CN109265711A

CN109265711A - A kind of preparation method of polymer particle

Info

Publication number: CN109265711A
Application number: CN201811020428.7A
Authority: CN
Inventors: 胡权
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-09-03
Filing date: 2018-09-03
Publication date: 2019-01-25
Anticipated expiration: 2038-09-03
Also published as: WO2020048435A1; CN109265711B

Abstract

The invention discloses a kind of polymer particle preparation methods to form drop for polymer solution and/or reactive monomer containing functional material；By can the solution of gelation wrap up the drop；By be enclosed with the drop can the solution of gelation be added in coagulating bath so that be enclosed with the drop can gelation solution gels, form gel；After forming particle inside gel, the gel is dissolved.Polymer particle preparation method provided by the invention can obtain the good particle of homogeneity.

Description

Preparation method of polymer particles

Technical Field

The invention relates to the field of material preparation, in particular to a preparation method of polymer particles.

Background

Polymer particles having a particle size of from 1 micron to 6000 microns, preferably from 30 microns to 5000 microns, especially samples having a narrow distribution in particle size distribution, have found wide industrial use.

The drug-loaded microspheres with the diameter of 50-500 microns can be widely used for long-acting release or interventional therapy; the polymer porous scaffold with the diameter of 50-2000 microns can be used as a carrier for cell culture or a carrier for drug release; the microspheres added with the magnetic nano particles can be used for cell separation, and the microspheres added with the fluorescent dye can be used for detection; capsules of double-layer structure with a diameter of 1 to 4mm are widely used for flavor wrapping and production of popping cigarettes.

However, the preparation of materials of this size by solvent evaporation or suspension polymerization has also been an industrial difficulty.

Polymer particles are prepared by solvent evaporation or suspension polymerization: the first step is to establish a dispersion system, which is a system formed by one or more substances dispersed in a medium, wherein the dispersed substances are called dispersed phases, and 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 for establishing the dispersed phase is generally to divide the dispersed phase into small droplets under the action of shear force by a stirring or homogenizing machine. Taking a preparation method of a typical polylactic acid microsphere as an example, polylactic acid is dissolved in chloroform to be a disperse phase; the aqueous solution of PVA and span80 (span80) is used as continuous phase, the two are mixed to obtain a layered system with water as the upper layer and trichloromethane as the lower layer, the layered system is set on a stirrer, and the machine is started to disperse the trichloromethane solution of polylactic acid into small liquid drops to suspend in the dispersed phase.

In the conventional method for preparing polymer particles by solvent volatilization or polymerization, after a dispersion system is established, long-time stirring is required to suspend a dispersed phase in a dispersion medium, and taking the preparation of a typical polylactic acid microsphere as an example, after the dispersion system is established, continuous stirring is required for more than ten hours to volatilize trichloromethane, so that solid particles can be obtained. However, in the stirring and drying process, there are several problems as follows:

1. the stirring force is not enough, and the liquid drops are gathered at the bottom or the upper part under the action of gravity to agglomerate.

2. The stirring force is too strong and the stirring shear force may cause the droplets to break up again.

3. Since the stirring is performed in the container, even if the stirring speed is constant, the linear velocity of the liquid flow is significantly different along the radial direction of the stirring shaft according to the difference in the radius, and the shearing force caused by the difference in the flow velocity is different, which also results in widening the particle size distribution of the particles, and it is difficult to obtain particles having uniform size.

Disclosure of Invention

The invention aims to overcome the defects of the existing preparation method and provide a preparation method of polymer particles, which can obtain particles with good uniformity.

The invention adopts the following technical scheme:

a method for producing polymer particles, characterized in that,

forming a polymer solution containing a functional material and/or a reactive monomer into droplets;

wrapping the droplet with a gelable solution;

adding the gelable solution wrapped with the droplets to a coagulation bath to gel the gelable solution wrapped with the droplets to form a gel;

after the particles are formed inside the gel, the gel is dissolved.

In the polymer solution and/or the reactive monomer droplets containing the functional material, the functional material may be uniformly distributed in the polymer solution and/or the reactive monomer in a homogeneous state, or may be dispersed or encapsulated in the polymer solution and/or the reactive monomer in a heterogeneous state.

Preferably, the gelable solution surrounding the droplets forms gel fibers after gelling in the coagulation bath.

Preferably, the coagulation bath is moved relative to the discharge port 100 while the solution in which the droplets are wrapped and gellable is added to the coagulation bath. .

Preferably, the gel fibers are stretched while the gel fibers are formed.

Preferably, the droplets are encapsulated by a gelable solution at the same time as the droplets are formed.

