WO2024007588A1 - Procédés de préparation sans tensioactif de microsphères et de microcapsules polymères - Google Patents

Procédés de préparation sans tensioactif de microsphères et de microcapsules polymères Download PDF

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Publication number
WO2024007588A1
WO2024007588A1 PCT/CN2023/076041 CN2023076041W WO2024007588A1 WO 2024007588 A1 WO2024007588 A1 WO 2024007588A1 CN 2023076041 W CN2023076041 W CN 2023076041W WO 2024007588 A1 WO2024007588 A1 WO 2024007588A1
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Prior art keywords
water
solution
continuous phase
microspheres
capillary
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PCT/CN2023/076041
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English (en)
Inventor
Chaoquan HU
Yanlin Zhang
Yong Wang
Xuebing Xu
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Nanjing Ipe Institute Of Green Manufacturing Industry
Institute Of Process Engineering , Chinese Academy Of Sciences
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Priority claimed from CN202210802648.5A external-priority patent/CN115155472B/zh
Priority claimed from CN202211164516.0A external-priority patent/CN117797118A/zh
Priority claimed from CN202211164573.9A external-priority patent/CN117797738A/zh
Application filed by Nanjing Ipe Institute Of Green Manufacturing Industry, Institute Of Process Engineering , Chinese Academy Of Sciences filed Critical Nanjing Ipe Institute Of Green Manufacturing Industry
Publication of WO2024007588A1 publication Critical patent/WO2024007588A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/12—Making microcapsules or microballoons by phase separation removing solvent from the wall-forming material solution
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting

Definitions

  • the present application belongs to the technical field of polymer chemistry, and relates to the technical field of polymer chemistry for the manufacture of particulate materials for various applications, in particular relates to a group of surfactant-free preparation methods of polymer microspheres and microcapsules.
  • Polymer microspheres have found divergent application in various areas, including LCD screen spacer, drug delivery, medical study, flow cytometry, e-paper, etc. Microcapsules are also useful materials in different areas such as controlled release of drugs, perfumes, and insecticides. Conventional manufacturing techniques of these particulate materials are underlined by batch-wise chemical methods and physical methods. In chemical methods, polymer particles are synthesized from their monomers in which initiators are employed to start the polymerization reactions and terminators are used to end the reactions, and the reactions are usually performed under strictly controlled conditions. Sometimes, tough conditions are needed for the reaction which may cause damage to the structure and nature of some special additive components such as proteins and peptides. In addition, not all polymers can be made into spheres by polymerization process.
  • the polymer is usually dissolved in a solvent as the dispersed phase which is dispersed in a continuous phase in the presence of a surface-active substance as the surfactant or emulsifier.
  • a surface-active substance as the surfactant or emulsifier.
  • droplets of the polymer solution are generated by application of shear force through agitation, sonication or shaking, which are dispersed in the continuous phase with the protection of a surfactant layer. Formation of solid particles are attained when the dispersed phase solvent is removed via diffusion into the continuous phase across the surfactant layer surrounding the droplets and subsequent removal from the continuous phase via evaporation under gentle agitation.
  • the solvent must bear some special physical properties, including low boiling point and adequate solubility in water, apart from their solubilizing ability for the polymer. This is a basic reason why dichloromethane and some similar solvents are often used in the manufacturing of polymer microspheres.
  • an object of the present invention to provide a group of surfactant-free techniques for the manufacturing of polymeric microspheres and microcapsules.
  • methods comprising (1) providing a dispersed phase by dissolving one or more polymers in a water-immiscible solvent, (2) providing a continuous phase by mixing an amphiphilic solvent with water, (3) dispersing the dispersed phase in the form of droplets in the continuous phase in the absence of surfactant, and (4) de-solvation of the dispersed phase droplets in the continuous phase to form isotropic microspheres.
  • methods comprising (1) providing a core solution therein involving one or more polymers and/or other additive components dissolved in a solvent, (2) providing a shell solution by dissolving one or more polymers in a water-immiscible solvent, (3) providing a continuous phase by mixing an amphiphilic solvent with water, (4) dispersing a mixture of the core solution and the shell solution in the form of droplets in the continuous phase in the absence of surfactant, wherein the droplets are configured such that the core solution is substantially in the center of the droplets and the shell solution is adjacent to the core solution, (5) de-solvation of the droplets in the continuous phase therein to form core shell microspheres.
  • methods comprising (1) providing a first solution containing one or more polymers dissolved in a water-immiscible solvent, (2) providing a second solution containing one or more polymers dissolved in a water-immiscible solvent, (3) providing a continuous phase by mixing an amphiphilic solvent with water, (4) dispersing the first solution and the second solution as the dispersed phase in the continuous phase in the form of droplets in the absence of surfactant, (5) de-solvation of the droplets in the continuous phase to form Janus microspheres.
  • methods comprising (1) providing a core solution containing polymer and/or other components, (2) providing a shell solution by dissolving one or more polymers in a water-immiscible solvent, (3) providing a continuous phase by mixing an amphiphilic solvent with water, (4) dispersing a mixture of the core solution and the shell solution in the form of droplets in the continuous phase in the absence of surfactant, wherein the droplets are configured such that the core solution is substantially in the center of the droplets and the shell solution is adjacent to the core solution, (5) de-solvation of the droplets in the continuous phase therein to form microcapsules.
