WO2017073963A1 - Procédés de production de microparticules polymères ayant une structure de réseau - Google Patents

Procédés de production de microparticules polymères ayant une structure de réseau Download PDF

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Publication number
WO2017073963A1
WO2017073963A1 PCT/KR2016/011862 KR2016011862W WO2017073963A1 WO 2017073963 A1 WO2017073963 A1 WO 2017073963A1 KR 2016011862 W KR2016011862 W KR 2016011862W WO 2017073963 A1 WO2017073963 A1 WO 2017073963A1
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polymer
mixed solvent
dmso
network structure
polymer solution
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PCT/KR2016/011862
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English (en)
Korean (ko)
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WO2017073963A9 (fr
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김근풍
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주식회사 바임
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Priority to CN201680062806.0A priority Critical patent/CN108350180B/zh
Priority to BR112018008405-0A priority patent/BR112018008405B1/pt
Publication of WO2017073963A1 publication Critical patent/WO2017073963A1/fr
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    • 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 polymer microparticles having a network structure, and more specifically, polyester-based polymers are ethylene carbonate (hereinafter referred to as "EC") and dimethylsulfoxide (hereinafter referred to as “EC”).
  • EC ethylene carbonate
  • EC dimethylsulfoxide
  • DMSO which is dissolved in a mixed solvent, is injected into a hydrocarbon having a temperature lower than the freezing point of the mixed solvent to obtain a solid containing EC / DMSO / polymer, and then the solid is added to water to give the solid.
  • the present invention relates to a method for producing polymer fine particles having a network structure by removing a mixed solvent from the mixture.
  • Porous biodegradable polymeric microparticles are widely used as drug delivery systems and scaffolds for tissue regeneration. These polymer microparticles are required to have porosity, and in particular, the internal structure of the particles has a network structure, which not only increases the strength of the particles, but also has good cell adhesion, and is therefore promising to be used as an injection agent for cell carriers, cell cultures, and tissue regeneration. This is an advantage in designing drug release systems.
  • microparticles for injection is the Emulsification-Solvent Evaporation Method.
  • the W / O / W type dual emulsification method undergoes two emulsification steps, and the porous structure is determined according to the stability of the first emulsification step, the water-in-oil (W / O) emulsion.
  • W / O water-in-oil
  • emulsions are thermodynamically unstable, they are difficult to manufacture because the aqueous phase and the organic phase try to separate from each other through processes such as coalescence, fusion, and phase separation (see M. Kanouni, HL Rosano). , N. Naouli, Adv.Colloid Interface Sci. 99 (2002) 229-254; AJ Webster, ME Cates, Langmuir, 14 (1998) 2068-2079).
  • a particulate carrier comprising an oil-in-water type double emulsification step of adding an aqueous solution of an effervescent salt dissolved in an aliphatic polyester polymer to form an oil-in-water emulsion and redispersing and emulsifying it in an aqueous solution containing a hydrophilic surfactant.
  • the particulate carrier has properties such as biodegradability, high porosity, excellent interconnectivity between pores, but has a weak mechanical strength and a difficult mass production process.
  • biodegradable polymer microparticle manufacturing method is to dissolve the biodegradable polymer in DMSO (Dimethyl Sulfoxide), spray on a low temperature hydrocarbon solution to freeze the DMSO / polymer solution and remove the DMSO from the low temperature salt solution.
  • DMSO Dimethyl Sulfoxide
  • microparticles for tissue regeneration support, it is necessary to develop microparticles that can maximize the tissue regeneration effect by increasing the cell adhesion by making the internal structure of the microparticles have a network structure.
  • the present inventors studied the particle formation step of the conventional microparticle manufacturing process, and when the biodegradable polyester-based microsolution droplets dissolved in the EC / DMSO mixed solvent are frozen in a low temperature hydrocarbon, the polymer dissolved in the microsolution is reticulated. By discovering the phenomenon of solidification to the structure, the present invention was completed by finding out that the polymer microparticles having the maximum cell adhesion ability can be prepared.
  • Method for producing a polymer microparticle having a network structure (1) preparing a polymer solution by dissolving the polymer in a mixed solvent containing EC and DMSO; (2) a solid preparation step of preparing a solid by adding the polymer solution obtained in the polymer solution preparation step into a liquid hydrocarbon at a temperature below the freezing point of the mixed solvent; And (3) removing the solids obtained in the solids manufacturing step, and removing the mixed solvent in the solids by adding the separated solids to water.
  • the present invention as described above it can be produced in a yield of 80% or more polymer microparticles having a network structure.
  • the polymer microparticles were spherical particles having a diameter of 20 to 1,000 ⁇ m, which can be adjusted according to the injection amount and the amount of injection air during the injection of the polymer solution, the porosity of the polymer microparticles is controlled by the polymer concentration of the polymer solution Can be.
  • the present invention is not only biocompatible, biodegradable, porous, but also the internal structure of the particle has a network structure, it can be used as an excellent cell carrier and cell culture, can be injected by a syringe, it is injected in vivo to restore damaged tissue It can be usefully used as a cell carrier for excellent tissue regeneration.