Preferably, the droplets are formed while being encapsulated by a gelable solution, using a droplet formation encapsulation device,

the drop formation wrap device comprises a first chamber and a second chamber,

a first chamber for placing a polymer solution containing a functional material and/or a reactive monomer;

a second chamber for flowing the gelable solution;

the first chamber communicates with the second chamber through a drop formation orifice.

Preferably, a conduit is provided at the outlet of the second and fifth pipes.

Preferably, the gelable solution is an ion sensitive system solution, or a pH sensitive system solution, or a temperature sensitive solution.

Preferably, the ion-sensitive system solution is a sodium alginate solution-multivalent salt solution system.

Preferably, the pH sensitive system solution is chitosan hydrochloride solution-sodium hydroxide solution system.

Preferably, the temperature sensitive solution is a poloxamer solution.

Preferably, the functional material is one or more of protein molecules, drug molecules, nanoparticles, magnetic particles, fluorescent dyes, essences, spices, pore-forming agents and quantum dots.

Preferably, the polymer solution is one or more of polylactic acid-glycolic acid copolymer solution, polylactic acid solution, polymethyl methacrylate solution and polycaprolactone solution;

the reactive monomer is styrene or divinylbenzene, and one or more of acrylic acid and methacrylic acid are combined.

Compared with the prior art, the preparation method of the polymer particles provided by the invention has the following advantages:

1. the droplets formed by the polymer solution containing the functional material and/or the reactive monomer are solidified in the environment after the gelable solution is wrapped and formed into gel, because of the huge viscosity of the gel, the droplets do not collide with each other and do not generate aggregation effect, the solvent is not required to be stirred in the volatilization and solidification process, and the droplets are also prevented from being damaged by shearing force, so that particles with good uniformity can be obtained.

2. In the prior art, in order to avoid aggregation of particles in the curing process, a surfactant is adopted to reduce the surface tension so as to maintain the stability of liquid drops.

Drawings

FIG. 1 is a flow chart of the preparation of the present invention;

FIG. 2 three forms of droplet formation according to the invention;

wherein, in fig. 2:

a, uniformly distributing functional materials in a polymer solution and/or a reactive monomer in a homogeneous state;

b, uniformly dispersing the functional material in a polymer solution and/or a reactive monomer in a heterogeneous state;

c, uniformly wrapping the functional material in a polymer solution and/or a reactive monomer in a heterogeneous state;

FIG. 3 is a schematic diagram of a droplet forming apparatus according to an embodiment of the present invention;

FIG. 4 is a schematic view of another embodiment of a droplet forming and encapsulation apparatus according to the present invention;

FIG. 5 is a schematic diagram of a droplet formation and encapsulation apparatus with an elongated structure according to an embodiment of the present invention;

FIG. 6 is a schematic structural view of a third droplet forming and packing apparatus according to an embodiment of the present invention;

FIG. 7 is a schematic structural view of a fourth droplet formation and encapsulation apparatus in an embodiment of the present invention;

FIG. 8 is a photograph of a drop in gel microscope according to an embodiment of the present invention;

FIG. 9 is a photograph of a 100 μm particle mirror in accordance with one embodiment of the present invention;

fig. 10 is a photograph of a particle beam microscope according to a seventh embodiment.

Wherein,

01-functional material, 100-discharge hole,

31-a first line, 32-a second line,

41-a third line, 42-a fourth line, 43-a fifth line,

61-first chamber, 62-second chamber, 63-droplet forming orifice,

71-polymer solution and/or reactive monomer containing functional material, 72-gelable solution,

73-coagulation bath, 711-droplets, 722-gel,

800-traction device.

Detailed Description

In order to make the technical solutions of the present invention better understood, the following description of the technical solutions of the present invention with reference to the accompanying drawings of the present invention is made clearly and completely, and other similar embodiments obtained by a person of ordinary skill in the art without any creative effort based on the embodiments in the present application shall fall within the protection scope of the present application.

As shown in fig. 1, an embodiment of the present invention provides a method for preparing polymer particles, which includes the following steps:

101. forming droplets 711 from a polymer solution containing a functional material and/or a reactive monomer 71;

103. wrapping the droplets 711 with a gelable solution 72;

105. adding the gelable solution 72 wrapped with the droplets 711 to a coagulation bath 73 to gel the gelable solution 72 wrapped with the droplets 711 to form a gel;

107. after the particles are formed inside the gel, the gel is dissolved.

In the method for producing polymer particles according to the embodiment of the present invention, the polymer solution containing the functional material and/or the reactive monomer 71 is a dispersed phase, the gellable solution 72 is a continuous phase, and the coagulation bath 73 is used to gel the gellable solution 72.

