자 미세 입자를 멸균하는 단계를 더 포함할 수 있다. 멸균하는 단계는 예를 들어, 감마선 멸균, 에틸렌옥사이드 멸균, 또는 감압 멸균으로 수행되는 것일 수 있다.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.
주사제는 안면 성형 필러, 남성 보형물, 또는 요실금 치료제로 사용되는 것일 수 있다. 안면 성형 필러에 사용되는 생분해성 고분자 미세 입자의 크기는 10 내지 100㎛일 수 있다. 남성 보형물 또는 요실금 치료제에 사용되는 생분해성 고분자 미세 입자의 크기는 100 내지 300㎛일 수 있다.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.
본 발명의 일 실시예에 따른 주사제의 제조 방법 및 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조 방법은 쿠에트 테일러 유체 흐름을 사용하여, 생분해성 고분자 미세 입자의 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이하다.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.
이하에서는 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기에 대하여 설명한다. 이하에서는 본 발명의 일 실시예에 따른 주사제의 제조 방법 및 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조 방법과의 차이점에 대하여 설명하고, 동일 또는 유사한 것은 생략한다.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.
도 3은 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기를 개략적으로 나타낸 단면도이다.3 is a cross-sectional view schematically showing a reactor for producing biodegradable polymer microparticles according to an embodiment of the present invention.
도 3을 참조하면, 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기(100)는 제1 투입구(9), 제2 투입구(10), 연속 반응기(100), 반응액 토출부(11), 및 연속 원심 분리기(12)를 포함한다. 본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기(100)는 유화 용액 보관소(1), 분산 용액 보관소(2), 폐액 배출구(13), 생분해성 고분자 미세 입자 회수부(14)를 더 포함한다.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.
연속 반응기(100)에서는 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자가 형성된다. 코에트 테일러 유체 흐름은 제1 투입구(9)로부터 제공된 유화 용액 및 제2 투입구(10)로부터 제공된 생분해성 고분자가 분산된 분산 용액이 서로 교반되어 형성된다. 제1 투입구(9)는 유화 용액 보관소(1)와 연결된다. 제2 투입구(10)는 분산 용액 보관소(2)와 연결된다.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.
연속 반응기(100)에서 생성된 생분해성 고분자 미세 입자를 포함하는 반응액은 반응액 토출부(11)로 토출된다. 반응액 토출부(11)로 토출된 반응액은 연속 원심 분리기(12)에서 폐액과 생분해성 고분자 미세 입자로 분리된다. 폐액은 폐액 배출구(13)로 배출된다. 생분해성 고분자 미세 입자는 생분해성 고분자 미세 입자 회수부(14)에서 회수된다.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.
연속 반응기(100)는 내부 실린더(5), 온도 조절부, 외부 실린더(7), 및 반응부(8)를 포함한다. 내부 실린더(5)는 고속으로 회전되어 반응액을 교반시키는 역할을 한다. 외부 실린더(7)에는 주입구 토출구 등이 장착되어있고 반응내부를 보호하는 역할 을 한다. 온도 조절부(6)는 반응부(8)와 외부 실린더(7) 사이에 냉각장치가 연결되어 온도를 조절할 수 있다. 반응부(8)는 반응액이 채워지는 빈 공간으로서 코에트 테일러 유체 흐름에 의해 생분해성 고분자 미세 입자가 형성된다.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.
연속 반응기(100)는 교반 모터(3), 구동축(4), 교반봉을 더 포함한다. 교반 모터(3)는 교반봉을 회전 시키는 것일 수 있다. 교반봉은 교반 모터(3)에 의해 구동된다. 교반봉은 내부 실린더(5)에 제공된 유화 용액과 분산 용액을 교반한다. 교반봉은 구동축(4)에 중심으로, 교반 모터(3)에서 외력을 제공받아 구동된다. 교반봉은 반응부(8)와 이격된다.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).
교반 모터(3)는 10 내지 2000 rpm의 회전 속도를 갖는 것일 수 있다. 10 rpm 미만이면 유화 용액과 분산 용액이 충분히 교반되지 않고, 2000 rpm 초과이면 제공되는 외력대비 교반 효율이 높지 않다.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.