  • any water-immiscible solvent is applicable for the preparation of the polymer solution, wherein its boiling point is not a concern as in conventional emulsion-based techniques, thus low-toxic solvents can be preferably used in application.
  • the techniques are also well applicable.
  • the de-solvation of polymer solution droplets is substantially faster than conventional surfactant-based processes, wherein normally no more than several minutes is needed for complete de-solvation of the droplets with the present invention.
  • Yet another feature of the techniques is that the solvents, both for the polymer solution and for the continuous phase, are not released into the atmosphere but virtually recyclable.
  • a microfluidic system for droplet generation of the dispersed phase with a “T” type segmentation component as depicted by Fig. 4 for the manufacturing of isotropic polymeric microspheres, wherein the apparatus comprising a dispersed phase solution container, a dispersed phase solution pump, a first aqueous solution container, a first aqueous solution pump, a “T” type segmentation component, a second aqueous solution vessel, and a second aqueous solution contained in the vessel, wherein the segmentation component is positioned upwards at the bottom or downwards at the top of the continuous phase vessel, depending on the density of the dispersed phase relative to the continuous phase and the size of the microdroplets of the dispersed phase.
  • a microfluidic system as illustrated by Fig. 5 for droplet generation of the dispersed phase with a co-axial capillary segmentation component and manufacturing of isotropic polymer microspheres
  • the apparatus comprising a dispersed phase solution container, a dispersed phase solution pump, a first aqueous solution container, a first aqueous solution pump, a co-axial capillary segmentation component, a second aqueous solution vessel, and a second aqueous solution prefilled in the vessel, wherein the segmentation component is positioned upwards at the bottom or downwards at the top of the continuous phase vessel, depending on the density of the dispersed phase relative to the continuous phase and the size of the microdroplets of the dispersed phase.
  • the co-axial capillary segmentation component comprises a capillary called the first tube, another capillary surrounding the first tube called the second tube, and an orifice positioned at the end of the second tube.
  • the end of the first tube is inside the end of the second tube.
  • the first tube, the second tube and the orifice are co-axial and there is a gap between the end of the first tube and the orifice.
  • the dispersed phase solution and the first aqueous solution are delivered to the segmentation component wherein the dispersed phase solution flows through the first tube and the first aqueous solution flows through the second tube of the segmentation component and the dispersed phase solution is segmented by the first aqueous solution via hydrodynamic focusing at the entrance of the orifice and the segments of the dispersed phase solution are brought into the second aqueous solution through the orifice in the form of microdroplets which are de-solvated in the second aqueous solution to form isotropic microspheres.
  • polymer microspheres are obtained.
  • a microfluidic system for droplet generation of the dispersed phase with a segmentation component for the manufacturing of Janus polymer microspheres as illustrated by Fig. 6, wherein the apparatus comprises a first polymer solution container, a first polymer solution pump, a second polymer solution container, a second polymer solution pump, a first aqueous solution container, a first aqueous solution pump, a capillary segmentation component, a second aqueous solution vessel, and a second aqueous solution prefilled in the vessel, wherein the segmentation component is positioned upwards at the bottom or downwards at the top of the continuous phase vessel, depending on the density of the dispersed phase relative to the continuous phase and the size of the microdroplets of the dispersed phase.
  • the segmentation component comprises two pieces of capillary kept in parallel and adjacent called the first tube and the second tube, respectively, yet another capillary surrounding the two tubes called the third tube, and a tubular orifice positioned at the end of the third tube.
  • the ends of the first tube and the second tube are inside the end of the third tube and there is a gap between the end of the first and the second tubes and the orifice.
  • the first tube and the second tube normally have the same dimensions.
  • the first polymer solution, the second polymer solution and the first aqueous solution are delivered to the segmentation component wherein the first polymer solution flows through the first tube, the second polymer solution flows through the second tube, and the first aqueous solution flows through the third tube, all in the same direction, and outside the first tube and the second tube the first polymer solution stream and the second polymer solution stream flowing abreast are segmented by the first aqueous solution via hydrodynamic focusing at the entrance of the orifice and the segments of the first polymer solution and the second polymer solution are propelled into the second aqueous solution through the orifice in the form of microdroplets wherein the droplets are de-solvated to form Janus microspheres through solvent diffusion into the second aqueous solution.
  • Janus polymer microspheres are obtained.
  • a microfluidic system for droplet generation of the dispersed phase with a co-axial segmentation component for the manufacturing of core shell polymer microspheres as illustrated by Fig. 7, wherein the apparatus comprises a core solution container, a core solution pump, a shell solution container, a shell solution pump, a first aqueous solution container, a first aqueous solution pump, a co-axial capillary segmentation component, a second aqueous solution vessel, and a second aqueous solution prefilled in the vessel, wherein the co-axial capillary segmentation component comprising a capillary called the first tube, another capillary surrounding the first tube called the second tube, yet another capillary surrounding the second tube called the third tube, and an orifice positioned at the end of the third tube, wherein the segmentation component is positioned upwards at the bottom or downwards at the top of the continuous phase vessel, depending on the density of the dispersed phase relative to the continuous phase and the size
  • the first tube, the second tube, the third tube and the orifice are co-axial.