In the prior art, the preparation of polymer particles is generally carried out by mechanical stirring, and the process is as follows, the dispersed phase is added into a dispersion medium, a suitable surfactant is added, and the dispersed phase is changed into liquid drops to be dispersed in the dispersion medium by stirring or a homogenizer. Then, the solvent is volatilized or the monomer is polymerized by stirring for a long time to obtain solid polymer particles. Since the dispersion still requires a long period of time for the solvent to volatilize or for the polymerization reaction to proceed after the dispersion is formed, the continuous stirring at this stage may cause the particles that have been formed to aggregate due to interfacial tension, gravity, collision, or the like, or to break due to shearing force of the stirring, or to vary the shearing force due to different flow rates at different points in the vessel, resulting in a broadening of the particle size distribution.

Compared with the prior art, the preparation method of the polymer particles provided by the embodiment of the invention has the advantages that the dispersed phase is limited in the gel, so that the particles cannot be contacted, and the problems of aggregation caused by interfacial tension, gravity and collision, crushing caused by stirring shearing force, different shearing force caused by different flow velocities of various points in a container, wider particle size distribution and the like in the prior art cannot exist. Making it possible to prepare uniform particles.

The functional material in the embodiment of the present invention refers to an ingredient added to produce particles having a certain use. The components can be medicines, nanoparticles, pore-forming agent, fluorescent dye, perfume, etc. When preparing the drug sustained-release microspheres, the functional material is a drug molecule; when the magnetic microspheres are prepared, the functional material is ferroferric oxide nano particles; when the fluorescent microspheres are prepared, the functional material is fluorescent dye or quantum dots; when the bead blasting microsphere is prepared, the inner layer is spice or flavor substances.

It should be noted that, as shown in fig. 2,

the functional material 01 in this embodiment may be uniformly distributed in a homogeneous state in the polymer solution, or uniformly distributed in a homogeneous state in the reactive monomer, or uniformly distributed in a homogeneous state in a mixed liquid composed of the polymer solution and the reactive monomer, as shown in fig. 2 a.

The functional material 01 in this embodiment may be dispersed in a heterogeneous state in the polymer solution, the reactive monomer, or the mixed liquid of the polymer solution and the reactive monomer, as shown in fig. 2 b.

The functional material 01 in this embodiment may also be encapsulated in a heterogeneous state in a polymer solution, a reactive monomer, or a mixed liquid of a polymer solution and a reactive monomer, as shown in fig. 2 c.

In the method for producing polymer particles provided in this example, step 103 wraps the droplets 711 with the gelable solution 72, and generally wraps the droplets 711 with the gelable solution while forming the droplets 711.

The embodiment adopts a droplet 711 forming and wrapping device to form and wrap the droplet 711, and the structure of the device is shown in fig. 3, and the device comprises a first pipeline 31 for flowing a polymer solution containing a functional material and/or a reactive monomer; a second pipeline 32 which is sleeved outside the first pipeline 31, is coaxial with the first pipeline 31 and is used for the flow of the gelable solution.

When the formation and the wrapping of the droplets 711 are realized by this structure, the polymer solution containing the functional material and/or the reactive monomer is fed into the first pipe 31, and the gelable solution is fed into the second pipe 32.

The flow rates of the liquids in the first and second lines 31 and 32 are controlled. When the velocities of the fluid in the inner and outer pipelines are relatively low, one droplet 711 is directly formed at the outlet; when the fluid velocity of the inner and outer pipelines is higher, a coaxial fluid is formed firstly, then the outer layer is gelated to form gel fiber, the liquid in the gel fiber is changed into one droplet 711 from the continuously flowing liquid under the action of interfacial tension, and the droplets 711 are orderly arranged in the gel fiber in a single row. With this structure, since all the droplets 711 are formed through the first pipe 31, the uniformity of the formed droplets 711 is excellent.

When the functional material needs to be wrapped in the polymer solution and/or the reactive monomer, the device for wrapping the droplet 711 can be changed accordingly, as shown in fig. 4, in this case, the device for wrapping the droplet 711 includes a third pipeline 41 for flowing the liquid containing the functional material, a fourth pipeline 42 for flowing the polymer solution and/or the reactive monomer, which is sleeved outside the third pipeline 41 and is coaxial with the third pipeline 41, and a fifth pipeline 43 for flowing the gelable solution, which is sleeved outside the fourth pipeline 42 and is coaxial with the fourth pipeline 42.

When the formation and the wrapping of the droplets 711 are realized by this structure, the liquid containing the functional material is fed into the third line 41, the polymer solution and/or the reactive monomer is fed into the fourth line 42, and the gellable solution is fed into the fifth line 43.