제1 투입구(9)는 반응부(8)의 1/4 지점에 배치되는 것일 수 있으며, 충분한 회전력을 받는 지점에서 투입되어 강력한 교반력에 의해 구형의 미세입자를 형성하기 위함이다. 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.
본 발명의 일 실시예에 따른 생분해성 고분자 미세 입자의 제조용 반응기는 쿠에트 테일러 유체 흐름을 사용하여, 생분해성 고분자 미세 입자의 대량 생산이 용이하고, 생분해성 고분자 미세 입자의 크기와 형태의 조절이 용이하다.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.
이하, 구체적인 실시예를 통해 본 발명을 보다 구체적으로 설명한다. 하기 실시예는 본 발명의 이해를 돕기 위한 예시에 불과하며, 본 발명의 범위가 이에 한정되는 것은 아니다.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.
실시예 1: 폴리디옥사논 미세 입자의 제조Example 1: Preparation of polydioxanone fine particles
평균 분자량이 100,000인 폴리디옥사논(Polydioxanone) 90g과 삼원 공중합체 F-127(바스프사 제품, 평균분자량 12,600), 삼원 공중합체 F-68(바스프사 제품, 평균분자량 8,400) 60g을 헥사플루오로이소프로파놀(Hexafluoroisopropanol) 1500mL에 투입한 후 교반하여 혼합하였다.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.
상기 폴리디옥사논 분산 용액을 쿠에트 테일러 유체 흐름을 이용한 연속반응기에 10mL/min의 속도로 투입하면서 5% PVA(평균분자량 130,000) 용액 7,500mL를 동시에 50mL/mL의 속도로 투입하였다. 반응기 내 체류시간은 10분을 유지한 후 반응액이 토출될 수 있도록 조절하였다.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.
토출되는 반응액을 1% PVA(평균분자량 93,500) 7,500mL 용액에 투입하면서 교반시켰다. 토출액을 모두 투입한 후 감압 하에 24시간 교반시키면서 헥사플루오로이소프로파놀을 제거하여 생성된 생분해성 고분자 미세 입자를 안정화시켰다.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.
생분해성 고분자 미세 입자가 포함된 반응액을 원심 분리기로 고액 분리하여 불순불이 제거된 폴리디옥사논 미세 입자를 얻었다. 이를 다시 900 mL 증류수로 5회 세척 후 원심 분리를 진행하여 잔류 불순물을 완전히 제거하고 동결건조하여 생분해성 고분자 미세 입자인 폴리디옥사논 미세 입자를 완성하였다.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.
이 때, 연속 반응기의 유속을 500rpm, 1500rpm, 2000rpm으로 변화시키면서 생분해성 고분자 입자를 제조하였다.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.
또한, 연속 반응기에 투입되는 고분자 분산 용액과 유화 용액의 반응기 내 체류시간을 1 내지 10분까지 변화시키면서 생분해성 고분자 입자를 제조하였다.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.
실시예 2: 폴리락틴산 미세 입자의 제조Example 2: Preparation of polylactic acid fine particles
폴리디옥사논 대신 폴리락틱산(Polylactic acid), 헥사플루오로이소프로파놀 대신 다이클로로메탄(Dichloromethane)을 사용한 것을 제외하고는 실시예 1과 동일하게 실시하였다.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.
실시예 3: 폴리락틴산 미세 입자의 제조Example 3: Preparation of polylactic acid fine particles
폴리디옥사논 대신 폴리카프로락톤(Poly caprolactone), 헥사플루오로이소프로파놀 대신 다이클로로메탄(Dichloromethane)을 사용한 것을 제외하고는 실시예 1과 동일하게 실시하였다.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.