  • the ends of the first tube and the second tube are inside the end of the third tube and there is a gap between the end of the second tube and the orifice.
  • the core solution, the shell solution and the first aqueous solution are delivered to the segmentation component, wherein the core solution flows through the first tube, the shell solution flows through the second tube, and the first aqueous solution flows through the third tube, all in the same direction, and the core solution stream is surrounded by the shell solution stream outside the first tube and the second tube and the core and shell streams are segmented by the first aqueous solution via hydrodynamic focusing at the entrance of the orifice and the segments of the core solution and the shell solution are brought into the second aqueous solution through the orifice in the form of microdroplets, wherein the droplets are de-solvated to form core shell microspheres through solvent diffusion into the second aqueous solution.
  • a microfluidic system for droplet generation of the dispersed phase with a co-axial segmentation component for the manufacturing of polymeric microcapsules as illustrated by Fig. 7, wherein the apparatus comprising a core solution container, a core solution pump, a shell solution container, a shell solution pump, a first aqueous solution container, a first aqueous solution pump, a co-axial capillary segmentation component, a second aqueous solution vessel, and a second aqueous solution contained in the vessel, wherein the segmentation component is positioned upwards at the bottom or downwards at the top of the continuous phase vessel, depending on the density of the dispersed phase relative to the continuous phase and the size of the microdroplets of the dispersed phase.
  • the co-axial capillary segmentation component comprises a capillary called the first tube, another capillary surrounding the first tube called the second tube, yet another capillary surrounding the second tube called the third tube, and an orifice positioned at the end of the third tube.
  • the first tube and the second tube have their ends inside the end of the third tube.
  • the first tube, the second tube, the third tube and the orifice are all co-axial and there is a gap between the end of the first and the second tube and the orifice.
  • the core solution, the shell solution and the first aqueous solution are delivered to the segmentation component wherein the core solution flows through the first tube, the shell solution flows through the second tube, and the first aqueous solution flows through the third tube, all in the same direction, and the core solution stream is surrounded by the shell solution stream outside the first tube and the core and shell solution streams are segmented by the first aqueous solution via hydrodynamic focusing at the entrance of the orifice and the segments of the core solution and the shell solution are brought into the second aqueous solution through the orifice in the form of microdroplets wherein the droplets are de-solvated to form microcapsules through solvent diffusion into the second aqueous solution.
  • microcapsules with polymer shell are obtained.
  • a membrane emulsification apparatus for droplet generation of the dispersed phase for the manufacturing of isotropic polymeric microspheres as illustrated by Fig. 8, wherein the apparatus comprises a dispersed phase solution container, a dispersed phase solution pump, a microporous membrane, a continuous phase solution vessel and the continuous phase contained in the vessel.
  • the dispersed phase solution is delivered to the porous membrane for droplet generation and subsequent de-solvation in the continuous phase and isotropic polymer microsphere formation.
  • isotropic polymer microspheres are obtained.
  • a membrane emulsification apparatus for droplet generation of the dispersed phase for the manufacturing of core shell polymeric microspheres as illustrated by Fig. 8, wherein the apparatus comprises a dispersed phase solution container, a dispersed phase solution pump, a microporous membrane, a continuous phase solution vessel and a continuous phase contained in the vessel.
  • a core solution is first dispersed in a polymer shell solution dissolved in a water-immiscible solvent to form emulsion by mechanical agitation or sonication in advance and then the emulsion is delivered to and extruded out of the porous membrane for droplet generation and subsequent de-solvation in the continuous phase and multi-core core shell polymer microsphere formation.
  • core shell polymer microspheres are obtained.
  • the dispersed phase solution and the first aqueous solution are delivered to the segmentation component wherein the dispersed phase solution flows through the first tube in the segmentation component and the first aqueous phase solution flows through the second tube of the segmentation component and the dispersed phase solution is segmented by the first aqueous solution using frequency generation-based segmentation and the segments of the dispersed phase solution are brought into the second aqueous solution in the form of microdroplets which are de-solvated in the second aqueous solution to form isotropic microspheres.
  • isotropic polymer microspheres are obtained.
  • a manufacturing apparatus for droplet generation of the dispersed phase with frequency generation-based segmentation for the manufacturing of core shell polymer microspheres as illustrated by Fig. 10, wherein the apparatus comprising a core solution container, a core solution pump, a shell polymer solution container, a shell polymer solution pump, a first aqueous solution container, a first aqueous solution pump, a co-axial segmentation component, a frequency generator, a second aqueous solution vessel, and a second aqueous solution contained in the vessel. Similar to that in Fig.
  • the co-axial segmentation component comprises a capillary called the first tube, another capillary surrounding the first tube called the second tube, yet another capillary surrounding the second tube called the third tube, and a frequency generator and a piezoelectric buzzing ceramic piece.