The third line 41, the fourth line 42 are controlled to use the flow rate of the liquid in the fifth line 43. When the speeds of the fluids in the three pipelines are relatively low, one droplet 711 is directly formed at the outlet, the most central part of the droplet 711 is the functional material, the outer layer of the droplet 711 is the polymer solution and/or the reactive monomer, and the droplet 711 is wrapped by the gelable solution; when the speed of the fluid in the three pipelines is higher, a coaxial fluid is formed firstly, then the outermost layer is gelatinized to form gel fiber, the liquid in the gel fiber is changed into one droplet 711 from the continuously flowing liquid under the action of interfacial tension, the droplets 711 are arranged in the gel fiber in a single row in order, at the moment, the most center of the droplet 711 is the functional material, and the outer layer of the droplet 711 is the polymer solution and/or the reactive monomer.

The droplet 711 forming and wrapping apparatus of this embodiment may also adopt a structure as shown in fig. 6, which includes a first chamber 61 for placing a polymer solution containing a functional material and/or a reactive monomer; a second chamber 62 for the flow of the gelable solution; the first chamber 61 communicates with the second chamber 62 through a droplet forming hole 63.

When the structure is adopted to realize the formation and the wrapping of the liquid drops 711, the polymer solution and/or the reactive monomer containing the functional material is introduced into the first cavity 61, the polymer solution and/or the reactive monomer containing the functional material in the first cavity 61 flows to the second cavity 62 through the liquid drop forming holes 63, the liquid drops 711 are formed when entering the second cavity 62 and are attached to the inner wall of the second cavity 62, meanwhile, the gelable solution is introduced into the second cavity 62, and the liquid drops 711 attached to the inner wall of the second cavity 62 are washed away by the gelable solution, so that the wrapping of the liquid drops 711 by the gelable solution is completed. The formation and the wrapping of the liquid drops 711 are realized by adopting the structure, and the number of the liquid drop forming holes 63 on the first cavity 61 can be increased according to actual needs, so that the structure is suitable for preparing particles in large batch; since the droplet forming holes 63 have a uniform size, it is possible to ensure that the uniformity of the prepared particles is good, in addition to the mass production of the particles. Both the first chamber 61 and the second chamber 62 in this configuration are preferably tubular chambers. It is of course also possible to divide a chamber into two parts by a partition, one part being the first chamber 61 and the other part being the second chamber 62, and to provide the droplet forming holes 63 on the partition, in which case the shape of the chamber is not limited.

As a special case of the above structure, as shown in fig. 7, in this case, the first chamber 61 is a pipe, the second chamber 62 is also a pipe, and the droplet forming hole 63 is an outlet of the first chamber 61. The principle and process for forming and wrapping the droplets 711 are the same as those of the droplet 711 forming and wrapping device shown in fig. 6.

In the method for preparing polymer particles according to the embodiment of the present invention, in step 105, the gelable solution wrapped with the droplets 711 is added to the coagulation bath 73, so that the gelable solution wrapped with the droplets 711 is gelled to form the gel 722.

The gelable solution coated with the droplets 711 is fed into the coagulation bath 73, and may be fed dropwise or injected.

When the dropping method is employed, the discharge port 100 is located above the coagulation bath 73. Here, the outlet 100 is an outlet of the gelable solution in which the droplets 711 are wrapped. The gelable solution formed at the discharge port 100 and having the droplets 711 wrapped therein is dropped into the coagulation bath 73, and then the gelable solution is formed into a gel.

When injection is used, the discharge port 100 is submerged in the coagulation bath 73. At this time, the gelable solution in which the droplets 711 are wrapped forms gel fibers at the outlet 100. In this way, since the gelable solution forms gel fibers having a certain strength immediately after encountering the coagulation bath 73, not only the stability of the droplets 711 can be maintained, but also the droplets 711 having a small particle diameter can be more easily obtained.

Wherein the gelable solution wrapped with the droplets 711 is added to the coagulation bath 73 by injection to form gel fibers. The gel fiber is continuously generated at the discharge hole 100, so that the gel fiber is bent or folded, and the liquid drops 711 in the gel fiber are deformed or gathered due to extrusion, thereby affecting the appearance and uniformity of the gel fiber.

To solve this problem, in the embodiment of the present invention, the coagulation bath 73 is moved relative to the discharge hole 100 while the gellable solution wrapped with the droplets 711 is added to the coagulation bath 73. As the gel fibers are continuously generated at the discharge port 100, the gel fibers are orderly accumulated in the coagulation bath 73, and deformation or aggregation of the inner droplets 711 due to squeezing caused by excessive bending of the fibers is avoided, which is advantageous for obtaining particles with good uniformity.