물성 측정Property measurement
1. 도 4는 실시예 1 내지 3의 생분해성 고분자 미세 입자를 촬영한 전자 현미경 사진이다. 도 4를 참조하면, 본 발명의 제조 방법에 의해 생분해성 고분자 미세 입자를 제조할 경우, 생분해성 고분자의 종류에 상관 없이 동일한 형태의 생분해성 고분자 미세 입자를 형성할 수 있는 것을 확인할 수 있었다.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. 도 5는 연속 반응기 내에서의 체류 시간에 따른 생분해성 고분자 미세 입자를 촬영한 전자 현미경 사진이다. 체류시간이 길수록 생분해성 고분자 미세 입자를 원활히 제조할 수 있는 것을 확인할 수 있었다.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. 도 6은 교반 속도에 따른 생분해성 고분자 미세 입자를 촬영한 사진이다. 교반 속도가 빠를수록 생분해성 고분자 미세 입자를 원활히 제조할 수 있는 것을 확인할 수 있었다.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. 도 7은 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x200 배율의 전자현미경으로 촬영한 사진이다. 도 8은 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x1,000 배율의 전자현미경으로 촬영한 사진이다. 도 9는 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x5,000 배율의 전자현미경으로 촬영한 사진이다. 도 10은 본 발명의 실시예 1에 따라 제조된 생분해성 고분자 미세 입자의 x10,000 배율의 전자현미경으로 촬영한 사진이다.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.
도 7 내지 도 10을 참조하면, 본 발명의 일 실시예의 생분해성 고분자 미세 입자의 제조 방법에 의해 제조된 생분해성 고분자 미세 입자는 대량으로 생산하여도 크기와 형태의 조절이 용이한 것을 확인할 수 있다.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. .
이상, 첨부된 도면을 참조하여 본 발명의 실시예를 설명하였지만, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자는 본 발명이 그 기술적 사상이나 필수적인 특징으로 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예는 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.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. 연속 반응기에, 생분해성 고분자가 분산된 분산 용액을 주입하는 단계;Injecting a dispersion solution in which a biodegradable polymer is dispersed in a continuous reactor;
    유화 용액을 상기 연속 반응기에 주입하여, 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자를 생성하는 단계;Injecting an emulsifying solution into the continuous reactor to produce biodegradable polymer microparticles with a Kuet Taylor fluid flow;
    상기 연속 반응기에서 상기 생분해성 고분자 미세 입자를 포함하는 토출액을 토출하고, 안정화액이 교반된 반응기에 상기 토출액을 주입하여, 상기 생분해성 고분자 미세 입자를 안정화하는 단계; 및Stabilizing 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
    상기 생분해성 고분자 미세 입자를 분리하는 단계;를 포함하는 생분해성 고분자 미세 입자의 제조 방법.Separating the biodegradable polymer fine particles; Method for producing biodegradable polymer fine particles comprising a.
  2. 제1항에 있어서,According to claim 1,
    상기 분산 용액을 주입하는 단계에서,In the step of injecting the dispersion solution,
    상기 생분해성 고분자는 폴리디옥사논(Polydioxanone, PDO), 폴리락트산(Polylactic acid, PLA) 및 그 이성질체, 폴리글리콜산(Polyglycolic acid, PGA) 및 그 이성질체, 및 폴리카프로락톤(Polycarprolactone, PCL) 중에서 선택되고,The biodegradable polymer is polydioxanone (PDO), polylactic acid (PLA) and its isomers, polyglycolic acid (PGA) and its isomers, and polycaprolactone (Polycarprolactone, PCL) Is selected,
    상기 생분해성 고분자의 평균 분자량은 50,000 내지 300,000인 생분해성 고분자 미세 입자의 제조 방법.The biodegradable polymer has an average molecular weight of 50,000 to 300,000.
