JP2010201350A - Method for manufacturing microcapsule - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for manufacturing a microcapsule which can manufacture a microcapsule of a uniform particle size. <P>SOLUTION: A first polymer electrolyte solution 8 prepared by dissolving a first polymer electrolyte is extruded through a needle 2. At this time, the extruded first polymer electrolyte solution 8 is electrically charged by applying voltage on the needle 2 to be jetted as minute liquid droplets. By bringing a second polymer electrolyte solution 9 prepared by dissolving a second polymer electrolyte into contact with the jetted minute liquid droplets and by subjecting to reaction, a spherical interface consisting of a polymer electrolyte composite is formed to manufacture a microcapsule. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing microcapsules using a polymer electrolyte.

  A microcapsule is a minute particle having a hollow structure, and is usually composed of an organic substance such as a polymer or an inorganic substance. Microcapsules are used in capsules for medical products, recording materials, optical materials, and the like, and are applied in various fields.

  As a method for producing microcapsules, various methods such as an interfacial polymerization method, a core solvation method, and a submerged drying method have been proposed. In addition, a method for producing a microcapsule of a polyion complex by dropping a polyion solution into a polyion solution having a charge opposite to that of the polyion and causing the polyions to react with each other is also conventionally known.

  As a method for producing microcapsules using such polyions, for example, there is a method disclosed in Patent Document 1. According to the method of Patent Document 1, a polyanion solution is produced as microdroplets by an ultrasonic nozzle or an aerosol generator (atomizer) and collided with an aqueous solution containing a polycation that flows down into a film shape to produce microcapsules. It is to do.

Japanese translation of PCT publication No. 2002-507473

  However, in the manufacturing method of Patent Document 1, since the polyanion solution is ejected as micro droplets using an ultrasonic nozzle or an aerosol generator, the ejected micro droplets merge into a large droplet while moving. It is difficult to produce microcapsules with a uniform particle size. In addition, since ultrasonic waves have a considerable effect on proteins and cells, it is difficult to microencapsulate unstable substances.

  The objective of this invention is providing the microcapsule manufacturing method which can manufacture the microcapsule of a uniform particle diameter continuously on mild conditions.

Means for Solving the Problems and Effects of the Invention

  The method of manufacturing a microcapsule according to claim 1 includes a step of extruding a first polymer electrolyte solution in which a first polymer electrolyte is dissolved from a needle, and applying the voltage to the needle to extrude the first polymer electrolyte solution. A step of charging the liquid droplets into fine droplets, and bringing the discharged fine droplets into contact with and reacting with the second polymer electrolyte solution in which the second polymer electrolyte is dissolved. Forming a spherical interface composed of a body to produce a microcapsule.

  In the first polymer electrolyte solution, the first polymer electrolyte is ionized into polyions and low molecular ions. When manufacturing the microcapsule, the first polymer electrolyte solution is pushed out of the needle while a voltage is applied to the needle. Then, since the voltage is applied to the needle, the first polymer electrolyte solution comes out at the tip of the needle and forms a conical meniscus. In this meniscus, polyions are gathered. Then, in this meniscus, when the electrostatic repulsion force of the charge of the polyion exceeds the surface tension, fine droplets are separated from the meniscus. At the time of separation, the microdroplets are uniform in size due to the action of electrostatic repulsion and surface tension. Since the separated minute droplets are strongly charged, they are ejected in a spray form by electrostatic repulsion between the droplets.

  When the ejected microdroplet is brought into contact with the second polymer electrolyte solution, the polyion present on the surface of the microdroplet reacts with the polyion in the second polymer electrolyte solution, and the polymer electrolyte complex A spherical interface is formed to produce a microcapsule.

