WO2020048435A1 - 一种聚合物粒子的制备方法 - Google Patents

一种聚合物粒子的制备方法 Download PDF

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WO2020048435A1
WO2020048435A1 PCT/CN2019/104138 CN2019104138W WO2020048435A1 WO 2020048435 A1 WO2020048435 A1 WO 2020048435A1 CN 2019104138 W CN2019104138 W CN 2019104138W WO 2020048435 A1 WO2020048435 A1 WO 2020048435A1
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solution
droplets
gelable
pipeline
preparation
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PCT/CN2019/104138
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French (fr)
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胡权
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胡权
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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0062—General methods for three-dimensional culture
    • 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
    • C08J2325/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Derivatives of such polymers
    • C08J2325/02—Homopolymers or copolymers of hydrocarbons
    • C08J2325/04—Homopolymers or copolymers of styrene
    • C08J2325/06—Polystyrene
    • 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
    • C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
    • C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
    • 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
    • C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
    • C08J2405/04—Alginic acid; Derivatives thereof
    • 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
    • C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
    • C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • 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
    • C08J2433/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
    • C08J2433/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters
    • C08J2433/06—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters of esters containing only carbon, hydrogen, and oxygen, the oxygen atom being present only as part of the carboxyl radical
    • C08J2433/10—Homopolymers or copolymers of methacrylic acid esters
    • C08J2433/12—Homopolymers or copolymers of methyl methacrylate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2513/00—3D culture
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C12N2533/40—Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers

Definitions

  • the invention relates to the field of material preparation, in particular to a method for preparing polymer particles.
  • Drug-loaded microspheres with a diameter of 50 to 500 microns can be widely used in long-acting release or interventional therapy; polymer porous scaffolds with a diameter of 50 to 2000 microns can be used as carriers for cell culture or drug release carriers; Microspheres can be used for cell separation, and microspheres with fluorescent dyes can be used for detection; double-layered capsules with a diameter of 1 to 4 mm are widely used in the production of perfume packages and pop-up cigarettes.
  • the first step is to first establish a dispersion system.
  • a dispersion system refers to a system in which one or more substances are dispersed in a certain medium.
  • the dispersed substance is called dispersion Phase
  • the continuous medium is a dispersion medium or a continuous phase.
  • the second step is to solidify the dispersed phase into hard particles by solvent evaporation or polymerization.
  • the traditional method of establishing a dispersed phase is generally to divide the dispersed phase into small droplets under the action of a shearing force through a stirring or homogenizer.
  • a typical preparation method of polylactic acid microspheres polylactic acid is dissolved in chloroform as a dispersed phase; an aqueous solution of PVA and Span 80 (span80) is a continuous phase. The two are mixed to obtain the upper layer.
  • the layered system is water and the lower layer is chloroform. Place the system on a stirrer and turn on the machine.
  • the trichloromethane solution of polylactic acid will be dispersed into small droplets due to the shearing action of the suspension. In the dispersed phase.
  • the traditional solvent volatilization or polymerization reaction to prepare polymer particles generally requires a long time stirring after the dispersion system is established so that the dispersed phase is suspended in the dispersion medium.
  • the preparation of typical polylactic acid microspheres is continued as an example. After the system is established, it is necessary to continue stirring for more than ten hours to allow chloroform to evaporate in order to obtain solid particles.
  • the following problems may exist:
  • the stirring force is not enough, and the droplets are aggregated at the bottom or upper part due to gravity.
  • the stirring force is too strong, and the stirring shearing force may cause the droplets to break up again.
  • the technical problem to be solved by the present invention is to provide a method for preparing polymer particles, which can obtain particles with good uniformity.
  • the present invention provides a method for preparing polymer particles:
  • the gel is dissolved.
  • the functional material may be uniformly distributed in the polymer solution and / or the reactive monomer in a homogeneous state, or may be in a heterogeneous state. , Is dispersed or encapsulated in a polymer solution and / or a reactive monomer.
  • the gelable solution encapsulating the droplets forms gel fibers after gelation in the coagulation bath.
  • the gelled solution containing the droplets is added to a coagulation bath while the coagulation bath is moved relative to the discharge port 100.
  • the gel fibers are stretched while the gel fibers are being formed.
  • the droplets are wrapped by a gelable solution while the droplets are being formed.
  • the droplets are wrapped by a gelable solution while the droplets are being formed, and the droplet forming and wrapping device is used to complete the droplet formation.
  • the droplet formation wrapping device includes:
  • the first cavity communicates with the second cavity through a droplet forming hole.
  • a conduit is provided at the outlet of the second pipeline and the fifth pipeline.
  • the gelable solution is an ion-sensitive system solution, or a pH-sensitive system solution, or a temperature-sensitive solution.
  • the ion-sensitive system solution is a sodium alginate solution—a polyvalent salt solution system.
  • the pH-sensitive system solution is a chitosan hydrochloric acid solution-sodium hydroxide solution system.
  • the temperature-sensitive solution is a poloxamer solution.
  • the functional material is one or more of protein molecules, or drug molecules, or nanoparticles, or magnetic particles, or fluorescent dyes, or flavors, or fragrances, or pore-forming agents, or quantum dots.
  • the combination is one or more of protein molecules, or drug molecules, or nanoparticles, or magnetic particles, or fluorescent dyes, or flavors, or fragrances, or pore-forming agents, or quantum dots. The combination.
  • the polymer solution is a polylactic acid-glycolic acid copolymer solution, or a polylactic acid solution, or a polymethyl methacrylate solution, or a combination of one or more of the polycaprolactone solutions;
  • the reactive monomer is, or styrene, or a combination of one or more of divinylbenzene, acrylic acid, and methacrylic acid.
  • the method for preparing polymer particles provided by the present invention has the following advantages:
  • the droplets formed by the polymer solution and / or reactive monomer containing functional materials are solidified in the environment after the gelled solution is wrapped and formed into a gel. Due to the huge viscosity of the gel, the droplets do not Collisions will occur, no aggregation effect will occur, no stirring is required during the solvent volatilization and solidification process, and the damage of the droplets by the shear force is avoided, so that particles with good uniformity can be obtained.
  • a surfactant is used to reduce the surface tension to maintain the stability of the droplets.
  • a surfactant may not be used.
  • FIG. 1 is a preparation flow chart of the present invention
  • FIG. 1 three forms of droplet formation according to the present invention.
  • the functional materials are uniformly distributed in the polymer solution and / or the reactive monomer in a homogeneous state;
  • the functional materials are uniformly dispersed in the polymer solution and / or the reactive monomer in a heterogeneous state;
  • FIG. 3 is a schematic structural diagram of a droplet forming and wrapping device according to an embodiment of the present invention.
  • FIG. 4 is a schematic structural diagram of another droplet forming and wrapping device according to an embodiment of the present invention.
  • FIG. 5 is a schematic structural diagram of a droplet forming and wrapping device with a stretching structure according to an embodiment of the present invention
  • FIG. 6 is a schematic structural diagram of a third type of droplet forming and wrapping device according to an embodiment of the present invention.
  • FIG. 7 is a schematic structural diagram of a fourth droplet forming and wrapping device according to an embodiment of the present invention.
  • Example 8 is a photomicrograph of a droplet in a gel in Example 1 of the present invention.
  • Example 9 is a photomicrograph of a 100 micron particle in Example 1 of the present invention.
  • FIG. 10 is a particle light micrograph of the seventh embodiment.
  • 61 first cavity
  • 62 second cavity
  • 63 droplet formation hole
  • an embodiment of the present invention provides a method for preparing polymer particles.
  • the method includes the following steps:
  • a polymer solution and / or a reactive monomer 71 containing a functional material is formed into droplets 711;
  • the gel is dissolved.
  • the polymer solution and / or the reactive monomer 71 containing the functional material is a dispersed phase
  • the gelable solution 72 is a continuous phase to make the gelable
  • the gelation of the solution 72 is a coagulation bath 73.
  • mechanical particles are generally used to prepare polymer particles.
  • the process is as follows.