  3. 제1항에 있어서,According to claim 1,
    상기 분산 용액을 주입하는 단계에서,In the step of injecting the dispersion solution,
    상기 분산 용액은 용매를 포함하고,The dispersion solution contains a solvent,
    상기 용매는The solvent
    과불소알콜, DMF (N,N-Dimethylforamide), DMSO (Dimethyl sulfoxide), 염소화탄화수소, 탄화수소 및 알킬알콜 중 적어도 하나를 포함하고,Perfluorinated alcohol, DMF (N,N-Dimethylforamide), DMSO (Dimethyl sulfoxide), at least one of chlorinated hydrocarbons, hydrocarbons and alkyl alcohols,
    상기 생분해성 고분자의 함량은, 상기 분산 용액을 기준으로, 1 내지 20 중량%인 것인 생분해성 고분자 미세 입자의 제조 방법.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. 제1항에 있어서,According to claim 1,
    상기 분산 용액을 주입하는 단계에서,In the step of injecting the dispersion solution,
    상기 분산 용액은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 더 포함하고,The dispersion solution further comprises a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer,
    상기 삼원 공중합체의의 평균분자량은 7,000 내지 15,000이고,The average molecular weight of the ternary copolymer is 7,000 to 15,000,
    상기 삼원 공중합체의 함량은, 상기 분산 용액을 기준으로, 1 내지 20 중량%인 것인 생분해성 고분자 미세 입자의 제조 방법.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. 제1항에 있어서,According to claim 1,
    상기 생분해성 고분자 미세 입자를 생성하는 단계에서,In the step of generating the biodegradable polymer fine particles,
    상기 생분해성 고분자 미세 입자의 크기는 1 내지 300㎛인 것인 생분해성 고분자 미세 입자의 제조 방법.The size of the biodegradable polymer microparticles is 1 to 300㎛ the method for producing biodegradable polymer microparticles.
  6. 제1항에 있어서,According to claim 1,
    상기 생분해성 고분자 미세 입자는The biodegradable polymer fine particles
    안면 성형 필러, 남성 보형물, 또는 요실금 치료제에 사용되는 것인 생분해성 고분자 미세 입자의 제조 방법.A method for producing biodegradable polymer microparticles that is used in facial cosmetic fillers, male implants, or incontinence treatments.
  7. 제1항에 있어서,According to claim 1,
    상기 생분해성 고분자 미세 입자를 생성하는 단계에서,In the step of generating the biodegradable polymer fine particles,
    상기 유화 용액은 폴리비닐알콜(Polyvinyl alcohol), 폴리옥시에틸렌 솔비탄 및 그 염, 대두 레시틴(soybean Lecithin), 및 모노글리세리드(monoglyceride 중 적어도 하나를 포함하는 것인 생분해성 고분자 미세 입자의 제조 방법.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. 제1항에 있어서,According to claim 1,
    상기 생분해성 고분자 미세 입자를 안정화하는 단계에서,In the step of stabilizing the biodegradable polymer fine particles,
    상기 안정화액은 폴리비닐알콜(Polyvinyl alcohol), 폴리옥시에틸렌 솔비탄 및 그 염, 대두 레시틴(soybean Lecithin), 및 모노글리세리드(monoglyceride 중 적어도 하나를 포함하는 것인 생분해성 고분자 미세 입자의 제조 방법.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. 제1항에 의해 제조된 생분해성 고분자 미세 입자를 포함하는 수용액을 준비하는 단계; 및Preparing an aqueous solution containing the biodegradable polymer fine particles prepared by claim 1; And
    상기 수용액에 알긴산(Alginic acid) 및 그 염, 히알루론산(Hyalurinic acid) 및 그 염, 카르복시메틸 셀룰로오스(Carboxylmethyl cellulose) 및 그 염, 덱스트란(Dextran) 및 그 염, 콜라겐(collagen), 젤라틴(Gelatin), 및 엘라스틴(Elastin) 중 적어도 하나를 제공하고, 동결 건조하는 단계를 포함하는 주사제의 제조 방법.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. 제9항에 있어서,The method of claim 9,
    상기 수용액을 준비하는 단계에서,In the step of preparing the aqueous solution,
    상기 생분해성 고분자 미세 입자는 상기 수용액을 기준으로 10 내지 80 중량% 포함되는 것인 주사제의 제조 방법.The biodegradable polymer fine particles are 10 to 80% by weight based on the aqueous solution, the method of manufacturing an injection.