According to this microcapsule manufacturing method, fine droplets of uniform size can be ejected from the needle by the action of electrostatic repulsion and surface tension. In addition, since the ejected micro droplets are charged, the droplets do not coalesce while moving, and can be brought into contact with the second polymer electrolyte solution in a state of uniform size. Accordingly, microcapsules having a uniform particle diameter can be produced under mild conditions of solution extrusion and voltage application.
In addition, the microcapsule is manufactured only by a series of steps in which the first polymer electrolyte solution is pushed out from the needle while the voltage is applied to the needle, and the ejected microdroplet is dropped into the second polymer electrolyte solution. be able to. Furthermore, microcapsules can be continuously produced by continuously extruding the first polymer electrolyte solution from the needle at a constant flow rate and continuously collecting the second polymer electrolyte solution. Therefore, it is excellent in productivity.

  According to a second aspect of the present invention, there is provided a method for producing a microcapsule according to the first aspect, wherein the electrode is disposed facing the needle so that the charged micro droplet ejected from the needle is directed to the second polymer electrolyte solution. An electric field is formed between the needle and the electrode.

  According to this configuration, the charged micro droplet ejected from the needle receives a force from the electric field formed between the needle and the electrode, and flies toward the second polymer electrolyte solution. Therefore, a part of the fine droplets ejected from the needle is prevented from falling outside the container or the like containing the second polymer electrolyte solution, and almost all the fine droplets ejected from the needle are reliably secured. To the second polymer electrolyte solution.

  According to a third aspect of the present invention, there is provided a method for producing a microcapsule according to the first or second aspect, wherein the polyion of the first polymer electrolyte and the polyion of the second polymer electrolyte are oppositely charged.

  According to this configuration, by bringing the microdroplet into contact with the second polymer electrolyte solution, the polyion in the microdroplet and the polyion in the second polymer electrolyte solution are combined by electrical interaction, A spherical interface composed of a molecular electrolyte complex can be formed.

  A microcapsule manufacturing method according to a fourth aspect is the method according to any one of the first to third aspects, wherein a predetermined substance is added in advance to the first polymer electrolyte solution pushed out from the needle so that the microcapsule is produced inside the interface. The microcapsule manufacturing method according to claim 1, wherein a microcapsule having the predetermined substance is manufactured.

  By using the first polymer electrolyte solution to which the predetermined substance is added, the predetermined substance can be included in the fine droplets ejected from the needle. By making the microdroplet and the second polymer electrolyte solution come into contact with each other and reacting them, a microcapsule having a predetermined substance inside the spherical interface can be manufactured.

  The microcapsule manufacturing method according to claim 5 is the microcapsule manufacturing method according to claim 4, wherein the predetermined substance is a cell, protein, nucleic acid, polysaccharide, dye, catalyst, physiologically active substance, nutrient, drug, aroma component, pigment, and It contains at least one of the adsorbing substances.

  In this microcapsule manufacturing method, it is not necessary to use an organic solvent. Therefore, when an active substance such as a cell or protein is encapsulated in the microcapsule, the microcapsule is encapsulated without impairing the active state of the cell or protein. Can do.

  The microcapsule manufacturing method according to claim 6 is the method according to any one of claims 1 to 5, wherein the voltage applied to the needle, the inner diameter of the needle, the flow rate of the first polymer electrolyte solution pushed out from the needle, and The particle size of the microcapsules is controlled by controlling at least one of the polymer electrolyte concentrations in the polymer electrolyte solution.

  The particle size of the fine droplets ejected from the needle is controlled by controlling the applied voltage, the inner diameter of the needle, the flow rate of the first polymer electrolyte solution extruded from the needle, and the concentration of the first polymer electrolyte solution. be able to. Therefore, the particle size of the microcapsules can be reliably controlled by controlling the applied voltage and the like. Thereby, microcapsules having a desired particle size and uniform sizes can be obtained.

It is a figure which shows the outline | summary of the microcapsule manufacturing apparatus used for the microcapsule manufacturing method which concerns on embodiment of this invention. It is an optical micrograph of the microcapsule which includes the yeast produced by the microcapsule manufacturing method of the present invention. It is an optical micrograph of a microcapsule in a state where yeast is grown. It is a graph which shows distribution of the particle size of a microcapsule. It is a graph which shows the relationship between the particle size of a microcapsule, and the applied voltage to a needle. It is a graph which shows the relationship between the particle size of a microcapsule, and the internal diameter of a needle. It is a graph which shows the relationship between the particle size of a microcapsule, and the flow volume of the 1st polymer electrolyte solution extruded from a needle. It is a graph which shows the relationship between the particle size of a microcapsule, and the density | concentration of the 1st polymer electrolyte in a 1st polymer electrolyte.