  • the dispersed phase is added to the dispersion medium, a suitable surfactant is added, and the dispersed phase is turned into a liquid by stirring or a homogenizer.
  • the drops are dispersed in a dispersion medium.
  • the solvent is volatilized or the monomers are polymerized through long-term stirring to obtain solid polymer particles.
  • the dispersed phase still needs a long time to volatilize the solvent or carry out the polymerization reaction.
  • Continuous stirring at this stage will cause the formed particles to aggregate due to interfacial tension, gravity, collision, etc.
  • the shearing force is broken due to stirring, or the shearing force is different due to the different flow velocity of each point in the container, which causes the particle size distribution to widen.
  • the method for preparing the polymer particles provided in the embodiment of the present invention, because the dispersed phase is confined in the gel, the particles cannot be brought into contact, and there is no traditional due to interfacial tension, gravity, or collision. Aggregation, or fragmentation due to agitated shearing forces, or different shearing forces due to different flow rates at various points in the container, and other problems such as widening of particle size distribution. This makes it possible to produce uniform particles.
  • the functional materials in the examples of the present invention refer to ingredients added in order to make the prepared particles have certain uses.
  • the component can be a drug, a nanoparticle, a porogen, a fluorescent dye, a fragrance, or the like.
  • the functional material in the preparation of drug sustained-release microspheres, is a drug molecule; in the preparation of magnetic microspheres, the functional material is ferric oxide nanoparticles; in the preparation of fluorescent microspheres, the functional material is fluorescent dye or quantum Point; when preparing bead microspheres, it is the inner layer of spices or flavor substances.
  • the functional material 01 in this embodiment can be uniformly distributed in the polymer solution in a homogeneous state, or uniformly in a reactive monomer in a homogeneous state, or uniformly in a polymerized special solution in a homogeneous state.
  • the mixed liquid with the reactive monomer is shown in Fig. 2a.
  • the functional material 01 in this embodiment may also be dispersed in a polymer solution in a heterogeneous state, or in a reactive monomer, or in a mixed liquid composed of a polymer solution and a reactive monomer, such as Figure 2b.
  • the functional material 01 in this embodiment may also be wrapped in a polymer solution or a reactive monomer in a heterogeneous state, or in a mixed liquid composed of a polymer solution and a reactive monomer, such as Figure 2c.
  • step 103 the droplet 711 is wrapped by the gelable solution 72, and generally, the droplet 711 is wrapped by the gelable solution at the same time as the droplet 711 is formed. .
  • a droplet 711 forming and wrapping device is used to realize the formation and wrapping of the droplet 711.
  • the structure thereof is shown in FIG. 3, and the device includes a polymer solution and / or a reactive monomer for containing functional materials.
  • the polymer solution and / or the reactive monomer containing the functional materials are fed into the first pipe 31, and the condensable is fed into the second pipe 32 at the same time.
  • Gelatinized solution When this structure is used to achieve the formation and wrapping of the droplets 711, the polymer solution and / or the reactive monomer containing the functional materials are fed into the first pipe 31, and the condensable is fed into the second pipe 32 at the same time. Gelatinized solution.
  • the flow velocity of the liquid in the first pipeline 31 and the second pipeline 32 is controlled.
  • the velocity of the fluid in the inner and outer pipelines is relatively low, one droplet 711 will be formed directly at the outlet; when the velocity of the fluid in the inner and outer pipelines is higher, a coaxial fluid will be formed first.
  • the outer layer gels to form gel fibers, and the liquid inside the gel fibers changes from a continuously flowing liquid into droplets 711 under the effect of interfacial tension.
  • the droplets 711 are in a single row. The order is arranged inside the gel fibers. With this structure, since all the droplets 711 are formed through the first pipe 31, the uniformity of the formed droplets 711 is excellent.
  • the wrapping device 711 includes a third pipeline 41 for flowing a liquid containing functional materials, and is sleeved outside the third pipeline 41 and is coaxial with the third pipeline 41 for supplying a polymer solution and / or The fourth pipeline 42 through which the reactive monomer flows, and the fifth pipeline 43 sleeved outside the fourth pipeline 42 and coaxial with the fourth pipeline 42 and used for flowing the gelable solution.
  • the polymer solution and / or the reactive monomer are fed into the fourth pipe 42 while the liquid containing the functional material is fed into the third pipe 41, At the same time, a gelable solution is sent to the fifth line 43.
  • the third pipeline 41 and the fourth pipeline 42 are controlled to use the flow velocity of the liquid in the fifth pipeline 43.
  • the velocity of the fluid in the three pipelines is relatively low, droplets 711 are formed directly at the outlet.
  • the center of the droplet 711 is a functional material, and the outer layer of the droplet 711 is a polymer solution.
  • the droplet 711 is wrapped by a gelable solution; when the fluid velocity of the three pipelines is high, a coaxial fluid is formed first, and then the outermost layer is gelled to form Gel fibers, and the liquid inside the gel fibers changes from a continuously flowing liquid into droplets 711 under the effect of interfacial tension.
  • the droplets 711 are arranged in a single row in an orderly manner inside the gel fibers. At this time, the center of the droplet 711 is a functional material, and the outer layer of the droplet 711 is a polymer solution and / or a reactive monomer.
  • the liquid droplet 711 forming wrapping device of this embodiment may also adopt a structure as shown in FIG. 6, which includes a first cavity 61 for placing a polymer solution containing a functional material and / or a reactive monomer; A second cavity 62 for the gelable solution to flow; the first cavity 61 and the second cavity 62 communicate with each other through a droplet forming hole 63.
  • a polymer solution containing functional materials and / or a reactive monomer are passed into the first cavity 61, and the polymer containing functional materials in the first cavity 61 is passed.
  • the solution and / or reactive monomer will flow to the second cavity 62 through the droplet formation hole 63, and form a droplet 711 when entering the second cavity 62, and attach to the inner wall of the second cavity 62, and at the same time, go to the second cavity
  • a gelatinizable solution is passed into 62, and the droplets 711 attached to the inner wall of the second cavity 62 are washed out by the gelable solution to complete the encapsulation of the droplets 711 by the gelable solution.
  • Both the first cavity 61 and the second cavity 62 in this structure are preferably tubular cavities. Of course, it is also possible to divide a cavity into two parts through a partition, one of which is the first cavity 61 and the other is the second cavity 62, and the droplet forming hole 63 is provided on the partition. At this time, the The shape is not limited.
  • the first cavity 61 is a pipeline
  • the second cavity 62 is also a pipeline
  • the droplet formation hole 63 is the first cavity 61.
  • the principle and process of forming and wrapping liquid droplets 711 are the same as those of the device for forming and wrapping liquid droplets 711 shown in FIG. 6.
  • step 105 a gelable solution coated with droplets 711 is added to a coagulation bath 73, so that the gelable solution coated with droplets 711 is gelled.
  • the solution was gelled to form a gel 722.
  • the gelatinizable solution containing the liquid droplets 711 is added to the coagulation bath 73, which may be performed by a dropwise method or by an injection method.
  • the discharge port 100 is located above the coagulation bath 73.
  • the discharge port 100 here refers to an outlet of the gelable solution wrapped with the droplets 711. After the gelable solution wrapped with the liquid droplets 711 formed at the discharge port 100 is dropped into the coagulation bath 73, the gelable solution forms a gel.
  • the discharge port 100 is submerged in the coagulation bath 73.
  • the gelable solution wrapped with the droplets 711 forms gel fibers at the discharge opening 100.
  • the gelable solution forms gel fibers with a certain strength immediately after encountering the coagulation bath 73, not only the stability of the droplet 711 can be maintained, but droplets with a smaller particle size can be more easily obtained. 711.
  • the gelable solution containing the droplets 711 is added to the coagulation bath 73 by an injection method to form gel fibers.
  • the gel fiber will be continuously generated at the discharge port 100, causing the gel fiber to bend or fold, and the droplets 711 inside the gel fiber are deformed or aggregated due to being squeezed, which affects its morphology and uniformity.