  • the core solution, the shell solution and the first aqueous solution are delivered to the segmentation component wherein the core solution flows through the first tube, the shell solution flows through the second tube, and the first aqueous solution flows through the third tube, all in the same direction, and out of the first tube and the second tube, the core solution stream is surrounded by the shell solution stream and the core and shell solution streams are segmented by the first aqueous solution via the high-frequency energy exerted by the piezoelectric ceramic buzzing piece surrounding the third tube and the segments of the core solution and the shell solution are brought into the second aqueous solution in the form of core shell microdroplets wherein the droplets are de-solvated to form core shell microspheres through solvent diffusion into the second a
  • the co-axial segmentation component comprises a capillary called the first tube, another capillary surrounding the first tube called the second tube, yet another capillary surrounding the second tube called the third tube, and a piezoelectric ceramic buzzing piece surrounding the third tube at its end.
  • Fig. 1. illustrates the flow chart for the process of lab-scale surfactant-free preparation of isotropic polymer microspheres.
  • Fig. 2. illustrates the flow chart for the process of lab-scale surfactant-free preparation of core shell polymer microspheres and microcapsules.
  • Fig. 3 illustrates the flow chart for the process of lab-scale surfactant-free preparation of Janus microspheres.
  • Fig. 4 illustrates the configuration of the device with “T” -type segmentation component for droplet generation and manufacturing of isotropic polymeric microspheres.
  • Fig. 5. illustrates the configuration of the device with co-axial segmentation component for droplet generation and manufacturing of isotropic polymeric microspheres.
  • Fig. 7. illustrates the configuration of the device for co-axial droplet generation and manufacturing of core shell polymeric microspheres as well as microcapsules.
  • Fig. 9. illustrates the configuration of frequency generation-based segmentation device for the droplet generation and manufacturing of isotropic polymeric microspheres.
  • Fig. 10 illustrates the configuration of the device with frequency generation-based segmentation device for droplet generation and manufacturing of core-shell polymeric microspheres and microcapsules.
  • Fig. 11. illustrates the SEM image of the microspheres manufactured in Example 1.
  • Fig. 13. illustrates the SEM image of the microspheres manufactured in Example 3.
  • Fig. 14. illustrates the SEM image of the microspheres manufactured in Example 4.
  • Fig. 15. illustrates the SEM image of the microspheres manufactured in Example 5.
  • Fig. 19. illustrates the SEM image of the microspheres manufactured in Example 9.
  • Fig. 20 illustrates the SEM image of the microspheres manufactured in Example 10.
  • Fig. 21 illustrates the SEM image of the microspheres manufactured in Example 11.
  • Fig. 22. illustrates the optical image of the microspheres manufactured in Example 12.
  • Fig. 23. illustrates the optical image of the microspheres manufactured in Example 13.
  • Fig. 24 illustrates the fluorescent image of the microspheres manufactured in Example 14.
  • Fig. 25 illustrates the SEM image of the microspheres manufactured in Example 15.
  • Fig. 26 illustrates the confocal microscopic image of the microspheres in Example 16.
  • Fig. 27 illustrates the SEM image of the microspheres manufactured in Example 17.
  • Fig. 28. illustrates the SEM image of the microspheres manufactured in Example 18.
  • Fig. 29. illustrates the transmission optical image of the microcapsules manufactured in Example 19.
  • Fig. 30 illustrates the transmission optical image of the microcapsules manufactured in Example 20.
  • Fig. 31. illustrates the SEM image of the microspheres manufactured in Example 21.
  • Fig. 32. illustrates the SEM image of the microspheres manufactured in Example 22.
  • Fig. 33 illustrates the SEM image of the microspheres manufactured in Example 23.
  • the terms “capillary” , “tubing” , “tube” , “container” , “vessel” and “connect” should be understood in a broad sense; for example, there may be a bottle, a flask, a beaker, a glass cylinder, or a plastic container as the used term “container” .
  • the two terms “polymer microsphere” and “polymeric microsphere” are virtually identical in this application.
  • the two terms “segmentation component” and “droplet generator” are identical components. For those skilled in the art, specific meanings of the above terms in the present application can be understood through specific situations.
  • the present application generally relates to a group of techniques of surfactant-free manufacturing of polymeric microspheres and microcapsules with microfluidic droplet generation, membrane emulsification droplet generation, and frequency generation-based droplet generation.
  • Polymeric microspheres and microcapsules are especially valuable and useful in different areas including LCD screen spacer, drug delivery, medical research and application, flow cytometry, chemical analysis, environmental analysis, e-paper, etc.
  • concerns relating to the manufacturing of polymer microspheres and microcapsules include the use of surface-active substances and highly toxic solvents and their consequent impacts on the manufacturing process and the quality of the products.
  • alternative techniques which can eliminate the impact of surface-active substances and highly toxic solvents are highly desired.
  • FIG. 1. illustrates the flow chart for the process of preparation of isotropic polymer microspheres, wherein the process includes: 1) Preparing a dispersed phase by dissolving a polymer (and sometimes incorporating other additive components such as therapeutic agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc. ) in a water-immiscible solvent; 2) Preparing a continuous phase by mixing an amphiphilic solvent with water; 3) Generating droplets of the dispersed phase in the continuous phase by dispersing the dispersed phase into the continuous phase with the aid of droplet generation device such as “T” segmentation component (Fig.