Hereinafter, embodiments of the present invention will be described.
FIG. 1 is a diagram showing an outline of a microcapsule manufacturing apparatus 1 used in a microcapsule manufacturing method according to an embodiment of the present invention.
As shown in FIG. 1, the microcapsule manufacturing apparatus 1 includes a syringe 3 having a needle 2 attached to the tip, an electrode plate 4 disposed opposite to the needle 2, and a gap between the electrode plate 4 and the needle 2. The power source unit 5 applies a voltage to the stirrer 6, the stirrer 6 disposed on the electrode plate 4, and the container 7 disposed on the stirrer 6. The syringe 3 is filled with a first polymer electrolyte solution 8, and the container 7 holds a second polymer electrolyte solution 9.

  The polyelectrolyte is a polymer that can be dissociated into a polyion (polycation or polyanion) having a positive or negative charge and a number of low molecular ions having a charge opposite to that of the polyion. A polymer electrolyte having a polycation is a polycationic polymer, and a polymer electrolyte having a polyanion is a polyanionic polymer.

  The first polymer electrolyte solution 8 is a solution obtained by dissolving the first polymer electrolyte in a solvent. The first polymer electrolyte may be a polycationic polymer or a polyanionic polymer. The first polymer electrolyte may be a single type of polymer or a combination of multiple types of polymers. However, when a plurality of types of polymers are used in combination, a polyionic polymer having the same sign is used.

  Specific examples of the polycationic polymer used in the first polymer electrolyte include chitosan, polyallylamine hydrochloride (PAH), polyethyleneimine (PEI), polydimethylammonium chloride (PDDA), protein, polylysine and the like. . Specific examples of the polyanionic polymer used in the first polymer electrolyte include alginic acid, polystyrene sulfonic acid (PSS), hyaluronic acid, polyglutamic acid, polyacrylic acid, protein, DNA, RNA, and the like. Depending on the use of the microcapsule, it is particularly preferable to use chitosan or alginic acid which is excellent in biocompatibility and biodegradability. The concentration of the first polymer electrolyte is, for example, 0.1 to 20 wt%, although it depends on the type of polymer. Further, water is used as the solvent of the first polymer electrolyte solution 8.

  A predetermined substance (hereinafter referred to as a core substance) to be included in the microcapsules is added to the first polymer electrolyte solution 8 and dispersed therein. Examples of the core substance include cells such as yeast and E. coli, molds, animals, plants, insects, proteins, nucleic acids, inorganic fine particles and other catalysts, adsorbents, drugs, physiologically active substances, aromatic components, and nutrients.

  The concentration of the core substance in the first polymer electrolyte solution 8 is 1 ppm to 50 wt%, depending on the type. For example, when the core substance is a cell, 0.01 to 10 wt% is preferable, and when the core substance is a protein such as an enzyme, 1 ppm to 1 wt% is preferable. When yeast is used as the core substance, a liquid (medium) for cultivating yeast may be further added to the first polymer electrolyte solution 8. The core substance does not necessarily have to be added.

  The second polymer electrolyte solution 9 is a solution obtained by dissolving the second polymer electrolyte in a solvent. The second polymer electrolyte is preferably a polymer having a polyion opposite in charge to the polyion of the first polymer electrolyte, but forms an interface as described later by reacting with the polyion of the first polymer electrolyte. If so, it may be a polymer having a polyion having the same sign as the polyion of the first polymer electrolyte.

The second polymer electrolyte may be a single type of polymer or a combination of multiple types of polymers. However, when a plurality of types of polymers are used in combination, it is preferable to use polyionic polymers having the same sign. As the second polymer electrolyte, the same type as the polycationic polymer or polyanionic polymer used for the first polymer electrolyte polymer described above is used. The concentration of the second polymer electrolyte is, for example, 0.1 to 20 wt% although it depends on the type of polymer.
Moreover, as a solvent of the 2nd polymer electrolyte solution 9, although it is preferable to use water from a viewpoint of the safety | security to a biological body depending on the use of a microcapsule, it is not specifically limited to water.