  • the coagulation bath 73 is moved relative to the discharge port 100 while the gelable solution wrapped with the liquid droplets 711 is added to the coagulation bath 73.
  • the gel fibers are sequentially stacked in the coagulation bath 73, so that the internal droplets 711 caused by the excessive bending of the fibers are not deformed or agglomerated due to compression, It is beneficial to obtain particles with good uniformity.
  • the coagulation bath 73 moves relative to the discharge port 100.
  • the coagulation bath 73 may be rotated by an external device, or the discharge port 100 may be rotated by an external device.
  • the formed gel fiber can be stretched by setting the traction device 800.
  • stretching the formed fibers not only the orderly arrangement of the fibers can be achieved, but the internal droplets 711 caused by the excessive bending of the fibers can be prevented from deforming or agglomerating due to extrusion, which is beneficial for obtaining uniform particles; It is possible to change the diameter of the droplet 711 by drawing fine fibers, and obtain a droplet 711 having a smaller diameter.
  • a duct may be provided at the discharge port 100 of the structure shown in FIG. 3 and FIG. 4.
  • the process of gelation of the gelled solution is delayed, and the polymer solution and / or reactive monomer containing functional materials can be formed into droplets 711 in the gelable solution to avoid formation.
  • the situation with coaxial fibers occurs.
  • the gelable solution in the embodiment of the present invention may be an ion-sensitive system solution, a pH-sensitive system solution, or a temperature-sensitive solution.
  • the ion-sensitive system solution preferably uses a sodium alginate solution—a polyvalent salt solution system, which can be a sodium alginate-calcium chloride system.
  • a sodium alginate solution will form an ion-crosslinked gel when it meets the calcium chloride solution, and the gel can be re-dissolved by using sodium citrate. Polymer particles can be obtained at a lower cost.
  • a chitosan-sodium hydroxide solution system can be preferably used as the pH-sensitive system solution.
  • Chitosan is dissolved in a 2% acetic acid aqueous solution.
  • alkaline solutions such as sodium hydroxide and potassium hydroxide, it will solidify into gel fibers.
  • the gel fibers can be re-dissolved by adding acid again. Polymer particles can be obtained at a lower cost.
  • the temperature-sensitive solution may be preferably a poloxamer solution.
  • the poloxamer solution is liquid at low temperature, and it can also be transformed into a gel state when injected into an empty container at high temperature.
  • Example 1 Preparation of drug-loaded polylactic acid-glycolic acid copolymer (PLGA) embolized microspheres for interventional therapy
  • PLGA polylactic acid-glycolic acid copolymer
  • This embodiment uses the liquid droplet 711 shown in FIG. 3 to form a wrapping device:
  • the inner diameter of the first pipeline 31 is 0.25 mm and the outer diameter is 0.48 mm; the inner diameter of the second pipeline 32 is 0.75 mm and the outer diameter is 1.10 mm.
  • the first pipeline 31 and the second pipeline 32 are They were all submerged in the coagulation bath 73, and 100%, 120 microns, 160 microns, 200 microns, 220 microns, 240 microns, and 100 micron in diameter were prepared.
  • the functional material in this embodiment is a paclitaxel drug molecule, which is uniformly distributed in the droplets 711 in a homogeneous form.
  • Solution preparation Disperse phase solution, a certain amount of PLGA is dissolved in chloroform, and the corresponding solution is configured according to the mass fraction of 0.5%, 1%, 3%, 5%, 8%, and 10%, and then according to the PLGA The ratio of mass to drug mass was 10: 1, and paclitaxel was added separately.
  • Configure the outer layer continuous phase solution Weigh 1g of sodium alginate and dissolve it in 100g of deionized water. In order to improve the hydrophilicity of the microsphere surface, 1g of polyvinyl alcohol (PVA) is added.
  • PVA polyvinyl alcohol
  • Configure a coagulation bath 73 Weigh 1 g of calcium chloride and dissolve it in 1000 g of deionized water.
  • the flow rates of all samples were set as follows: the flow rate of the dispersed phase solution through the first line 31 was set at 60 ml / hour, the flow rate of the continuous phase solution through the second line 32 was set at 300 ml / hour, and the speed of the coagulation bath 73 was 20 rpm.
  • the dispersed phase solution droplets 711 are surrounded by gel fibers formed by the continuous phase solution and flow out from the nozzle uniformly, and are collected in the coagulation bath 73.
  • the obtained gel fiber containing one droplet 711 was dried in water, and the chloroform was completely evaporated.
  • FIG. 6 is a light microscope photograph of droplets 711 in the gel
  • FIG. 7 is a light microscope photograph of 100 micron particles after separation.
  • the drug-loaded microspheres can be directly introduced into the patient through a microcatheter and blocked in the tumor blood vessels.
  • the microspheres can block tumor blood vessels and block tumor feeding, on the other hand, the drugs released by the drug-loaded microspheres can inhibit and kill tumor cells and play a dual antitumor effect.
  • the drug-loaded microspheres prepared by the method of the present invention have the advantages of uniform size and completely controllable size, and thus can fully meet the strict clinical requirements for the size of drug-loaded microspheres (embolized microspheres).
  • the porous spherical cell scaffold needs to have a suitable volume size, and preferably has a through-channel structure.
  • the spherical scaffold has good rolling properties, and the cells grow on its surface or in the internal channels, which is suitable for large-scale 3D culture.
  • the functional material is a porogen sodium bicarbonate aqueous solution, which is dispersed in the droplets 711 in a heterogeneous form.
  • This embodiment uses the droplet 711 shown in FIG. 3 to form a wrapping device: the inner diameter of the first pipe 31 is 0.35 mm and the outer diameter is 0.65 mm; the inner diameter of the second pipe 32 is 1.15 mm and the outer diameter of the pipe is 1.50mm, prepare a spherical cell culture scaffold with a diameter of about 0.8mm.
  • Configure a coagulation bath 73 Weigh 1 g of calcium chloride and dissolve it in 1000 g of deionized water.
  • the flow rate of the dispersed phase solution through the first line 31 is set at 60 ml / hour, and the flow rate of the continuous phase solution through the second line 32 is set at 300 ml / hour.
  • the coagulation bath 73 is rotated at a speed of 20 rpm.
  • the dispersed phase solution droplets 711 are wrapped by the gel fibers formed by the continuous phase solution one by one and flow out uniformly from the discharge port 100 and are collected in the coagulation bath 73.
  • the obtained gel fiber containing the droplet 711 was dried in water, and the dichloromethane was completely evaporated. Sodium citrate was then added to depolymerize the fibers (the drying and depolymerization processes were the same as in Example 1). A uniform pellet with a diameter of 800 microns was obtained.
  • the obtained pellet was stirred in 0.1M sodium hydroxide for 1 hour to obtain a porous spherical cell culture scaffold having a through channel and a uniform microsphere size.
  • This embodiment uses the liquid droplet 711 shown in FIG. 3 to form a wrapping device:
  • the inner diameter of the first pipeline 31 is 0.24 mm and the outer diameter is 0.45 mm; the inner diameter of the second pipeline 32 is 0.7 mm and the outer diameter is 1.06 mm.
  • the functional material is ferric oxide particles, which are dispersed in the droplets 711 in a heterogeneous form.
  • a coagulation bath 73 was configured: 1 g of calcium chloride was dissolved in 1000 ml of deionized water.
  • the flow rate of the dispersed phase solution through the first line 31 is set at 40 ml / hour, and the flow rate of the continuous phase solution through the second line 32 is set at 400 ml / hour.
  • the dispersed phase solution droplets 711 are wrapped by the gel fibers formed by the continuous phase solution one by one and flow out uniformly from the discharge port 100 and are collected in the coagulation bath 73.
  • the temperature of the coagulation bath 73 was raised to 90 degrees Celsius, and the microspheres were allowed to react and solidify at this temperature for 1 hour. After the microspheres are completely cured, sodium citrate is used to depolymerize the fibers (the depolymerization process is the same as in Example 1) to obtain magnetic microspheres with a diameter of 380 microns.