  11. 제9항에 있어서,The method of claim 9,
    상기 수용액에 카르복시메틸 셀룰로오스를 제공할 때,When providing carboxymethyl cellulose to the aqueous solution,
    상기 생분해성 고분자 미세 입자는 상기 카르복시메틸 셀룰로오스가 포함된 상기 수용액을 기준으로, 30 내지 60 중량% 포함되는 것인 주사제의 제조 방법.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. 제9항에 있어서,The method of claim 9,
    상기 생분해성 고분자 미세 입자의 크기는 10 내지 300㎛인 것인 주사제의 제조 방법.The size of the biodegradable polymer microparticles is 10 to 300㎛ injection method.
  13. 제9항에 있어서,The method of claim 9,
    상기 동결 건조한 생분해성 고분자 미세 입자를 멸균하는 단계를 더 포함하고,Further comprising the step of sterilizing the lyophilized biodegradable polymer fine particles,
    상기 멸균하는 단계는The sterilizing step
    감마선 멸균, 에틸렌옥사이드 멸균, 또는 감압 멸균으로 수행되는 것인 주사제의 제조 방법.Gamma-ray sterilization, ethylene oxide sterilization, or a method for producing an injection that is performed by sterilization under reduced pressure.
  14. 제9항에 있어서,The method of claim 9,
    상기 주사제는 안면 성형 필러, 남성 보형물, 또는 요실금 치료제로 사용되는 것인 주사제의 제조 방법.The injection is a method of manufacturing an injection that is used as a facial cosmetic filler, male implant, or incontinence treatment.
  15. 쿠에트 테일러 유체 흐름으로 생분해성 고분자 미세 입자가 형성되는 연속 반응기;A continuous reactor in which biodegradable polymer fine particles are formed by a Kuet Taylor fluid flow;
    유화 용액을 상기 연속 반응기에 투입하는 제1 투입구;A first inlet for introducing an emulsifying solution into the continuous reactor;
    생분해성 고분자가 분산된 분산 용액을 상기 연속 반응기에 투입하는 제2 투입구;A second inlet for introducing a dispersion solution in which a biodegradable polymer is dispersed into the continuous reactor;
    상기 연속 반응기에서 생성된 생분해성 고분자 미세 입자를 포함하는 반응액을 토출하는 반응액 토출부; 및A reaction solution discharge unit for discharging a reaction solution containing biodegradable polymer fine particles generated in the continuous reactor; And
    상기 반응액에서 상기 생분해성 고분자 미세 입자를 분리하는 연속 원심 분리기;를 포함하는 생분해성 고분자 미세 입자의 제조용 반응기.A continuous reactor for separating the biodegradable polymer microparticles from the reaction solution; Reactor for the production of biodegradable polymer microparticles comprising a.
  16. 제15항에 있어서,The method of claim 15,
    상기 연속 반응기는The continuous reactor
    상기 생분해성 고분자 미세 입자가 생성되는 반응부;A reaction unit in which the biodegradable polymer fine particles are generated;
    실린더의 일측에 배치되는 교반 모터; 및A stirring motor disposed on one side of the cylinder; And
    상기 반응부와 이격되고, 상기 교반 모터에 의해 구동되는 교반봉을 포함하는 것인 생분해성 고분자 미세 입자의 제조용 반응기.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. 제16항에 있어서,The method of claim 16,
    상기 교반 모터는The stirring motor
    10 내지 2000rpm의 회전 속도를 갖는 것인 생분해성 고분자 미세 입자의 제조용 반응기.A reactor for producing biodegradable polymer microparticles having a rotational speed of 10 to 2000 rpm.
  18. 제16항에 있어서,The method of claim 16,
    상기 제1 투입구는 상기 반응부의 1/4 지점에 배치되는 것인 생분해성 고분자 미세 입자의 제조용 반응기.The first inlet is a reactor for producing biodegradable polymer fine particles that are arranged at a quarter of the reaction part.
PCT/KR2018/015668 2018-12-11 2018-12-11 Method for manufacturing biodegradable polymeric microparticles by using continuous reaction, method for manufacturing injection comprising same, and reactor for manufacturing biodegradable polymeric microparticles WO2020122268A1 (en)

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