The coagulation bath 73 may be moved relative to the discharge port 100 by rotating the coagulation bath 73 by an external device, or by rotating the discharge port 100 by an external device.

When the formed fiber is strong enough, the formed gel fiber can be stretched by setting the pulling device 800. By stretching the formed fibers, not only can the fibers be orderly arranged, but also the deformation or aggregation of the inner liquid drops 711 caused by the excessive bending of the fibers due to extrusion is avoided, and particles with good uniformity can be obtained; and the diameter of the droplets 711 can be changed by attenuating the fibers to obtain smaller diameter droplets 711.

When the gellable solution is solidified too fast in the coagulation bath 73, there is a possibility that the gellable solution-coated polymer solution containing the functional material and/or the reactive monomer does not yet form the droplets 711, and the gellable solution is gelled to form the coaxial fibers, and individual particles cannot be obtained. In order to avoid this, in the present embodiment, a duct may be provided at the discharge port 100 of the structure shown in fig. 3 and 4.

After the conduit is provided, the gelation process of the gelled solution is delayed, so that the polymer solution containing the functional material and/or the reactive monomer can form the droplets 711 in the gelable solution, and the formation of the coaxial fiber can be avoided.

The gellable solution in embodiments of the invention may be an ion sensitive system solution, or a pH sensitive system solution, or a temperature sensitive solution.

Wherein, the ion sensitive system solution preferably adopts a sodium alginate solution-multivalent salt solution system, which can be a sodium alginate-calcium chloride system. Wherein the sodium alginate solution meets the calcium chloride solution to form an ion-crosslinked gel, and the gel can be re-dissolved by using sodium citrate. The polymer particles can be obtained at a lower cost.

Wherein, the pH sensitive system solution can preferably adopt a chitosan-sodium hydroxide solution system. The chitosan is dissolved in 2% acetic acid water solution, and when the chitosan is subjected to alkaline solution such as sodium hydroxide, potassium hydroxide and the like, the chitosan is solidified into gel fiber, and the gel fiber can be re-dissolved by re-adding acid. The polymer particles can be obtained at a lower cost.

Among them, the temperature sensitive solution may preferably be a poloxamer solution. The poloxamer solution is liquid at low temperature, and can be injected into high temperature empty container to convert into gel state.

In order to make the technical solution of the present invention better understood, the following description is given for a clear and complete description of the present invention with reference to several specific preparation examples, in which:

the first embodiment is as follows: preparation of medicine-carrying polylactic-co-glycolic acid (PLGA) embolism microsphere for interventional therapy

This embodiment uses the droplet 711 shown in fig. 3 to form a packet device:

wherein, the inner diameter of the first pipeline 31 is 0.25mm, and the outer diameter is 0.48 mm; the inner diameter of the tube of the second pipeline 32 is 0.75mm, the outer diameter is 1.10mm, the first pipeline 31 and the second pipeline 32 are immersed in the coagulating bath 73, and the paclitaxel-loaded microspheres with the diameters of 100 micrometers, 120 micrometers, 160 micrometers, 200 micrometers, 220 micrometers and 240 micrometers are respectively prepared.

The functional material in this example is a paclitaxel drug molecule that is uniformly distributed in a homogeneous form in the droplets 711.

Preparing a solution: dispersing phase solution, dissolving a certain amount of PLGA in chloroform, preparing corresponding solution according to the mass fraction of 0.5%, 1%, 3%, 5%, 8% and 10%, and then preparing the solution according to the mass to medicine mass ratio of PLGA of 10: adding taxol respectively in the proportion of 1.

Preparing an outer-layer continuous-phase solution: 1g of sodium alginate is weighed and dissolved in 100g of deionized water, and 1g of polyvinyl alcohol (PVA) is added in order to improve the hydrophilicity of the surface of the microspheres.

Preparation of coagulation bath 73: 1g of calcium chloride was weighed and dissolved in 1000g of deionized water.

The flow rates for all samples were set as follows: the flow rate of the dispersed phase solution through the first line 31 was set at 60 ml/hr, the flow rate of the continuous phase solution through the second line 32 was set at 300 ml/hr, and the rotational speed of the coagulation bath 73 was 20 rpm.

Starting the machine, it can be seen that the dispersed phase solution droplets 711 are uniformly discharged from the nozzle, one by one, surrounded by gel fibers formed of the continuous phase solution, and collected in the coagulation bath 73. The resulting gel fiber containing one droplet 711 is dried in water, waiting for the chloroform to evaporate completely.

After the particles were solidified, sodium citrate was then added to depolymerize the fibers. The drug-loaded microspheres with the diameters of 100 micrometers, 120 micrometers, 160 micrometers, 200 micrometers and 240 micrometers are obtained respectively. Fig. 6 is a photo of a light mirror of the droplets 711 in the gel, and fig. 7 is a photo of a light mirror of the separated 100 μm particles.