  • the explosion beads produced on the market are oily explosion beads, and the inside is mineral oil, liquid paraffin substances, which are harmful to the human body.
  • the size of the blasting ball is from 2mm to 4mm, and it is difficult to ensure that the traditional water / oil / water system is not broken.
  • a droplet 711 is used to form a wrapping device as shown in FIG. 4.
  • the inner diameter of the third pipe 41 is 0.75 mm and the outer diameter is 1.10 mm.
  • the inner diameter of the fourth pipe 42 is 1.65 mm and the outer diameter is 2.15. mm;
  • the fifth pipe 43 has an inner diameter of 3.50 mm and an outer diameter of 4.00 mm.
  • the aqueous solution of the functional material menthol is wrapped in the droplets 711 in a heterogeneous form.
  • the inner layer uses an aqueous system: we dissolve 0.5 g of menthol as a flavor substance in 1000 ml of deionized water.
  • Intermediate layer dispersed phase solution (oil phase): Polymethyl methacrylate (PMMA) was used as a capsule wall material and dissolved in a mixed solvent of ethyl acetate and dichloromethane.
  • PMMA Polymethyl methacrylate
  • Outer continuous phase solution 1 g of sodium alginate was dissolved in 100 ml of deionized water.
  • a coagulation bath 73 was configured: 1.5 g of calcium chloride was dissolved in 1000 ml of deionized water.
  • the flow rate of the aqueous phase solution through the third line 41 is set at 60 ml / hour
  • the flow rate of the oil phase of the fourth line 42 is 60 ml / hour
  • the flow rate of the water phase of the fifth line 43 is 300 ml / hour.
  • the coagulation bath 73 was rotated at 10 rpm. After the obtained fiber gel containing the droplet 711 is dried in water (the drying process is the same as in Example 1), a PMMA-encapsulated liquid pop-up capsule with a particle diameter of about 3 mm is prepared.
  • Embodiment 5 Preparation of Polylactic Acid Microspheres by Using Chitosan Acetic Acid Solution as the Outer Layer
  • This embodiment uses the droplet 711 shown in FIG. 5 to form a wrapping device:
  • the inner diameter of the first pipeline 31 is 0.25 mm and the outer diameter is 0.48 mm; the inner diameter of the second pipeline 32 is 0.75 mm and the outer diameter is 1.10 mm.
  • Disperse phase solution in inner layer take 5g of polylactic acid and dissolve in 95ml of dichloromethane;
  • Outer continuous phase solution 5g of chitosan was dissolved in 100ml of 2% acetic acid aqueous solution;
  • Coagulation bath 73 Take 500 grams of sodium hydroxide and dissolve in 5 liters of ethanol solution.
  • the flow rate of the dispersed phase solution through the first line 31 is set at 20 ml / hour, and the flow rate of the continuous phase solution through the second line 32 is set at 100 ml / hour.
  • the dispersed phase solution droplets 711 are surrounded by gel fibers formed by the continuous phase solution and flow out from the nozzle uniformly, and are collected in the coagulation bath 73.
  • the microsphere size can be adjusted by the pulling speed of the traction device 800.
  • the obtained gel fibers each containing droplets 711 were dried in water, and then acetic acid was added to dissolve the shell of the chitosan fiber to obtain polylactic acid particles having a diameter of 200 microns.
  • the liquid droplet 711 shown in FIG. 6 is used to form a wrapping device, wherein the inner wall of the first cavity 61 is a tubular film and the tubular film is a tetrafluoroethylene film with an inner diameter of 3 mm.
  • the film has uniform small holes with average holes. The diameter is 0.7mm.
  • Disperse phase solution in inner layer take 5g of polycaprolactone and dissolve in 95ml of dichloromethane;
  • Outer continuous phase solution take 0.75g of sodium alginate and dissolve in 100ml of deionized water;
  • Coagulation bath 73 Weigh 1 g of calcium chloride and dissolve it in 1000 ml of deionization.
  • the dispersed phase solution flow rate was set at 200 ml / hour, and the outer continuous phase solution flow rate was set at 2000 ml / hour.
  • the dispersed phase solution droplets 711 are surrounded by gel fibers formed by the continuous phase solution and flow out uniformly from the nozzle, and are collected in the coagulation bath 73.
  • the obtained gel fiber containing the droplet 711 was dried in water, and then sodium citrate was added to depolymerize the fiber (the drying and depolymerization processes are the same as those in Example 1).
  • Polycaprolactone (PCL) particles having a diameter of about 0.36 mm can be obtained.
  • the liquid droplet 711 shown in FIG. 7 is used to form a wrapping device, wherein the second cavity 62 is a pipe with an inner diameter of 1 mm, and the first cavity 61 is a pipe with an inner diameter of the pipe of 0.2 mm.
  • Disperse phase solution in inner layer take 3g of polycaprolactone and dissolve in 97ml of dichloromethane;
  • Outer continuous phase solution take 1g of sodium alginate and dissolve in 100ml of deionized water;
  • Coagulation bath 73 Weigh 1 g of calcium chloride and dissolve it in 1000 ml of deionization.
  • the flow rate of the dispersed phase solution through the first cavity 61 is set at 15 ml / hour, and the flow rate of the continuous phase solution through the second cavity 62 is set at 150 ml / hour.
  • the dispersed phase solution droplets 711 are surrounded by gel fibers formed by the continuous phase solution and flow out from the vertical main pipe outlet one by one, and are collected in the coagulation bath 73.
  • the obtained gel fibers each containing droplets 711 were dried in water, and then sodium citrate was added to depolymerize the fibers (the drying and depolymerization processes are the same as in Example 1).
  • PLGA particles with a diameter of about 0.16 mm can be obtained.
  • Figure 8 is a particle light micrograph.