  Examples of the combination of the first polymer electrolyte and the second polymer electrolyte include PAH and PSS, alginic acid and chitosan, hyaluronic acid and chitosan, polylysine and polymethacrylic acid, and the like.

Hereinafter, the microcapsule manufacturing apparatus 1 will be described in detail.
The inner diameter of the needle 2 provided at the tip of the syringe 3 is 10 to 1000 μm. The first polymer electrolyte solution 8 in the syringe 3 is pushed out from the tip of the needle 2 by pressing the pusher 3 a of the syringe 3 by a drive unit (not shown). The pushing speed of the pusher 3a by the drive unit can be controlled. Therefore, the flow rate of the first polymer electrolyte solution 8 pushed out from the needle 2 can be controlled. The flow rate of the first polymer electrolyte solution 8 pushed out from the needle 2 is set to an appropriate value according to the inner diameter of the needle 2.

  For the needle 2, a conductive material such as metal is recommended, but other non-conductive materials such as glass can also be used. The needle 2 is connected to a power supply unit 5 so that a high voltage is applied. When the first polymer electrolyte is a polycationic polymer, the positive electrode of the power supply unit 5 is connected to the needle 2, and when the first polymer electrolyte is a polyanionic polymer, the negative electrode of the power supply unit 5 is used. Is connected to the needle 2. FIG. 1 shows a case where the positive electrode of the power supply unit 5 is connected to the needle 2.

  In addition, the electrode opposite to the electrode connected to the needle 2 of the power supply unit 5 is grounded and connected to the electrode plate 4. Thereby, an electric field is formed between the needle 2 and the electrode plate 4. As the power supply unit 5, a DC power supply is used, and the voltage applied to the needle 2 (potential difference between the needle 2 and the electrode plate 4) is, for example, 5 to 30 kV, and particularly preferably 10 to 25 kV. The electrode plate 4 is made of a conductive material such as metal.

  The stirrer 6 is for stirring the second polymer electrolyte solution 9 in the container 7. The stirrer 6 is of a magnetic type, for example, and a stirrer (not shown) disposed in the container 7 is rotated by a magnetic force to stir the second polymer solution. The container 7 may be formed of a conductive material, but may be formed of an insulating material.

  Next, the manufacturing method of the microcapsule using the microcapsule manufacturing apparatus 1 will be described by taking as an example the case where a polycationic polymer is used as the first polymer electrolyte.

  The first polymer electrolyte solution 8 is extruded from the needle 2 at a constant speed. At this time, a voltage is applied between the needle 2 and the electrode plate 4. Then, the first polymer electrolyte solution 8 comes out at the tip of the needle 2 and a conical meniscus is formed. In this meniscus, since polycations are gathered, electric field concentration occurs. In this conical meniscus, when the electrostatic repulsive force of the charges exceeds the surface tension, the fine droplets are separated from the meniscus. At the time of separation, the microdroplets are uniform in size due to the action of electrostatic repulsion and surface tension. Since the separated minute droplets are strongly charged, they are ejected in a spray form by electrostatic repulsion between the droplets. The polycation in the microdroplet is mainly present on the surface side of the microdroplet so that the electrostatic repulsive force of the charge is minimized. In addition, a core substance and a solvent are present inside the microdroplet.

  Since an electric field is formed between the needle 2 and the electrode plate 4, the fine droplets charged with the opposite sign to the electrode plate 4 are attracted to the electrode plate 4 and are drawn into the second polymer electrolyte solution 9. It flies towards the second polymer electrolyte solution 9 and drops.