  • the polymers used in the present invention are selected from the group consisting of: poly (vinyl chloride) (PVC) , polystyrene (PS) , poly lactic acid (PLA) , poly (lactic acid-co-glycolic acid) (PLGA) , polycaprolactone (PCL) , polyvinylidene fluoride (PVDF) , poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) , polymethyl methacrylate (PMMA) , ethyl cellulose (EC) , and tri-cellulose acetate (TCA) , but not limited thereto.
  • PVC poly (vinyl chloride)
  • PS polystyrene
  • PLA poly lactic acid
  • PLGA poly (lactic acid-co-glycolic acid)
  • PCL polycaprolactone
  • PVDF polyvinylidene fluoride
  • PVDF-HFP poly (vinylid
  • the weight-average molecular weight of the above polymers is not particularly limited, but ranges between 3,000 and 500,000 Da, preferably between 3,000 and 200,000 Da, and more preferably between 3,000 and 100,000 Da. Selection of the polymers is the same in all the following embodiments.
  • the water-immiscible solvents used in the present invention are selected from the types of: ether, ester, alkene, ketone, aromatic hydrocarbon, halogenated hydrocarbon.
  • ether solvent for the dispersed phase preparation are dibutyl ether, methyl phenyl ether, and 2-methyl tetrahydrofuran, but not limited thereto.
  • ester solvent for the dispersed phase preparation are ethyl acetate, butyl acetate, and ethyl benzoate, but not limited thereto.
  • Examples of ketone solvent for the dispersed phase preparation are methyl isobutyl ketone, cyclohexanone, but not limited thereto.
  • Examples of aromatic hydrocarbon solvents for the dispersed phase preparation are benzene, toluene, xylene, and trimethylbenzene, but not limited thereto.
  • Examples of halogenated hydrocarbon solvents for the dispersed phase preparation are dichloromethane, chloroform, tetrachloromethane, dibromomethane, and iodomethane, but not limited thereto. Selection of the water-immiscible solvents is the same in all the following embodiments.
  • Amphiphilic solvents for the preparation of the continuous phase are selected from alcohol, ether, aldehyde, ketone, ester, nitrile, sulfone, amide, and heterocyclic compounds.
  • alcohol for the continuous phase preparation are methanol, ethanol, ethylene glycol, and glycerine, but not limited thereto.
  • ether for the continuous phase preparation are ethyl ether, butyldiglycol ether, tetrahydrofuran, but not limited thereto.
  • aldehyde for the continuous phase preparation is acetaldehyde, but not limited thereto.
  • Example of ketone for the continuous phase preparation is acetone, but not limited thereto.
  • ester for the continuous phase preparation examples include ethyl glycolate, 2-ethoxyethyl acetate, and ethylene glycol diacetate, but not limited thereto.
  • nitrile for the continuous phase preparation is acetonitrile, but not limited thereto.
  • sulfone for the continuous phase preparation is dimethyl sulfoxide, but not limited thereto.
  • amide for the continuous phase preparation are N, N-dimethyl formamide and N, N-dimethyl acetamide, but not limited thereto.
  • heterocyclic compound for the continuous phase preparation is N-methylpyrrolidin-2-one, but not limited thereto. Selection of the amphiphilic solvents is the same in all the following embodiments.
  • FIG. 2. illustrates the flow chart for the process of surfactant-free preparation of core shell polymer microspheres, wherein the process includes: 1) Preparing a core solution by dissolving one or more polymers (and sometimes incorporating other additive components such as pharmaceutical agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc. ) in a solvent; 2) Preparing a shell solution by dissolving one or more polymers (and sometimes incorporating other additive components such as pharmaceutical agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc.
  • FIG. 2 also illustrates the flow chart for the process of surfactant-free preparation of microcapsules with polymer shell, wherein the process includes: 1) Preparing a core solution by dissolving a polymer and/or other components such as therapeutic agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc. in a liquid medium; 2) Preparing a shell solution by dissolving a polymer (and sometimes incorporating other additive components such as pharmaceutical agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc.
  • Fig. 3 illustrates the flow chart for the process of preparation of Janus microspheres, wherein the process includes: 1) Preparing a first solution by dissolving one or more polymers (and sometimes incorporating other additive components such as pharmaceutical agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc.
  • additive components such as pharmaceutical agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc.
  • a second solution by dissolving one or more polymers (and sometimes incorporating other additive components such as pharmaceutical agent, protein, peptide, nucleic acid, antibody, nanoparticles, magnetic nanoparticles, dyes, fluorescent dyes, quantum dots, flavors, graphene, carbon nanotube, etc. ) in a water-immiscible solvent; 3) Preparing a continuous phase by mixing an amphiphilic solvent with water; 4) With the first solution and the second solution together as the dispersed phase, generating droplets of the dispersed phase in the continuous phase by dispersing the dispersed phase into the continuous phase with the aid of droplet generation device (Fig.