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Abstract

本发明公开了一种聚合物粒子制备方法，将含有功能性物料的聚合物溶液和/或反应性单体，形成液滴；通过可凝胶化的溶液包裹所述液滴；将包裹有所述液滴的可凝胶化的溶液加入到凝固浴中，以使得包裹有所述液滴的可凝胶化的溶液凝胶化，形成凝胶；在凝胶内部形成粒子后，溶解所述凝胶。本发明提供的聚合物粒子制备方法，能够获得均一性良好的粒子。

Description

一种聚合物粒子的制备方法
本申请要求于2018年9月3日提交中国专利局、申请号为201811020428.7、发明名称为“一种聚合物粒子的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及材料制备领域，特别涉及一种聚合物粒子的制备方法。
背景技术
粒径在1微米到6000微米，优选为30微米到5000微米的聚合物粒子，尤其是在粒径分布上具有窄分布的样品，在工业上有着广泛的用途。
直径50～500微米的载药微球可以广泛用于长效释放或者介入治疗中；直径50微米～2000微米的聚合物多孔支架可以作为细胞培养的载体或者药物释放的载体；加入磁性纳米粒子的微球，可以用于细胞分离，加入荧光染料的微球可以用于检测；直径1到4毫米的双层结构胶囊广泛运用于香料包裹以及爆珠香烟的生产中。
然而，通过溶剂挥发法或者悬浮聚合法制备该尺寸的材料也一直是工业上的难点。
通过溶剂挥发法或者悬浮聚合法来制备聚合物粒子：第一步是先建立分散体系，分散体系是指一种或者几种物质分散在某种介质中所形成的体系，被分散的物质叫做分散相，连续的介质为分散介质或连续相。第二步是通过溶剂挥发或者聚合反应让分散相固化成坚硬的粒子。
传统的建立分散相的方法一般为通过搅拌或者均质机将分散相在剪切力的作用下，被分割成小的液滴。以典型的聚乳酸微球的制备方法举例，将聚乳酸溶解在三氯甲烷中，为分散相；溶解有PVA，司盘80(span80)的水溶液为连续相，将2者混合，可以得到上层为水，下层为三氯甲烷的分层体系，将该体系放置在搅拌器上，开启机器，聚乳酸的三氯甲烷溶液就会由于搅拌的剪切作用，被分散成小的液滴悬浮在分散相中。
传统的溶剂挥发或者聚合反应来制备聚合物粒子的一般在分散体系建立以后，需要长时间的搅拌，使得分散相悬浮在分散介质中，继续以典型的聚乳酸微球的制备为例，在分散体系建立后，还需要持续搅拌十几小时以上，让三 氯甲烷挥发，才能得到固体的粒子。但是，在搅拌干燥过程中，会存在如下几个问题:
1.搅拌力度不够，液滴由于重力作用聚集在底部或者上部发生团聚。
2.搅拌力度过强，搅拌剪切力可能导致液滴重新发生破碎。
3.由于搅拌在容器中进行，即便搅拌速度恒定，沿着搅拌轴的径向方向上，随着半径的不同，液体流动的线速度也会明显不同，流速不同导致的剪切力不一样，也会导致粒子粒径分布变宽,很难获得尺寸均一的粒子。
发明内容
有鉴于此，本发明要解决的技术问题在于提供一种聚合物粒子的制备方法，能够获得均一性良好的粒子。
为了解决以上技术问题，本发明提供一种聚合物粒子的制备方法：
将含有功能性物料的聚合物溶液和/或反应性单体，形成液滴；
通过可凝胶化的溶液包裹所述液滴；
将包裹有所述液滴的可凝胶化的溶液加入到凝固浴中，以使得包裹有所述液滴的可凝胶化的溶液凝胶化，形成凝胶；
在凝胶内部形成粒子后，溶解所述凝胶。
含有功能性物料的聚合物溶液和/或反应性单体液滴中，功能性物料可以以均相的状态均匀分布在聚合物溶液和/或反应性单体中，也可以以非均相的状态，被分散或者被包裹在聚合物溶液和/或反应性单体中。
优选地，包裹有所述液滴的可凝胶化的溶液在所述凝固浴中凝胶化后形成凝胶纤维。
优选地，将包裹有所述液滴可凝胶化的溶液加入到凝固浴中的同时，使得所述凝固浴相对于出料口100运动。
优选地，在所述凝胶纤维形成同时对所述凝胶纤维进行拉伸。
优选地，在形成所述液滴的同时通过可凝胶化的溶液包裹所述液滴。
优选地，在形成所述液滴的同时通过可凝胶化的溶液包裹所述液滴，采用液滴形成包裹装置完成，
所述液滴形成包裹装置，包括，
用于放置含有功能性物料的聚合物溶液和/或反应性单体的第一腔；
用于供所述可凝胶化的溶液流动的第二腔；
所述第一腔与所述第二腔通过液滴形成孔联通。
优选地，在所述第二管路和第五管路的出口设置有导管。
优选地，所述可凝胶化的溶液为离子敏感的体系溶液，或pH敏感的体系溶液，或温度敏感的溶液。
优选地，所述离子敏感的体系溶液为，海藻酸钠溶液——多价盐溶液体系。
优选地，所述pH敏感的体系溶液为，壳聚糖盐酸溶液——氢氧化钠溶液体系。
优选地，所述温度敏感的为溶液为泊洛沙姆溶液。
优选地，所述功能性物料为，蛋白分子，或药物分子，或纳米粒子，或磁性粒子，或荧光染料，或香精，或香料，或制孔剂，或量子点中的一种或多种的组合。
优选地，所述聚合物溶液为，聚乳酸—乙醇酸共聚物溶液，或聚乳酸溶液，或聚甲基丙烯酸甲酯溶液，或聚己内酯溶液中的一种或多种的组合；
所述反应性单体为，或苯乙烯，或二乙烯苯，丙烯酸和甲基丙烯酸中的一种或多种的组合。
本发明提供的聚合物粒子的制备方法，与现有技术相比较，具有以下优点：
1.含有功能性物料的聚合物溶液和/或反应性单体所形成的液滴在可凝胶化的溶液包裹且形成凝胶后的环境中固化，由于凝胶巨大的粘度，液滴不会发生相互碰撞，不会发生聚集效应，溶剂挥发固化过程无需搅拌，也避免了剪切力对液滴的破坏，从而可以获得均一性良好的粒子。
2.现有技术中，为了避免粒子在固化的过程中聚集，采用表面活性剂来减小表面张力，来保持液滴的稳定性，本发明由于单个粒子的固化被限制在凝胶内部进行，粒子与粒子之间被凝胶隔开，无法发生聚集，因此，可以不使用表面活性剂。
附图说明
图1本发明制备流程图；
图2本发明形成液滴的三种形式；
其中，图2中：
a功能性物料以均相的状态均匀分布在聚合物溶液和/或反应性单体中；
b功能性物料以非均相的状态均匀分散在聚合物溶液和/或反应性单体中；
c功能性物料以非均相的状态均匀包裹在聚合物溶液和/或反应性单体中；
图3为本发明实施例中的一种液滴形成包裹装置结构示意图；
图4为本发明实施例中的另一种液滴形成包裹装置结构示意图；
图5为本发明实施例中带拉伸结构的液滴形成包裹装置结构示意图；
图6为本发明实施例中的第三种液滴形成包裹装置结构示意图；
图7为本发明实施例中的第四种液滴形成包裹装置结构示意图；
图8为本发明实施例一中凝胶内液滴光镜照片；
图9为本发明实施例一中100微米粒子光镜照片；
图10为本实施例七的粒子光镜照片。
其中，
01—功能性物料，100—出料口，
31—第一管路，32—第二管路，
41—第三管路，42—第四管路，43—第五管路，
61—第一腔，62—第二腔，63—液滴形成孔，
71—含有功能性物料的聚合物溶液和/或反应性单体，72—可凝胶化溶液，
73—凝固浴，711—液滴，722—凝胶，
800—牵引装置。
具体实施方式
为了进一步了解本发明，下面结合实施例对本发明优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。
请如图1所示，本发明实施例提供一种聚合物粒子的制备方法，该方法包括以下步骤：
101.将含有功能性物料的聚合物溶液和/或反应性单体71，形成液滴711；
103.通过可凝胶化的溶液72包裹所述液滴711；
105.将包裹有所述液滴711的可凝胶化的溶液72加入到凝固浴73中，以使得包裹有所述液滴711的可凝胶化的溶液凝胶化72，形成凝胶；
107.在凝胶内部形成粒子后，溶解所述凝胶。