  When the microdroplet is brought into contact with the second polymer electrolyte solution 9, the polycation present on the surface side of the microdroplet and the polyanion in the second polymer electrolyte solution 9 are combined by electrical interaction, A spherical interface composed of the polymer electrolyte complex is formed. A core substance and a solvent are sealed inside the spherical interface. In this way, microcapsules enclosing the core substance are manufactured. The particle size of the produced microcapsule is several tens of μm to several hundreds of μm.

  As described above, the case where a polycationic polymer is used as the first polymer electrolyte has been described as an example. However, when a polyanionic polymer is used as the first polymer electrolyte, a microcapsule is manufactured in the same manner. Can do.

  According to the microcapsule manufacturing method described above, fine droplets of uniform size can be ejected from the needle by the action of electrostatic repulsion and surface tension. In addition, since the ejected minute droplets are charged, the droplets do not merge while moving, and can be brought into contact with the second polymer electrolyte solution 9 while maintaining the same size. Therefore, microcapsules having a uniform particle size can be produced.

The smaller the inner diameter of the needle 2, the smaller the particle size of the fine droplets ejected from the needle 2, and the smaller the particle size of the microcapsule. Therefore, the particle size of the microcapsules can be controlled by controlling the inner diameter of the needle.
If the inner diameter of the needle 2 is too large, the droplet ejected from the needle 2 has a large particle size and a small surface tension, and thus may break during movement. In this case, the particle size of the droplets at the time of contact with the second polymer electrolyte solution 9 becomes non-uniform, and the particle size of the microcapsules becomes non-uniform.
Therefore, by setting the inner diameter of the needle within an appropriate range according to the type of the first polymer electrolyte, microcapsules having a desired particle diameter can be obtained. Although depending on the type and flow rate of the first polymer electrolyte, the inner diameter of the needle 2 is preferably 10 to 1000 μm, for example.

When the inner diameter of the needle 2 is constant, the smaller the flow rate of the first polymer electrolyte solution 8 extruded from the needle 2, the smaller the particle size of the fine droplets ejected from the needle 2, and the smaller the particle size of the microcapsule. Become.
If the flow rate is too high, the particle size of the droplets ejected from the needle 2 becomes large, and the droplets may break during movement, thereby causing variations in the particle size of the microcapsules. On the other hand, if the flow rate is too small, fine droplets having a uniform particle diameter cannot be ejected from the needle 2, and the particle diameters of the microcapsules vary.
Therefore, by setting the flow rate of the first polymer electrolyte solution 8 to an appropriate value according to the inner diameter of the needle 2 or the like, microcapsules having a desired particle diameter can be obtained. For example, when the inner diameter of the needle is 130 μm and the voltage is 10 to 25 kV, the flow rate is preferably 0.05 to 2 ml / h.

The higher the voltage applied to the needle 2, the greater the electrostatic repulsion of the charge on the liquid surface at the tip of the needle 2, and the smaller the droplets, the smaller the particle size of the microcapsules.
If the applied voltage is too low, the particle size of the micro droplets ejected from the needle 2 becomes large, and the micro droplets may break up during movement, thereby causing variations in the particle size of the microcapsules. On the other hand, if the applied voltage is too high, droplets are forcibly formed before the first polymer electrolyte solution 8 is sufficiently supplied, resulting in nonuniform particle sizes.
Therefore, by setting the voltage applied to the needle 2 to an appropriate value, microcapsules having a desired particle diameter and uniform particle diameter can be obtained. Specifically, 10 to 25 kV is preferable.

Further, the lower the concentration of the first polymer electrolyte solution 8 is, the lower the viscosity of the first polymer electrolyte solution 8 is and the lower the surface tension of the liquid surface at the tip of the needle 2 is. To do. Therefore, the particle size of the microcapsule is also reduced.
If the concentration of the first polymer electrolyte solution 8 is too low, there are too few polyions in the microdroplets, so that the thickness of the interface made of the polymer electrolyte complex is not sufficient, and the strength of the microcapsules becomes low. On the other hand, if the concentration of the first polymer electrolyte solution 9 is too high, the viscosity becomes high. Therefore, it is necessary to devise operations such as raising the temperature of the first polymer electrolyte solution.
Therefore, by setting the concentration of the first polymer electrolyte solution 8 to an appropriate value according to the type of the first polymer electrolyte, etc., the microcapsules having a desired particle size with high strength and uniform particle size. Can be obtained.