The drug-loaded microspheres (embolism particles) can be directly introduced into the body of a patient through a microcatheter to block tumor vessels. On one hand, the microspheres can block tumor vessels to block tumor for feeding, and on the other hand, the medicine released by the medicine-carrying microspheres can inhibit and kill tumor cells to play a dual anti-tumor role. The drug-loaded microsphere prepared by the method has the advantages of uniform size and completely controllable size, so that the strict requirements on the size of the drug-loaded microsphere (embolism microsphere) in clinic can be completely met.

Example two: preparation of porous spherical scaffolds for cell culture

The porous spherical cell scaffold needs to have a proper volume size, and preferably has a through-hole structure. The spherical support has good rolling property, cells grow on the surface of the spherical support or in the pore channels inside the spherical support, the spherical support is suitable for large-scale 3D culture, only a small amount of microspheres cultured with the cells need to be transferred to a large amount of blank spherical culture media during cell amplification, traditional digestion and transfer are avoided, and the workload is greatly reduced. In this example, the functional material is an aqueous solution of a porogen sodium bicarbonate, which is dispersed in the droplets 711 in a heterogeneous form.

In this embodiment, the droplet 711 shown in FIG. 3 is used to form a packing device, wherein the first pipeline 31 has a pipe inner diameter of 0.35mm and an outer diameter of 0.65 mm; the second tube 32 had a tube inner diameter of 1.15mm and a tube outer diameter of 1.50mm, and a spherical cell culture scaffold having a diameter of about 0.8mm was prepared.

Preparing inner-layer dispersed phase solution (oil phase): 2g of polylactic acid is dissolved in 10ml of dichloromethane, then 2ml of sodium bicarbonate water solution with the concentration of 1M is added, 0.2ml of span80 is added, and the composite emulsion is prepared by ultrasonic or high-speed homogenization.

Preparation of outer continuous phase solution (aqueous phase): 1g of sodium alginate was weighed and dissolved in 1000g of deionized water.

The flow rate of the dispersed phase solution through the first line 31 was set at 60 ml/hr, and the flow rate of the continuous phase solution through the second line 32 was set at 300 ml/hr. The coagulation bath 73 was rotated at a speed of 20 rpm.

When the machine is started, it can be seen that the dispersed phase solution droplets 711 are uniformly discharged from the discharge port 100, one by one, while being wrapped with gel fibers formed of the continuous phase solution, and collected in the coagulation bath 73. The gel fiber containing the droplets 711 obtained is dried in water, waiting for the dichloromethane to evaporate completely. Sodium citrate was then added to depolymerize the fibers (drying and depolymerization process the same as in example one). Uniform pellets with a diameter of 800 microns were obtained.

The obtained pellet was stirred in 0.1M sodium hydroxide for 1 hour to obtain a porous spherical cell culture scaffold having through channels and uniform microsphere size.

Example three: preparation of polystyrene magnetic microsphere

This embodiment uses the droplet 711 shown in fig. 3 to form a packet device:

wherein, the inner diameter of the first pipeline 31 is 0.24mm, and the outer diameter is 0.45 mm; the second conduit 32 has an internal diameter of 0.7mm and an external diameter of 1.06 mm.

In this embodiment, the functional material is ferroferric oxide particles, which are dispersed in the droplets 711 in a heterogeneous form.

Preparing inner-layer dispersed phase solution (oil phase): 0.16g of magnetic nanoparticles is dispersed in 16ml of styrene, divinylbenzene, acrylic acid and methacrylic acid (mass ratio is 100: 20: 5: 5) monomers, and 0.3g of dibenzoyl peroxide is added as an initiator.

Preparation of outer continuous phase solution (aqueous phase): 1g of sodium alginate was dissolved in 100ml of deionized water.

Preparation of coagulation bath 73: 1g of calcium chloride was dissolved in 1000ml of deionized water.

The flow rate of the dispersed phase solution through the first pipe 31 was set at 40 ml/hr, and the flow rate of the continuous phase solution through the second pipe 32 was set at 400 ml/hr.

When the machine is started, it can be seen that the dispersed phase solution droplets 711 are uniformly discharged from the discharge port 100, one by one, while being wrapped with gel fibers formed of the continuous phase solution, and collected in the coagulation bath 73.

After the experiment was completed, the temperature of the coagulation bath 73 was raised to 90 degrees Celsius, and the microspheres were allowed to continue to react and cure at that temperature for 1 hour. After the microspheres are fully cured, the fibers are depolymerized using sodium citrate (the depolymerization process is the same as in example one), and magnetic microspheres 380 microns in diameter are obtained.