本发明实施例提供的聚合物粒子的制备方法中，含有功能性物料的聚合物溶液和/或反应性单体71为分散相，可凝胶化的溶液72为连续相，使可凝胶化的溶液72发生凝胶化的为凝固浴73。
现有技术中，一般采用机械搅拌的方式进行聚合物粒子的制备，其过程如下，将分散相加入到分散介质中，加入合适的表面活性剂，通过搅拌或者均质机将分散相变成液滴分散在分散介质中。然后通过长时间的搅拌使得溶剂挥发或者单体聚合，得到固体的聚合物粒子。由于分散体系形成后，分散相仍然需要很长的一段时间来进行溶剂的挥发或者聚合反应的进行，在此阶段的持续搅拌，会使得已经形成的粒子由于界面张力，重力，碰撞等原因发生聚集、或者由于搅拌的剪切力发生破碎、或者由于容器内各点流速不同导致的剪切力不一样这些原因，导致粒子粒径分布变宽。
本发明实施例提供的聚合物粒子的制备方法，与现有技术相比较，由于将分散相限制在凝胶内，导致粒子无法发生接触，不会存在传统的由于界面张力，重力，碰撞导致的聚集、或者由于搅拌的剪切力而发生的破碎、或者由于容器内各点流速不同导致的剪切力不一样，进而导致粒子粒径分布变宽等问题。使得制备均一性粒子成为可能。
其中，本发明实施例中的功能性物料是指为了使得制备的粒子具有一定的用途而添加的成分。该成分可以为药物，纳米粒子，致孔剂，荧光染料，香料等。如制备药物缓释微球时，该功能性物料为药物分子；制备磁性微球时，该功能性物料为四氧化三铁纳米粒子；制备荧光微球时，该功能性物料为荧光染料或者量子点；制备爆珠微球时，为内层香料或风味物质。
需要说明的是，请参见图2所示，
本实施例中的功能性物料01可以以均相的状态均匀分布在聚合物溶液中，或者以均相的状态均匀分布在反应性单体中，或者以均相的状态均匀分布在聚合特溶液与反应性单体所构成的混合液体中，如图2a所示。
本实施例中的功能性物料01也可以是以非均相的状态被分散在聚合物溶 液中、或反应性单体中、或聚合物溶液与反应性单体所构成的混合液体中，如图2b所示。
本实施例中的功能性物料01也可以是以非均相的状态被包裹在聚合物溶液中、或反应性单体中、或聚合物溶液与反应性单体所构成的混合液体中，如图2c所示。
本实施例提供的聚合物粒子的制备方法中，步骤103通过可凝胶化的溶液72包裹液滴711，且一般是在形成液滴711的同时就通过可凝胶化的溶液包裹液滴711。
本实施例采用液滴711形成包裹装置来实现液滴711的形成与包裹，其结构请如图3所示，该装置包括，用于供含有功能性物料的聚合物溶液和/或反应性单体流动的第一管路31；套设在第一管路31外，且与第一管路31同轴，用于供可凝胶化的溶液流动的第二管路32。
采用该结构实现液滴711的形成与包裹时，在向第一管路31送入含有功能性物料的聚合物溶液和/或反应性单体的同时，向第二管路32送入可凝胶化的溶液。
控制第一管路31与第二管路32内液体的流速。当内外两个管路的流体的速度在比较低时，会直接在出口形成一个一个的液滴711；当内外两个管路的流体的速度在较高时，会先形成同轴的流体，然后外层凝胶化后形成凝胶纤维，而凝胶纤维内部的液体在界面张力的作用下，从连续流动的液体变成一颗一颗的液滴711，液滴711以单列的形式有序的排列在凝胶纤维内部。采用该种结构，由于所有的液滴711均通过第一管路31形成，因此，形成的液滴711的均一性极好。
当需要功能性物料需要被包裹在聚合物溶液和/或反应性单体中时，上述液滴711形成包裹装置可以作出相应的改变，具体如图4所示，此时，该液滴711形成包裹装置包括，用于供含有功能性物料的液体流动的第三管路41，套设在第三管路41外，且与第三管路41同轴，用于供聚合物溶液和/或反应性单体流动的第四管路42，以及套设在第四管路42外，且与第四管路42同轴，用于供可凝胶化的溶液流动的第五管路43。
采用该结构实现液滴711的形成与包裹时，在向第三管路41送入含有功 能性物料的液体的同时，向第四管路42送入聚合物溶液和/或反应性单体，且同时，向第五管路43送入可凝胶化的溶液。
控制第三管路41、第四管路42以用第五管路43内液体的流速。当三个管路的流体的速度在比较低时，会直接在出口形成一个一个的液滴711，此时，液滴711的最中心为功能性物料，液滴711的外层为聚合物溶液和/或反应性单体，液滴711被可凝胶化溶液包裹；当三个管路的流体的速度在较高时，会先形成同轴的流体，然后最外层凝胶化后形成凝胶纤维，而凝胶纤维内部的液体在界面张力的作用下，从连续流动的液体变成一颗一颗的液滴711，液滴711以单列的形式有序的排列在凝胶纤维内部，此时，液滴711的最中心为功能性物料，液滴711的外层为聚合物溶液和/或反应性单体。
本实施例的液滴711形成包裹装置也可以采用如图6所示的结构，其包括，用于放置含有功能性物料的聚合物溶液和/或反应性单体的第一腔61；用于供可凝胶化的溶液流动的第二腔62；第一腔61与第二腔62通过液滴形成孔63联通。
采用该结构实现液滴711的形成与包裹时，向第一腔61内通入含有功能性物料的聚合物溶液和/或反应性单体，第一腔61内的含有功能性物料的聚合物溶液和/或反应性单体会通过液滴形成孔63向第二腔62流动，进入第二腔62时形成液滴711，附着在第二腔62的内壁，与此同时，向第二腔62内通入可凝胶化的溶液，通过可凝胶化的溶液将附着在第二腔62内壁上的液滴711冲刷下来，完成可凝胶化溶液对液滴711的包裹。采用该结构实现液滴711的形成与包裹，由于第一腔61上的液滴形成孔63的数量能够根据实际的需要增加，因此，适合大批量地制备粒子；由于液滴形成孔63具有均一的尺寸，因此，在大批量地制备粒子的基础之上，且能够保证制备出的粒子均一性良好。该结构中第一腔61与第二腔62均优选为管状腔。当然也可以是，将一腔体通过隔板分为二部分，其中一部分为第一腔61，另一部分为第二腔62，液滴形成孔63设置在隔板上，此时，腔体的形状不限。
作为上述结构的一种特殊情况，其具体如图7所示，该种情况下，第一腔61为管路，第二腔62也为管路，液滴形成孔63为第一腔61的出口。其实现液滴711的形成与包裹的原理、过程与图6所示的液滴711形成包裹装置相同。
本发明实施例提供的聚合物粒子的制备方法，其步骤105中，将包裹有液滴711的可凝胶化的溶液加入到凝固浴73中，以使得包裹有液滴711的可凝胶化的溶液凝胶化，形成凝胶722。
其中，将包裹有液滴711的可凝胶化的溶液加入到凝固浴73中，可以采用滴加的方式，也可以采用注入的方式。
当采用滴加的方式时，出料口100处于凝固浴73的上方。其中，此处的出料口100是指，包裹有所述液滴711的可凝胶化的溶液的出口。出料口100形成的包裹有所述液滴711的可凝胶化的溶液被滴入凝固浴73中后，可凝胶化的溶液形成凝胶。
当采用注入的方式时，出料口100没入凝固浴73中。此时，包裹有所述液滴711的可凝胶化的溶液会出料口100处形成凝胶纤维。采用此种方式，由于可凝胶化的溶液在遇到凝固浴73后立即形成具有一定强度的凝胶纤维，不仅能保持液滴711的稳定性，且更容易获得粒径较小的液滴711。
其中，采用注入的方式将包裹有所述液滴711的可凝胶化的溶液加入到凝固浴73中，形成凝胶纤维。凝胶纤维会在出料口100不断产生，使得凝胶纤维发生弯曲或折叠，处于凝胶纤维内部的液滴711因被挤压而发生变形或聚集，影响其形貌以及均一性。
为了解决该问题，本发明实施例，在将包裹有所述液滴711的可凝胶化的溶液加入到凝固浴73中的同时，使得凝固浴73相对于出料口100运动。如此，随着凝胶纤维在出料口100不断产生，凝胶纤维被有序堆积在凝固浴73中，避免了纤维的过度弯曲而导致的内部液滴711因挤压而发生变形或聚集，有利于获得均一性良好的粒子。