  In addition, the particle size of the fine droplets dropped on the second polymer electrolyte solution 9 can also be controlled by controlling the distance from the tip of the needle 2 to the liquid surface of the second polymer electrolyte solution 9. . Thereby, the particle size of the microcapsule can be controlled.

  Furthermore, the particle size of the microcapsules can also be controlled by controlling the concentration of the second polymer electrolyte in the second polymer electrolyte solution 9.

  Further, as described above, since an electric field is formed between the needle 2 and the electrode plate 4, the fine liquid droplets ejected from the needle 2 are attracted to the electrode plate 4, and the second in the container 7. It is dripped in the polymer electrolyte solution 9. Accordingly, a part of the fine droplets ejected from the needle 2 is prevented from falling out of the container 7, and almost all the fine droplets ejected from the needle 2 are reliably made into the second polymer electrolyte solution 9. Can be contacted.

  Further, in this microcapsule manufacturing method, the first polymer electrolyte solution 8 is pushed out from the needle 2 while applying a voltage to the needle 2, and the ejected microdroplet is dropped into the second polymer electrolyte solution 9. That is, microcapsules can be produced by only a series of steps. Moreover, the microcapsules can be continuously produced by continuously extruding the first polymer electrolyte solution 8 from the needle 2 at a constant flow rate and continuously recovering the second polymer electrolyte solution 9. Therefore, it is excellent in productivity.

  Further, for example, when microcapsules are manufactured by a method called an emulsion method, the ratio of the core material included in the microcapsule out of the used core material is less than 100%. The core material added to the first polymer electrolyte solution 8 can be entirely encapsulated in the microcapsule by extruding all the first polymer electrolyte solution 8 filled in 3 from the needle 2.

  Further, in this microcapsule manufacturing method, since it is not necessary to use an organic solvent, it is possible to obtain a microcapsule having a low environmental load and high safety for a living body. Further, when an active substance such as yeast is encapsulated in the microcapsule, it can be encapsulated in the microcapsule without impairing the active state of the yeast or the like.

  Furthermore, microcapsules can be used for pharmaceutical applications by using biocompatible polymers as the first polymer electrolyte and the second polymer electrolyte. In addition, by using a biodegradable polymer as the first polymer electrolyte and the second polymer electrolyte, microcapsules with a smaller environmental load can be obtained.

  Moreover, low molecular substances, such as a metal ion and glucose, can permeate | transmit the interface which consists of a polymer electrolyte composite_body | complex. Therefore, when yeast is encapsulated in the microcapsule, the microcapsules enter the inside of the interface because the nutrient substance in the medium enters by replacing the second polymer electrolyte solution 9 with a liquid medium after the microcapsule is produced. Yeast can be grown within. Further, a core substance such as a medicine can be slowly released to the outside. Such microcapsules are called sustained-release capsules.

  The preferred embodiment of the present invention has been described above, but the above embodiment can be modified as follows.

1] In the above embodiment, the number of needles 2 from which the first polymer electrolyte solution 8 is ejected is one, but may be plural.

2] In the above embodiment, the microdroplet is dropped on the second polymer electrolyte solution 9 in a stirred state. For example, the microdroplet is dropped on the second polymer electrolyte solution 9 that has flowed in one direction. May be.

3] The second polymer electrolyte solution 9 does not necessarily have to be stirred. That is, the container 7 may be disposed directly on the electrode plate 4 without providing the stirrer 6.

4] In the above embodiment, the stirrer 6 on which the container 7 is placed is directly disposed on the electrode plate 4, but the container 7 and the stirrer 6 do not necessarily have to be disposed directly on the electrode plate 4. In this case, the electrode plate 4 may have a surface area smaller than the area of the bottom surface of the container 7. Moreover, the electrode plate 4 may not be flat plate shape, for example, the quadrangular pyramid shape which the center part protruded may be sufficient. By using the electrode plate 4 having such a shape, electric field concentration can be generated between the needle 2 and the electrode plate 4, so that the fine liquid droplets ejected from the needle 2 can be more reliably contained in the container 7. The second polymer electrolyte solution 9 can be dropped.