  • 1 is a graph showing that the freezing point changes depending on the mixing ratio of the mixed solvent used in the present invention.
  • the present invention (1) a polymer solution manufacturing step of preparing a polymer solution by dissolving the polymer in a mixed solvent containing EC and DMSO; (2) a solid preparation step of preparing a solid by adding the polymer solution obtained in the polymer solution preparation step into a liquid hydrocarbon at a temperature below the freezing point of the mixed solvent; And (3) removing the solids obtained in the solids production step and removing the mixed solvent in the solids by adding the separated solids to water.
  • Method for producing a polymer microparticle having a network structure (1) preparing a polymer solution by dissolving the polymer in a mixed solvent containing EC and DMSO; (2) a solid preparation step of preparing a solid by adding the polymer solution obtained in the polymer solution preparation step into a liquid hydrocarbon at a temperature below the freezing point of the mixed solvent; And (3) removing the solids obtained in the solids production step and removing the mixed solvent in the solids by adding the separated solids to water.
  • the method for producing a polymer microparticle having a network structure (1) a polymer solution (solution containing a polymer / EC / DMSO) by dissolving the polymer in a mixed solvent containing EC and DMSO Preparing a polymer solution; (2) a solid content preparing step of preparing a frozen solid by spraying the polymer solution obtained in the polymer solution preparation step into a liquid hydrocarbon having 5 to 10 carbon atoms (C 5 to C 10 ) at a temperature of -20 to 0 ° C .; And (3) removing the solids obtained in the solids production step and removing the mixed solvent in the solids by adding the separated solids to distilled water at 0 to 4 ° C .;
  • the polymer is preferably a biodegradable polyester-based polymer having a weight average molecular weight of 10,000 to 250,000, more preferably polylactic acid (PLA), polyglycolic acid (PGA), poly (D, L-lactic acid-co-glycolic acid (PLGA: from the group consisting of Poly (D, L-lactic-co-glycolic acid), polycaprolactone (PCL), poly (valerolactone), poly (hydroxybutyrate) and poly (hydroxyvallate) It may be any one biodegradable polyester-based polymer selected.
  • the mixing ratio of EC: DMSO is in the range of 90:10 to 10:90 by weight, more preferably within the range of 80:20 to 20:80, most preferably 70:30 to 30:70 It may be a mixed solvent within the range.
  • the hydrocarbon may be any one selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane and petroleum ether. .
  • the polymer preferably a biodegradable polyester-based polymer, is an aliphatic polyester-based polymer, but is not limited thereto.
  • These polymers preferably have an average molecular weight (weight average molecular weight) of 10,000 to 250,000.
  • the method for preparing biodegradable polymer microparticles of the present invention has the characteristics of easily producing spherical microparticles and of easily controlling the size of microparticles. It is not limited.
  • the polymer is prepared as a polymer solution, wherein the polymer is dissolved in an EC / DMSO mixed solvent so as to have a concentration of 1 to 25 w / v% (weight / vol%), and can be used in various ways.
  • the porosity of the polymer microparticles can be adjusted through. If the concentration of the polymer solution is less than 1w / v%, the mechanical strength of the microparticles are weak and practicality, if the concentration is more than 25w / v%, there is a problem that the efficiency is low, such as the formation of fibers so high that the viscosity is too high have.
  • the mixed solvent used to dissolve the polymer in the present invention is a mixture of EC (Ethylene carbonate, freezing point 37 °C) and DMSO (Dimethylsulfoxide, freezing point 18 °C), the freezing point of the mixed solvent depends on the mixing ratio (Fig. 1), the freezing point of the mixed solvent may act as an important factor in the structure formation of aliphatic polyester polymer microparticles.
  • the internal structure of the polymer microparticles has a network structure.
  • Preferred mixed solvents having a network-like internal structure have a mixing ratio of EC: DMSO in the weight ratio within the range of 90: 10 to 10: 90, preferably within the range of 80: 20 to 20: 80, more preferably 70: It is a mixed solvent within the range of 30-30: 70.
  • the liquid hydrocarbon in the present invention is preferably a hydrocarbon having 5 to 10 carbon atoms (C 5 to C 10 ), which may not be frozen at a freezing point of the mixed solvent and may be phase separated from the solid containing the polymer / EC / DMSO.
  • saturated hydrocarbons such as pentane, hexane, heptane, octane, nonane, nonane, decane, petroleum ether and mixtures thereof, preferably It is recommended to use n-hexane which is highly volatile. Due to the high volatility of n-hexane, it can finally be easily removed during drying.
  • Hydrocarbons having less than 5 carbon atoms are too volatile and difficult to manufacture, and hydrocarbons having 10 or more carbon atoms may have a problem of poor practicality.
  • the temperature of the hydrocarbon solution is preferably maintained at a temperature below the melting point of the mixed solvent for freezing the mixed solvent. More preferably, in order to smoothly freeze the EC / DMSO mixed solvent and form fine particles, it is preferably -20 to 0 ° C, and most preferably -15 to -10 ° C.
  • Solids which are prepared as described above and separated from the liquid hydrocarbon at low temperature are separated from the liquid hydrocarbon, and are added to water to remove EC / DMSO and washed to obtain polymer microparticles having a network structure inside the microparticles.