Example four: preparation of water-based blasting bead for blasting bead cigarette production

The blasting beads produced in the market at present are oily blasting beads, and mineral oil and liquid paraffin substances are in the blasting beads and are harmful to human bodies.

The size of the blasting beads is 2mm to 4mm, and the traditional water/oil/water system is difficult to ensure to be not broken.

In this embodiment, the liquid drops 711 shown in fig. 4 are used to form a wrapping device, and the inner diameter of the third pipeline 41 is 0.75mm, and the outer diameter is 1.10 mm; the inner diameter of the pipe of the fourth pipeline 42 is 1.65mm, and the outer diameter is 2.15 mm; the fifth pipeline 43 has a pipe inner diameter of 3.50mm and an outer diameter of 4.00 mm.

In this example, an aqueous solution of a functional material, menthol, is encapsulated in the droplets 711 in a heterogeneous form.

The inner layer adopts a water phase system: we dissolved 0.5g menthol as flavour substance in 1000ml 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.

Outer layer continuous phase solution: 1g of sodium alginate was dissolved in 100ml of deionized water.

Preparation of coagulation bath 73: 1.5g of calcium chloride was dissolved in 1000ml of deionized water.

The flow rate of the aqueous phase solution through the third line 41 was set at 60 ml/hr, the flow rate of the oil phase in the fourth line 42 was set at 60 ml/hr, and the flow rate of the aqueous phase in the fifth line 43 was set at 300 ml/hr. The coagulation bath 73 was rotated at 10 rpm. After the obtained fiber gel containing the droplets 711 is dried in water (the drying process is the same as in the first example), a PMMA-coated liquid capsule with a particle size of about 3mm is prepared.

Example five: method for preparing polylactic acid microspheres by using chitosan acetic acid solution as outer layer

This example uses the droplets 711 shown in fig. 5 to form a wrap device:

wherein, the inner diameter of the first pipeline 31 is 0.25mm, and the outer diameter is 0.48 mm; the second pipeline 32 has a pipe inner diameter of 0.75mm and an outer diameter of 1.10 mm.

Preparing a solution:

inner layer dispersed phase solution: 5g of polylactic acid is dissolved in 95 ml of dichloromethane;

outer layer continuous phase solution: dissolving 5g of chitosan in 100ml of 2% acetic acid aqueous solution by mass fraction;

coagulation bath 73: 500 g of sodium hydroxide are dissolved in 5 l of ethanol solution.

The flow rate of the dispersed phase solution through the first line 31 was set at 20 ml/hr, and the flow rate of the continuous phase solution through the second line 32 was set at 100 ml/hr.

Starting the machine, it can be seen that the dispersed phase solution droplets 711 are uniformly discharged from the nozzle, one by one, surrounded by gel fibers formed of the continuous phase solution, and collected in the coagulation bath 73. The size of the microspheres can be adjusted by the pull-up speed of the pulling device 800. The obtained gel fiber containing the droplets 711 is dried in water, and then acetic acid is added to re-dissolve the chitosan fiber shell, so as to obtain polylactic acid particles with the diameter of 200 microns.

Example six: preparation of Polycaprolactone (PCL) particles using tubular porous membranes

This example uses a droplet 711 shown in fig. 6 to form a packing device, wherein the inner wall of the first chamber 61 is a tubular membrane, the tubular membrane is a tetrafluoroethylene membrane, the inner diameter of the tubular membrane is 3mm, the membrane has uniform small holes, and the average diameter of the holes is 0.7 mm.

Preparing a solution:

inner layer dispersed phase solution: dissolving 5g of polycaprolactone in 95 ml of dichloromethane;

outer layer continuous phase solution: dissolving 0.75g of sodium alginate in 100ml of deionized water;

coagulation bath 73: 1g of calcium chloride was weighed out and dissolved in 1000ml of deionized water.

The flow rate of the dispersed phase solution was set at 200 ml/hr, and the flow rate of the outer continuous phase solution was set at 2000 ml/hr.

Starting the machine, it can be seen that the dispersed phase solution droplets 711 are surrounded by gel fibers formed from the continuous phase solution, flow out of the nozzle uniformly, and are collected in the coagulation bath 73. The obtained gel fiber containing the droplets 711 is dried in water, and then sodium citrate is added to depolymerize the fiber (the drying and depolymerization process is the same as in example one). Polycaprolactone (PCL) particles with a diameter of about 0.36mm can be obtained.

Example seven: preparation of polylactic-co-glycolic acid (PLGA) particles

This embodiment uses a droplet 711 as shown in fig. 7 to form a packing device, wherein the second chamber 62 is a tube with an inner diameter of 1mm, and the first chamber 61 is a tube with an inner diameter of 0.2 mm.