其中，凝固浴73相对于出料口100运动，可以是，通过外部装置使得凝固浴73转动，也可以是，通过外部装置使得出料口100转动。
当形成的纤维强度足够大时，可以通过设置牵引装置800对形成的凝胶纤维进行拉伸。通过对形成的纤维进行拉伸，不仅能够实现纤维的有序排列，避免了纤维的过度弯曲而导致的内部液滴711因挤压而发生变形或聚集，有利于获得均一性良好的粒子；且能够通过拉细纤维来改变液滴711的直径，获得直径更小的液滴711。
当可凝胶化的溶液在凝固浴73中凝固过快时，可能出现可凝胶化的溶液包裹的含有功能性物料的聚合物溶液和/或反应性单体还未形成液滴711时，可凝胶化的溶液已凝胶化，形成同轴纤维，无法获得单独的粒子。为了避免该种情况发生，本实施例中，可以在图3与图4所示的结构的出料口100处设置有导管。
设置有导管后，延迟了凝胶化的溶液凝胶化的过程，能够使得含有功能性物料的聚合物溶液和/或反应性单体在可凝胶化的溶液先形成液滴711，避免形成同轴纤维的情况发生。
本发明实施例中的可凝胶化的溶液可以为离子敏感的体系溶液，或pH敏感的体系溶液，或温度敏感的溶液。
其中，离子敏感的体系溶液优选采用海藻酸钠溶液——多价盐溶液体系，其具为可以为海藻酸钠-氯化钙体系。其中，海藻酸钠溶液遇到氯化钙溶液会形成离子交联的凝胶，使用柠檬酸钠可以将该凝胶重新溶解。可以在较低成本下获得聚合物粒子。
其中，pH敏感的体系溶液可以优选采用壳聚糖-氢氧化钠溶液体系。壳聚糖溶解在2％的醋酸水溶液中，其遇到氢氧化钠，氢氧化钾等碱性溶液会凝固成凝胶纤维，通过重新加酸的方式可以使得该凝胶纤维重新溶解。可以在较低成本下获得聚合物粒子。
其中，温度敏感的溶液可以优选为泊洛沙姆溶液。泊洛沙姆溶液在低温下是液态，将其注入到高温的空容器里，也可转变成凝胶状态。
为了使本领域的人员更好地理解本发明的技术方案，下面结合几个具体的制备实施例，对本发明进行清楚、完整地说明，具体如下：
实施例一：用于介入治疗的载药聚乳酸—乙醇酸共聚物(PLGA)栓塞微球的制备
本实施例采用图3所示的液滴711形成包裹装置:
其中，第一管路31的管内径为0.25mm，外径为0.48mm；第二管路32的管内径为0.75mm，外径为1.10mm，将第一管路31与第二管路32均没入凝固浴73中，分别制备直径为100微米，120微米，160微米，200微米，220微米，240微米的载紫衫醇的微球。
本实施例中功能物料为紫杉醇药物分子，其以均相形式均匀分布在液滴711中。
溶液的配制：分散相溶液，将一定量的PLGA溶解在三氯甲烷中，按照质量分数为0.5％，1％，3％，5％，8％，10％的配置相应溶液，然后按照PLGA的质量与药物质量比为10：1的比例分别加入紫衫醇。
配置外层连续相溶液：称取1g海藻酸钠溶解在100g的去离子水中，为了改善微球表面的亲水性，加入1g的聚乙烯醇(PVA)。
配置凝固浴73：称取1g的氯化钙溶解在1000g去离子水中。
所有样品的流速设置如下：通过第一管路31的分散相溶液流速设置在60ml/小时，通过第二管路32的连续相溶液流速设置在300ml/小时，凝固浴73转速为20rpm。
启动机器，可见分散相溶液液滴711被由连续相溶液形成的凝胶纤维包裹着一粒一粒地从喷嘴均匀流出，收集在凝固浴73中。将获得的含一粒一粒液滴711的凝胶纤维在水中干燥，等待三氯甲烷挥发完全。
粒子固化后，然后加入柠檬酸钠进行解聚纤维。分别获得直径为100微米，120微米，160微米，200微米，240微米的载药微球。图6为凝胶内液滴711的光镜照片，图7为分离后100微米粒子的光镜照片。
载药微球(栓塞微粒)可直接经微导管导入病人体内，阻塞在肿瘤血管中。一方面微球可阻塞肿瘤血管阻断肿瘤给养，另一方面载药微球所释放的药物可抑杀肿瘤细胞，起双重抗肿瘤作用。利用本发明的方法所制备的载药微球具备尺寸均匀，尺寸完全可控的优点，因而可以完全满足临床上对载药微球(栓塞微球)的尺寸的严格要求。
实施例二：用于细胞培养的多孔球形支架的制备
多孔球形细胞支架需要具有合适的体积大小，最好具有贯通的孔道结构。球形支架具有良好的滚动性，细胞生长在其表面或者内部的孔道内，适合大规模的3D培养，细胞扩增时只需将少量的培养有细胞的微球转移到大量的空白球形的培养基中，避免传统的消化，转移，大大减少了工作量。本实施例中，功能物料为致孔剂碳酸氢钠水溶液，其以非均相的形式分散在液滴711中。
本实施例采用图3所示的液滴711形成包裹装置:第一管路31的管内径 为0.35mm，外径为0.65mm；第二管路32的管内径为1.15mm，管外径为1.50mm，制备直径在0.8mm左右的球形细胞培养支架。
配置内层分散相溶液(油相)：取2g聚乳酸溶解在10ml二氯甲烷中，然后加入2ml浓度为1M的碳酸氢钠水溶液，加上0.2ml司盘80，经过超声或者高速均质，制备得到复合乳液。
配置外层连续相溶液(水相)：称取1g海藻酸钠溶解在1000g的去离子水中。
配置凝固浴73：称取1g的氯化钙溶解在1000g去离子水中。
通过第一管路31的分散相溶液流速设置在60ml/小时，通过第二管路32的连续相溶液流速设置在300ml/小时。凝固浴73以20rpm的速度转动。
启动机器，可见分散相溶液液滴711被由连续相溶液形成的凝胶纤维包裹着一粒一粒地从出料口100均匀流出，收集在凝固浴73中。将获得的含液滴711的凝胶纤维在水中干燥，等待二氯甲烷挥发完全。然后加入柠檬酸钠进行解聚纤维(干燥和解聚过程与实施例一相同)。获得直径为800微米的均匀小球。
将获得的小球在0.1M的氢氧化钠中搅拌1小时，获得具有贯通通道且微球尺寸均匀的多孔球形细胞培养支架。
实施例三：聚苯乙烯磁性微球的制备
本实施例采用图3所示的液滴711形成包裹装置：
其中，第一管路31的管内径为0.24mm，外径为0.45mm；第二管路32的内径为0.7mm，外径为1.06mm。
本实施例中，功能物料为四氧化三铁粒子，其以非均相的形式分散在液滴711中。
配置内层分散相溶液(油相)：将0.16g磁性纳米粒子分散在16ml苯乙烯、二乙烯苯、丙烯酸和甲基丙烯酸(质量比为100：20：5：5)单体中，加入0.3g过氧化二苯甲酰作为引发剂。
配置外层连续相溶液(水相)：将1g海藻酸钠溶解在100ml去离子水中。
配置凝固浴73：将1g氯化钙溶解在1000ml去离子水中。
通过第一管路31的分散相溶液流速设置在40ml/小时，通过第二管路32 的连续相溶液流速设置在400ml/小时。
启动机器，可见分散相溶液液滴711被由连续相溶液形成的凝胶纤维包裹着一粒一粒地从出料口100均匀流出，收集在凝固浴73中。
实验结束后，凝固浴73的温度升高到90摄氏度，让微球在该温度下继续反应固化1小时。微球完全固化后，使用柠檬酸钠解聚纤维(解聚过程与实施例一相同)，可获得直径380微米的磁性微球。
实施例四：用于爆珠香烟生产的水性爆珠的制备
目前市场上生产的爆珠都是油性爆珠，其内部为矿物油，液体石蜡类物质，对人体有害。
爆珠的尺寸在2mm到4mm，传统的水/油/水体系很难保证不破。
本实施例采用如图4所示液滴711形成包裹装置,第三管路41的管内径为0.75mm，外径为1.10mm；第四管路42的管内径为1.65mm，外径为2.15mm；第五管路43的管内径为3.50mm，外径为4.00mm。
本实施例中，功能性物料薄荷醇的水溶液，其以非均相的形式包裹在液滴711中。
内层采用水相体系：我们将0.5g薄荷醇作为风味物质溶解在1000ml的去离子水中。
中间层分散相溶液(油相)：使用聚甲基丙烯酸甲酯(PMMA)作为胶囊壁材，溶解在乙酸乙酯和二氯甲烷的混合溶剂中。