  • the obtained polymer microparticles can be further charged into water, preferably distilled water, washed to remove residual mixed solvents and impurities, and further dried, preferably lyophilized.
  • Example 1 3.5 g of polylactic acid (PLA) having a weight average molecular weight of 110,000 was dissolved in 50 ml of an EC / DMSO (8/2) mixed solvent to prepare a 7W / V% polymer solution. The polymer solution was sprayed on n-hexane cooled to -15 ° C under the conditions of 5 ml / min of injection amount and 5 L / min of injection air. At this time, the injected polymer solution is frozen in spherical form at low temperature n-hexane.
  • PLA polylactic acid
  • Obtained frozen microparticles were added to the cooled (0 ⁇ 4 °C) distilled water and stirred to remove a mixed solvent, that is, EC and DMSO to obtain a polymer microparticles. This was again washed with 500 mL distilled water to remove residual EC, DMSO, and then lyophilized to obtain the polymer microparticles of the present invention.
  • a mixed solvent that is, EC and DMSO
  • Example 2 Polymer microparticles were obtained in the same manner as in Example 1, except that the EC / DMSO (8/2) mixed solvent was replaced with the EC / DMSO (7/3) mixed solvent.
  • Example 3 Polymer microparticles were obtained in the same manner as in Example 1, except that the EC / DMSO (8/2) mixed solvent was replaced with the EC / DMSO (5/5) mixed solvent.
  • Example 4 Polymer microparticles were obtained in the same manner as in Example 1, except that the EC / DMSO (8/2) mixed solvent was replaced with the EC / DMSO (3/7) mixed solvent.
  • Example 5 Polymer microparticles were obtained in the same manner as in Example 1, except that the EC / DMSO (8/2) mixed solvent was replaced with the EC / DMSO (2/8) mixed solvent.
  • Comparative Example 1 Polymer microparticles were prepared in the same manner as in Example 1 except that 3.5 g of polylactic acid (PLA) having an average molecular weight of 110,000 was dissolved in 50 ml of DMSO (DMSO alone) to prepare a 7w / v% polymer solution. Obtained.
  • PVA polylactic acid
  • DMSO DMSO alone
  • Comparative Example 2 Polymer microparticles were prepared in the same manner as in Example 1 except that 3.5 g of polylactic acid (PLA) having an average molecular weight of 110,000 was dissolved in 50 ml EC (EC alone) to prepare a 7w / v% polymer solution. Obtained.
  • PLA polylactic acid
  • the shape and production yield of the microparticles were measured.
  • the shape of the microparticles was measured by taking an electron microscope photograph, and the production yield was calculated by measuring the amount of the finally obtained microparticles relative to the amount of the injected polymer.
  • Figs. 2 to 8 (Fig. 2-Example 1, Fig. 3-Example 2, Fig. 4-Example 3, Fig. 5-Example 4, Fig. 6-Example 5, Fig. 7-Comparative Example 1, 8-Comparative Example 2) and as shown in Table 1 below, the internal structure of the fine particles (Comparative Examples 1, 2) prepared from the polymer solution dissolved in DMSO, EC alone solvent has an empty space (Fig. 7, 8), the internal structures of the spherical polymer microparticles prepared from the polymer solution dissolved in the EC / DMSO mixed solvent according to the present invention was confirmed to form a network structure (see Figures 2 to 6).
  • the microparticles prepared according to the preparation method of the present invention were a size suitable for injection into the body through a syringe, and the internal network structure of the microparticles was used as a cell carrier, a cell culture medium, and a cell carrier for tissue regeneration by facilitating cell attachment. It was determined that it could be used more usefully.
  • the present invention can be seen that it is a useful invention to provide a method for producing polymer microparticles that can inject a biodegradable polymer particulate carrier having a spherical and internal network structure with a syringe.
  • the microparticles having an internal network structure are expected to improve cell adhesion, which is expected to contribute to the bio industry through the use as cell carriers.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
  • Biological Depolymerization Polymers (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé de production de microparticules polymères ayant une structure de réseau par injection d'une solution polymère, obtenue par dissolution d'un polymère à base de polyester dans un mélange de solvants constitué de carbonate d'éthylène (ci-après, désigné "EC") et de diméthylsulfoxyde (ci-après, désigné "DMSO"), dans un hydrocarbure ayant une température inférieure au point de congélation du mélange de solvants pour obtenir des fractions solides de type EC/DMSO/polymère, puis placement des fractions solides dans l'eau pour éliminer le mélange de solvants desdites fractions solides. Le procédé comprend : (1) une étape de préparation d'une solution polymère consistant à dissoudre un polymère dans un mélange de solvants contenant du EC et DMSO pour préparer une solution polymère ; (2) une étape de préparation de fractions solides consistant à placer la solution polymère obtenue à l'étape de préparation d'une solution polymère dans un hydrocarbure liquide ayant une température égale ou inférieure au point de congélation du mélange de solvants pour préparer des fractions solides ; et (3) une étape d'élimination des solvants consistant à séparer les fractions solides obtenues à l'étape de préparation de fractions solides et à placer les fractions solides séparées dans l'eau pour éliminer le mélange de solvants présent dans lesdites fractions solides.
PCT/KR2016/011862 2015-10-27 2016-10-21 Procédés de production de microparticules polymères ayant une structure de réseau WO2017073963A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201680062806.0A CN108350180B (zh) 2015-10-27 2016-10-21 具有网状结构的高分子微细粒子的制备方法
BR112018008405-0A BR112018008405B1 (pt) 2015-10-27 2016-10-21 Método para preparar micropartículas de polímero com uma estrutura de rede