  • Fig. 4 Shown in Fig. 4 is the apparatus for lab-scale manufacturing of isotropic polymer microspheres based on a surfactant-free mechanism wherein the manufacturing process includes: 1) The polymer solution prepared in a water-immiscible solvent as the dispersed phase is delivered into a “T” segmentation component and a first aqueous solution is delivered as the segmentation agent to the segmentation component wherein the polymer solution stream is segmented by the first aqueous solution stream and droplets of the polymer solution are therein formed; 2) The therein formed polymer solution droplets are brought into the second aqueous solution as the continuous phase, i.e. a mix of amphiphilic solvent and water, pre-filled in its vessel; 3) The polymer solution droplets are de-solvated via solvent diffusion into the continuous phase and subsequently form isotropic solid polymer microspheres.
  • the manufacturing process includes: 1) The polymer solution prepared in a water-immiscible solvent as the dispersed phase is delivered into a “T
  • the role of the first aqueous solution is to flow between or around the dispersed phase and maintain them in relative contact and to provide an aqueous solution in the mixing zone such that at a certain point, droplets of the dispersed phase are formed due to the large difference in surface tension between the dispersed phase and the first aqueous solution and the shear force exerted to the dispersed phase flow by the first aqueous solution flow.
  • the first aqueous solution serves as a carrier for the droplets into the continuous phase prefilled in the continuous phase vessel.
  • the first aqueous solution may be water per se, however, it has been found that it is preferably saturated by the solvent of the dispersed phase solution (the solvent for the shell solution in case of core shell microspheres and microcapsules) . This is useful for prevention of polymer precipitation in the segmentation component due to possible considerable solubility of the solvent for the dispersed phase in water.
  • Fig. 5 Shown in Fig. 5 is the apparatus for lab-scale manufacturing of isotropic polymer microspheres based on a surfactant-free mechanism wherein the manufacturing process includes: 1) The polymer solution prepared in a water-immiscible solvent as the dispersed phase is delivered into a co-axial segmentation component and a first aqueous solution is delivered as the segmentation agent to the segmentation component wherein the polymer solution stream is segmented by the first aqueous solution stream and droplets of the polymer solution are therein formed; 2) The therein formed polymer solution droplets are brought to a second aqueous solution as the continuous phase, i.e. a mix of amphiphilic solvent and water, pre-filled in its vessel; 3) The polymer solution droplets are de-solvated via solvent diffusion into the continuous phase and subsequently form isotropic solid polymer microspheres.
  • the manufacturing process includes: 1) The polymer solution prepared in a water-immiscible solvent as the dispersed phase is delivered into a co
  • FIG. 6 Shown in Fig. 6 is the apparatus for lab-scale manufacturing of Janus polymer microspheres based on a surfactant-free mechanism wherein the manufacturing process includes: 1) A first polymer solution and a second polymer solution both prepared in water-immiscible solvent as the dispersed phase are delivered into a segmentation component and a first aqueous solution is delivered as the segmentation agent to the segmentation component wherein the first polymer solution and second polymer solution streams are segmented by the first aqueous solution stream and Janus droplets of the first polymer solution and second polymer solution are therein formed; 2) The therein formed Janus droplets are brought to a second aqueous solution as the continuous phase, i.e. a mix of amphiphilic solvent and water, pre-filled in its vessel; 3) The dispersed phase droplets are de-solvated via solvent diffusion into the continuous phase and subsequently form Janus microspheres.
  • the manufacturing process includes: 1) A first polymer solution and a second polymer solution both prepared in water
  • Fig. 7 Shown in Fig. 7 is the apparatus for lab-scale manufacturing of core shell polymer microspheres based on a surfactant-free mechanism wherein the manufacturing process includes: 1) A core solution prepared in a solvent and a shell solution prepared in a water-immiscible solvent as the dispersed phase are delivered into a co-axial segmentation component and a first aqueous solution is delivered as the segmentation agent to the segmentation component wherein the core solution and shell solution streams form co-axial flow which is segmented by the first aqueous solution stream and core shell droplets of the core solution and shell solution are therein formed; 2) The therein formed droplets are brought into a second aqueous solution as the continuous phase, i.e. a mix of amphiphilic solvent and water, pre-filled in its vessel; 3) The dispersed phase droplets are de-solvated via solvent diffusion into the continuous phase and subsequently form core shell solid polymer microspheres.
  • the manufacturing process includes: 1) A core solution prepared in a solvent and a
  • Fig. 7 also illustrates the apparatus for lab-scale manufacturing of microcapsules based on a surfactant-free mechanism wherein the manufacturing process is similar to that for core shell microspheres.
  • Fig. 8 Shown in Fig. 8 is the apparatus also for manufacturing of core shell polymer microspheres based on a surfactant-free mechanism wherein the manufacturing process includes: 1) A polymer solution in a solvent as the core solution (referred to as the first solution) dispersed in a polymer solution in a water-immiscible solvent as the shell solution (referred to as the second solution) by emulsification to form an emulsion by sonication, agitation, or shaking, and the emulsion as the dispersed phase is delivered into a porous membrane emulsifier and extruded out of the micropores of the membrane to get multi-core shell microdroplets; 2) The therein formed droplets are brought to an aqueous solution as the continuous phase, i.e. a mix of amphiphilic solvent and water, pre-filled in its vessel; 3) The dispersed phase droplets are de-solvated via solvent diffusion into the continuous phase and subsequently form multi-core shell polymer microspheres.