Preparing a solution:

inner layer dispersed phase solution: dissolving 3g of polycaprolactone in 97 ml of dichloromethane;

outer layer continuous phase solution: dissolving 1g of sodium alginate in 100ml of deionized water;

The flow rate of the dispersed phase solution through the first chamber 61 was set at 15 ml/hr, and the flow rate of the continuous phase solution through the second chamber 62 was set at 150 ml/hr.

Starting the machine, it can be seen that dispersed phase solution droplets 711 are uniformly discharged from the outlet of the vertical main pipe, one by one, wrapped by gel fibers formed of a continuous phase solution, and collected in a coagulation bath 73. The obtained gel fiber containing the droplets 711 was dried in water, and then sodium citrate was added to depolymerize the fiber (the drying and depolymerization process was the same as in example one). PLGA particles having a diameter of about 0.16mm can be obtained. Fig. 8 is a photograph of a particle beam microscope.

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for producing polymer particles, characterized in that,

wrapping the droplet with a gelable solution;

after the particles are formed inside the gel, the gel is dissolved.

2. The method according to claim 1, wherein the functional material is homogeneously distributed in the polymer solution and/or the reactive monomer in a homogeneous state, or is dispersed or encapsulated in the polymer solution and/or the reactive monomer in a heterogeneous state

3. The production method according to claim 1 or 2, wherein the gelable solution in which the droplets are wrapped is gelated in the coagulation bath to form gel fibers.

4. The production method according to any one of claims 1 to 3, wherein the gelable solution in which the droplets are wrapped is added to the coagulation bath while the coagulation bath is moved relative to the discharge port.

5. The method of claim 3, wherein the gel fiber is stretched while the gel fiber is formed.

6. The production method according to claim 1, wherein the droplet is wrapped with a gelable solution while forming the droplet.

7. The method for producing polymer particles according to claim 6, wherein the droplets are formed while being wrapped with a gelable solution by a droplet-forming-wrapping device,

the drop formation wrap device comprises a first chamber and a second chamber,

a second chamber for flowing the gelable solution;

8. The production method according to claim 6, wherein the droplet is formed while being wrapped with a gelable solution by a droplet-forming-wrapping device,

the drop formation wrap device comprises a first chamber and a second chamber,

a first line for flowing a polymer solution containing a functional material and/or a reactive monomer;

and the second pipeline is sleeved outside the first pipeline, is coaxial with the first pipeline and is used for allowing the gelable solution to flow.

9. The process according to claim 2, wherein the coating of the droplets of the functional material in the polymer solution and/or the reactive monomer in a heterogeneous state is carried out by a droplet-forming coating apparatus,

the drop formation wrap device comprises a first chamber and a second chamber,

a third pipeline for flowing liquid containing functional materials;

a fourth pipeline which is sleeved outside the third pipeline, is coaxial with the third pipeline and is used for the polymer solution and/or the reactive monomer to flow;

and the fifth pipeline is sleeved outside the fourth pipeline, is coaxial with the fourth pipeline and is used for the gelable solution to flow.

10. The production method according to claim 8 or 9, wherein a conduit is provided at an outlet of the second line and the fifth line.

11. The method of claim 1, wherein the gelable solution is an ion-sensitive system solution, or a pH-sensitive system solution, or a temperature-sensitive solution.

12. The method of claim 10, wherein the ion sensitive system solution is sodium alginate solution-multivalent salt solution system.

13. The method for preparing the chitosan/sodium hydroxide composite material according to claim 10, wherein the pH sensitive system solution is a chitosan hydrochloride solution-sodium hydroxide solution system.

14. The method of claim 10, wherein the temperature sensitive solution is a poloxamer solution.

15. The method according to claim 1, wherein the functional material is a combination of one or more of a protein molecule, a drug molecule, a nanoparticle, a magnetic particle, a fluorescent dye, a perfume, a pore-forming agent, and a quantum dot.

16. The production method according to claim 1 or 15,

the polymer solution is one or a combination of more of polylactic acid-glycolic acid copolymer solution, polylactic acid solution, polymethyl methacrylate solution or polycaprolactone solution;

the reactive monomer is one or more of styrene, divinylbenzene, acrylic acid and methacrylic acid;

the gelable solution is a sodium alginate solution-calcium chloride solution system, or a chitosan hydrochloric acid solution-sodium hydroxide solution system, or a poloxamer solution;

the functional material is one or more of protein molecules, drug molecules, nanoparticles, magnetic particles, fluorescent dyes, essences, spices, pore-making agents and quantum dots.