外层连续相溶液：将1g海藻酸钠溶解在100ml去离子水中。
配置凝固浴73：将1.5g氯化钙溶解在1000ml去离子水中。
通过第三管路41的水相溶液流速设置在60ml/小时，第四管路42的油相流速为60ml/小时，第五管路43的水相流速为300ml/小时。凝固浴73转速10rpm。将获得的含液滴711的纤维凝胶在水中干燥后(干燥过程与实施例一相同)，制备得到粒径在3mm左右的PMMA包裹液体的爆珠胶囊。
实施例五：使用外层为壳聚糖醋酸溶液的方法制备聚乳酸微球
本实施例采用所图5所示的液滴711形成包裹装置：
其中，第一管路31的管内径为0.25mm，外径为0.48mm；第二管路32的管内径为0.75mm，外径为1.10mm。
溶液的配制：
内层分散相溶液：取5g聚乳酸溶解在95毫升的二氯甲烷中；
外层连续相溶液：取5g壳聚糖溶解在100ml质量分数为2％的乙酸水溶液中；
凝固浴73：取500克氢氧化钠溶解在5升乙醇溶液。
通过第一管路31的分散相溶液流速设置在20ml/小时，通过第二管路32的连续相溶液流速设置在100ml/小时。
启动机器，可见分散相溶液液滴711被由连续相溶液形成的凝胶纤维包裹着一粒一粒地从喷嘴均匀流出，收集在凝固浴73中。通过牵引装置800的拉升速度可以调节微球大小。将获得的一粒一粒的含液滴711的凝胶纤维在水中干燥，然后加入醋酸，将壳聚糖纤维外壳重新溶解，可以获得直径为200微米的聚乳酸粒子。
实施例六：使用管状多孔膜制备聚己内酯(PCL)粒子
本实施例采用图6所示的液滴711形成包裹装置，其中，第一腔61的内壁为管状膜，管状膜为四氟乙烯膜，其内径3mm，膜上具有均匀的小孔，孔平均直径为0.7mm。
溶液的配制：
内层分散相溶液：取5g聚己内酯溶解在95毫升的二氯甲烷中；
外层连续相溶液：取0.75g海藻酸钠溶解在100ml去离子水中；
凝固浴73：称取1g氯化钙溶解在1000ml去离子中。
分散相溶液流速设置在200ml/小时，外层连续相溶液流速设置在2000ml/小时。
启动机器，可见分散相溶液液滴711被由连续相溶液形成的凝胶纤维包裹着从喷嘴均匀流出，收集在凝固浴73中。将获得的含液滴711的凝胶纤维在水中干燥，然后加入柠檬酸钠进行解聚纤维(干燥和解聚过程与实施例一相同)。可获得直径在0.36mm左右的聚己内酯(PCL)粒子。
实施例七：制备聚乳酸-乙醇酸共聚物(PLGA)粒子
本实施例采用如图7所示的液滴711形成包裹装置，其中，第二腔62为管路，其内径为1mm，第一腔61为管路，其管道内径为0.2mm。
溶液的配制：
内层分散相溶液：取3g聚己内酯溶解在97毫升的二氯甲烷中；
外层连续相溶液：取1g海藻酸钠溶解在100ml去离子水中；
凝固浴73：称取1g氯化钙溶解在1000ml去离子中。
通过第一腔61的分散相溶液流速设置在15ml/小时，通过第二腔62的连续相溶液流速设置在150ml/小时。
启动机器，可见分散相溶液液滴711被由连续相溶液形成的凝胶纤维包裹着一粒一粒地从竖直主管道出口处均匀流出，收集在凝固浴73中。将获得的一粒一粒的含液滴711的凝胶纤维在水中干燥，然后加入柠檬酸钠进行解聚纤维(干燥和解聚过程与实施例一相同)。可获得直径在0.16mm左右的PLGA粒子。图8为粒子光镜照片。
以上对本发明所提供的一种聚合物粒子的制备方法进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (16)

  1. 一种聚合物粒子的制备方法，其特征在于，
    将含有功能性物料的聚合物溶液和/或反应性单体，形成液滴；
    通过可凝胶化的溶液包裹所述液滴；
    将包裹有所述液滴的可凝胶化的溶液加入到凝固浴中，以使得包裹有所述液滴的可凝胶化的溶液凝胶化，形成凝胶；
    在凝胶内部形成粒子后，溶解所述凝胶。
  2. 根据权利要求1所述的制备方法，功能性物料以均相的状态均匀分布在聚合物溶液和/或反应性单体中，或者以非均相的状态，被分散或者被包裹在聚合物溶液和/或反应性单体中。
  3. 根据权利要求1或2所述的制备方法，其特征在于，包裹有所述液滴的可凝胶化的溶液在所述凝固浴中凝胶化后形成凝胶纤维。
  4. 根据权利要求1至3任意一项所述的制备方法，其特征在于，将包裹有所述液滴的可凝胶化的溶液加入到凝固浴中的同时，使得所述凝固浴相对于出料口运动。
  5. 根据权利要求3所述的制备方法，其特征在于，在所述凝胶纤维形成同时对所述凝胶纤维进行拉伸。
  6. 根据权利要求1所述的制备方法，其特征在于，在形成所述液滴的同时通过可凝胶化的溶液包裹所述液滴。
  7. 根据权利要求6所述的聚合物粒子的制备方法，其特征在于，在形成所述液滴的同时通过可凝胶化的溶液包裹所述液滴，采用液滴形成包裹装置完成，
    所述液滴形成包裹装置，包括，
    用于放置含有功能性物料的聚合物溶液和/或反应性单体的第一腔；
    用于供所述可凝胶化的溶液流动的第二腔；
    所述第一腔与所述第二腔通过液滴形成孔联通。
  8. 根据权利要求6所述的制备方法，其特征在于，在形成所述液滴的同时通过可凝胶化的溶液包裹所述液滴，采用液滴形成包裹装置完成，
    所述液滴形成包裹装置，包括，
    用于供含有功能性物料的聚合物溶液和/或反应性单体流动的第一管路；
    套设在所述第一管路外，且与所述第一管路同轴，用于供所述可凝胶化的溶液流动的第二管路。
  9. 根据权利要求2所述的制备方法，其特征在于，功能性物料以非均相的状态包裹在聚合物溶液和/或反应性单体中的液滴，采用液滴形成包裹装置完成，
    所述液滴形成包裹装置，包括，
    用于供含有功能性物料的液体流动的第三管路；
    套设在所述第三管路外，且与所述第三管路同轴，用于供所述聚合物溶液和/或反应性单体流动的第四管路；
    套设在所述第四管路外，且与所述第四管路同轴，用于供所述可凝胶化的溶液流动的第五管路。
  10. 根据权利要求8或9所述的制备方法，其特征在于，在所述第二管路和第五管路的出口设置有导管。
  11. 根据权利要求1所述的制备方法，其特征在于，所述可凝胶化的溶液为离子敏感的体系溶液，或pH敏感的体系溶液，或温度敏感的溶液。
  12. 根据权利要求10所述的制备方法，其特征在于，所述离子敏感的体系溶液为，海藻酸钠溶液——多价盐溶液体系。
  13. 根据权利要求10所述的制备方法，其特征在于，所述pH敏感的体系溶液为，壳聚糖盐酸溶液——氢氧化钠溶液体系。
  14. 根据权利要求10所述的制备方法，其特征在于，所述温度敏感的溶液为泊洛沙姆溶液。
  15. 根据权利要求1所述的制备方法，其特征在于，所述功能性物料为，蛋白分子，或药物分子，或纳米粒子，或磁性粒子，或荧光染料，或香精，或香料，或制孔剂，或量子点中的一种或多种的组合。
  16. 根据权利要求1或15所述的制备方法，其特征在于，
    所述聚合物溶液为，聚乳酸—乙醇酸共聚物溶液，或聚乳酸溶液，或聚甲基丙烯酸甲酯溶液，或聚己内酯溶液中的一种或多种的组合；
    所述反应性单体为，或苯乙烯，或二乙烯苯，丙烯酸和甲基丙烯酸中的一种或多种的组合；
    所述可凝胶化的溶液为，海藻酸钠溶液——氯化钙溶液体系，或壳聚糖盐酸溶液——氢氧化钠溶液体系，或泊洛沙姆溶液；
    所述功能性物料为，蛋白分子，或药物分子，或纳米粒子，或磁性粒子，或荧光染料，或香精，或香料，或制孔剂，或量子点中的一种或多种的组合。
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