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KR10-2015-0149151 2015-10-27
KR1020150149151A KR101725279B1 (ko) 2015-10-27 2015-10-27 망상구조를 갖는 고분자 미세입자의 제조방법

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KR102012441B1 (ko) 2017-11-29 2019-08-20 주식회사 울트라브이 연속반응을 이용한 생분해성 고분자 미세 입자의 제조 방법, 이를 포함하는 주사제의 제조 방법, 및 생분해성 고분자 미세 입자의 제조용 반응기
KR20230171675A (ko) * 2022-06-14 2023-12-21 주식회사 바임 복합체, 이의 제조방법 및 이를 이용한 성형용 필러 조성물
KR102587872B1 (ko) * 2022-06-14 2023-10-12 주식회사 바임 복합체, 이의 제조방법 및 이를 이용한 성형용 필러 조성물

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KR20010002589A (ko) * 1999-06-16 2001-01-15 김윤 생리활성물질 함유 생분해성 고분자 마이크로스피어의 제조방법
KR20100131244A (ko) * 2009-06-05 2010-12-15 주식회사 리젠 바이오텍 생분해성 고분자 미세입자와 그의 제조방법
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KR20140105174A (ko) * 2013-02-22 2014-09-01 주식회사 바임 폴리락트산(pla) 미세입자의 스프레이 공법에 따른 제조방법
WO2015019213A1 (fr) * 2013-08-09 2015-02-12 Kimberly-Clark Worldwide, Inc. Microparticules ayant une distribution de pore multimodale

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KR100429000B1 (ko) * 2001-08-14 2004-04-28 한국과학기술원 약물이 봉입된 다공성 생분해성 고분자 지지체의 제조방법
CN101214947B (zh) * 2008-01-18 2010-06-09 中国科学技术大学 一种采用催化炭化聚合物和/或沥青制备碳纳米管的方法

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Publication number Priority date Publication date Assignee Title
KR20010002589A (ko) * 1999-06-16 2001-01-15 김윤 생리활성물질 함유 생분해성 고분자 마이크로스피어의 제조방법
KR20100131244A (ko) * 2009-06-05 2010-12-15 주식회사 리젠 바이오텍 생분해성 고분자 미세입자와 그의 제조방법
KR20140094119A (ko) * 2013-01-21 2014-07-30 주식회사 바임 고분자 미세입자의 제조방법
KR20140105174A (ko) * 2013-02-22 2014-09-01 주식회사 바임 폴리락트산(pla) 미세입자의 스프레이 공법에 따른 제조방법
WO2015019213A1 (fr) * 2013-08-09 2015-02-12 Kimberly-Clark Worldwide, Inc. Microparticules ayant une distribution de pore multimodale

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Publication number Publication date
BR112018008405B1 (pt) 2022-01-25
WO2017073963A9 (fr) 2018-09-13
KR101725279B1 (ko) 2017-04-10
BR112018008405A2 (pt) 2018-10-30
CN108350180A (zh) 2018-07-31
CN108350180B (zh) 2021-01-01

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