  • Fig. 9 Shown in Fig. 9 is the apparatus for manufacturing of isotropic polymer microspheres based on a surfactant-free mechanism wherein the manufacturing process includes: 1) The polymer solution prepared in a water-immiscible solvent as the dispersed phase is delivered into a co-axial segmentation component and a first aqueous solution is delivered as the segmentation agent to the segmentation component wherein the polymer solution stream is segmented by the first aqueous solution stream with the aid of a piezoelectric ceramic buzzing piece and a frequency generator and droplets of the polymer solution are therein formed; 2) The therein formed polymer solution droplets are brought into a second aqueous solution as the continuous phase, i.e. a mix of amphiphilic solvent and water, pre-filled in its vessel; 3) The polymer solution droplets are de-solvated via solvent diffusion into the continuous phase and subsequently form isotropic solid polymer microspheres.
  • the manufacturing process includes: 1) The polymer solution prepared in a water-imm
  • Fig. 10 Shown in Fig. 10 is the apparatus for manufacturing of core shell polymer microspheres based on a surfactant-free mechanism wherein the manufacturing process includes: 1) A core solution prepared in a solvent and a shell polymer solution prepared in a water-immiscible solvent as the dispersed phase are delivered into a co-axial segmentation component and a first aqueous solution is delivered as the segmentation agent to the segmentation component wherein the core solution and shell solution streams form co-axial flow which is segmented by the first aqueous solution stream with the aid of a piezoelectric ceramic buzzing piece and a frequency generator and core shell droplets of the core solution and shell solution are therein formed; 2) The therein formed droplets are brought into a second aqueous solution as the continuous phase, i.e. a mix of amphiphilic solvent and water, pre-filled in its vessel; 3) The dispersed phase droplets are de-solvated via solvent diffusion into the continuous phase and subsequently form core shell solid polymer microspheres.
  • Fig. 10 also illustrates the apparatus for manufacturing of microcapsules based on a surfactant-free mechanism wherein the manufacturing process is similar to that for core shell microspheres.
  • the critical/important parameters are the hydrophilicity of the wall of the segmentation components, the concentration of the dispersed phase, the ratio between the amphiphilic solvent and water in the continuous phase, the interfacial tension between the dispersed phase and the continuous phase, the viscosity of the dispersed phase, the sizes of the tubes in the segmentation component, the pore size of the membrane in the membrane emulsification device, the frequency of the frequency generation device, and the flow rates of the fluid streams. It is possible to fix the hydrophilicity of the segmentation components by using stainless steel “T” , stainless steel tube, glass tube, stainless-steel orifice, and glass orifice.
  • the concentration of PMMA dissolved in ethyl acetate (EA) was varied between 0.5%and 4% (weight %) while holding the channel dimensions and the incoming flow rates constant by using the manufacturing apparatus shown in Fig. 5. It has been shown that the increase in PMMA concentration resulted in increase of the diameter of the microspheres between 20.6 ⁇ m and 48.9 ⁇ m, as shown in Table 1.
  • Example 1 Manufacturing of isotropic PMMA microspheres with microfluidic device with a “T” -segmentation component
  • the device shown in Fig. 4 was used for the manufacturing of isotropic PMMA microspheres.
  • the dispersed phase and water were delivered into the segmentation component through PTHF tubing with s
  • Example 2 Manufacturing of isotropic PVC microspheres with microfluidic device with a co-axial segmentation component
  • Example 3 Manufacturing of isotropic PMMA microspheres with microfluidic device with a co-axial segmentation component
  • Example 4 Manufacturing of isotropic PMMA microspheres with microfluidic device with a co-axial segmentation component
  • Example 5 Manufacturing of isotropic PMMA microspheres with microfluidic device with a co-axial segmentation component
  • Example 6 Manufacturing of isotropic PMMA microspheres with microfluidic device with a co-axial segmentation component
  • Example 7 Manufacturing of PS microspheres with microfluidic device with a co-axial segmentation component
  • Example 8 Manufacturing of porous PS microspheres with microfluidic device with a co-axial segmentation component
  • Example 10 Manufacturing of PLGA microspheres incorporated with paclitaxel with microfluidic device with a co-axial segmentation component
  • Example 11 Manufacturing of poly (lactic acid) microspheres incorporated with promethazine hydrochloride with microfluidic device with a co-axial segmentation component
  • Example 12 Manufacturing of magnetic PMMA microspheres incorporated with Fe 3 O 4 nanoparticles with microfluidic device with a co-axial segmentation component
  • Example 13 Manufacturing of colored PMMA microspheres incorporated with methyl red with microfluidic device with a co-axial segmentation component
  • the SEM image of the Janus microsphere is shown in Fig. 25.
  • CLSM confocal laser scanning microscope
  • Example 17 Manufacturing of magnetic core shell microspheres with microfluidic device
  • the SEM image of the core shell microsphere
  • Example 18 Manufacturing of Paclitaxel incorporated core shell microspheres with microfluidic device
  • the SEM image of the core shell microsphere is shown in Fig. 28.
  • Example 19 Manufacturing of ⁇ -carotene encapsulated microcapsules with microfluidic device
  • the transmission optical image of the microcapsules is shown in Fig. 29.
  • Example 20 Manufacturing of ⁇ -tocopherol and ⁇ -carotene encapsulated microcapsules with microfluidic device
  • the transmission optical image of the microcapsules is shown in Fig. 30.
  • Example 21 Manufacturing of microspheres with membrane emulsification device
  • a circular poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) membrane with pore size of 5 ⁇ m, thickness of 2 mm, and diameter of 10 mm; 3) A continuous phase vessel with an inner diameter of 300 mm and a height of 1,000 mm; 4) A composition of the continuous phase of ethanol: water 5: 95 (v/v) and a continuous phase volume of 40 L; 5) A dispersed phase flow rate of 2.5 mL min -1 ; and 6) A temperature at 25 ⁇ 2 °C.
  • the SEM image of the microspheres is shown in Fig. 31.
  • Example 22 Manufacturing of microspheres with frequency generation-based segmentation
  • Example 23 Manufacturing of core shell microspheres with frequency generation-based segmentation
  • the first tube a stainless steel capillary with inner diameter of 500 ⁇ m and length of 9 cm; the second tube: a stainless steel capillary with inner diameter of 1,000 ⁇ m and length of 9 cm, the third tube: a glass tube with inner diameter of 1,800 ⁇ m and length of 10 cm; a piezoelectric ceramic buzzing piece surrounding the third tube at its end; a frequency generator connected to the piezoelectric ceramic buzzing piece operated at 20 K Hz; 3)
  • a continuous phase vessel (referred to as the fourth tube) with an inner diameter of 60 mm and a height of 400 mm; 4)
  • a composition of the continuous phase of ethanol: water 10: 90 (v/v) and a continuous phase volume of 1000 mL; 5) A first solution flow rate of 200 ⁇ L min -1 , a second solution flow rate of 100 ⁇ L min -1 , and water as the first aqueous solution with flow rate of 2,000 ⁇ L min -1 ; and 6) A temperature at 25 ⁇ 2 °C.

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Abstract

Sont divulgués un groupe de procédés sans tensioactif pour la fabrication de microsphères et de microcapsules polymères. Les procédés de fabrication impliquent la génération de gouttelettes en l'absence de substances tensioactives et la désolvatation des gouttelettes par diffusion de solvant dans une phase continue composée d'un mélange de solvant amphiphile et d'eau. Les procédés impliquent des approches pour la fabrication de microsphères polymères isotropes, de microsphères polymères coeur-écorce, de microsphères Janus et de microcapsules. Dans la fabrication de microsphères polymères isotropes, un polymère ou un polymère plus des composants additifs sont dissous dans un solvant organique non miscible dans l'eau pour obtenir une phase dispersée. Un mélange de solvant amphiphile et d'eau est utilisé en tant que phase continue. La phase dispersée est transformée en gouttelettes dans la phase continue et dans celle-ci dé-solvatée par diffusion de solvant en l'absence de tensioactif pour former des microsphères isotropes solides. Dans la fabrication de microsphères Janus, deux solutions polymères dissoutes chacune dans un solvant organique non miscible dans l'eau forment une phase dispersée. Un mélange de solvant amphiphile et d'eau est utilisé en tant que phase continue. La phase dispersée est transformée en gouttelettes dans la phase continue et dans celle-ci dé-solvatée par diffusion de solvant en l'absence de tensioactif pour former des microsphères Janus solides. Dans la fabrication de microsphères de polymère cœur-écorce, une solution de cœur dans un solvant et une solution de polymère d'écorce dissoute dans un solvant organique non miscible dans l'eau forment une phase dispersée. Un mélange de solvant amphiphile et d'eau est utilisé en tant que phase continue. La phase dispersée est transformée en gouttelettes dans la phase continue et dans celle-ci dé-solvatée par diffusion de solvant en l'absence de tensioactif pour former des microsphères de coque à cœur solide. Dans la fabrication de microcapsules avec une écorce polymère, une solution de cœur dans un solvant et une solution de polymère d'écorce dissoute dans un solvant organique non miscible dans l'eau forment la phase dispersée. Un mélange de solvant amphiphile et d'eau est utilisé en tant que phase continue. La phase dispersée est transformée en gouttelettes dans la phase continue et dans celle-ci dé-solvatée par diffusion de solvant en l'absence de tensioactif pour former des microcapsules. Au moyen de ces procédés, les problèmes provoqués par l'utilisation de tensioactifs sont éliminés, l'utilisation de solvants toxiques est réduite au minimum, le débit des processus de fabrication est développé au maximum, et la libération de solvants toxiques dans l'atmosphère et leur pollution résultante sont réduites au minimum tandis que les solvants peuvent être recyclés.
PCT/CN2023/076041 2022-07-07 2023-02-15 Procédés de préparation sans tensioactif de microsphères et de microcapsules polymères WO2024007588A1 (fr)

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CN202211164516.0A CN117797118A (zh) 2022-09-23 2022-09-23 一种聚合物核壳微球及其制备方法和应用
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