5] Instead of the electrode plate 4, a mesh electrode may be used, and this electrode may be disposed on the container 7 and the stirrer 6. That is, the needle 2, the electrode 4, the container 7, and the stirrer 6 may be sequentially arranged so that the fine liquid droplets ejected from the needle 2 jump into the container 7 by the electric field.

6] In the above embodiment, the power supply unit 5 is connected to the electrode plate 4 in order to form an electric field between the electrode plate 4 and the needle 2, but an electric field is applied between the electrode plate 4 and the needle 2. The structure for forming is not limited to this. For example, a power supply unit other than the power supply unit 5 is provided, one electrode of the power supply unit is connected to the electrode plate 4, the other electrode is grounded, and an electric field is generated between the electrode plate 4 and the needle 2. May be formed.

7] In the above embodiment, an electric field is formed between the electrode plate 4 and the needle 2, but if a voltage is applied to the needle 2, such an electric field may not necessarily be formed. That is, the electrode plate 4 may not be provided, and an electrode opposite to the electrode connected to the needle 2 of the power supply unit 5 may be grounded. In this case, the fine droplets ejected from the needle 2 are dropped onto the second polymer electrolyte solution 9 in the container 7 by the force of the electric field and gravity.

8] In the above embodiment, water is used as the solvent of the first polymer electrolyte solution 8, but an organic solvent, a water mixture of water and alcohol, Oil-in-water, Water-in-oil, etc. An emulsion solution may be used as a solvent. However, it is preferable to use water from the viewpoint that it is excellent in safety to the living body and does not impair the active state of the core substance. In addition, when an organic solvent is used, the solvent (organic solvent) easily evaporates in the course of movement of the fine droplets separated from the liquid surface at the tip of the needle. When the solvent evaporates, the particle size becomes smaller, so that the charges concentrate, the electrostatic repulsion increases, and the surface tension decreases. As a result, the electrostatic repulsion of the charge may exceed the surface tension and break up into smaller droplets. When such splitting occurs in the course of movement, there is a slight variation in the particle size of the microdroplet when it is dropped into the second polymer electrolyte solution 9, and there is also a variation in the particle size of the microcapsule. There is. Therefore, it is preferable to use water as a solvent also in that microcapsules having a more uniform particle diameter can be obtained.

  Hereinafter, specific examples of the present invention will be described.

  A microcapsule manufacturing apparatus having the configuration shown in FIG. 1 was prepared. The syringe 3 was an all plastic disposable syringe (lock type, 5 ml, model H4050-LL). As the electrode plate 4 and the power supply unit 5, NF-104 of “Measuring device for nanofiber sample for LAB” manufactured by MEC Co., Ltd. was used. As the stirrer 6, a mini DC stirrer SW-M01 manufactured by Nisshin Rika Co., Ltd. was used. The container 7 used was a glass petri dish. Further, as the needle 2, the needle tip of the luer lock injection needle 90 °, round base type 18G (inner diameter 900 μm, outer diameter 1260 μm), 23G (inner diameter 330 μm, outer diameter 630 μm), 27G (inner diameter 190 μm, outer 410G) and 30G (inner diameter 130 μm, outer diameter 310 μm) and Pre-Pulled Glass Pipettes (TIP30TW1-L, World Precision Instruments, inner diameter 30 μm, outer diameter 40 μm) were prepared.

<Example 1>
As the first polymer electrolyte solution of Example 1, an aqueous solution containing 1.5 wt% alginic acid and 1.2 wt% wild type yeast was used. Further, a chitosan aqueous solution having a concentration of 0.5 wt% was used as the second polymer electrolyte solution. Using these first and second polymer electroelectrolyte solutions, microcapsules containing yeast were produced by the method for producing microcapsules described in the above embodiment.
In addition, the needle 2 having the above-described 30G (outer diameter 310 μm, inner diameter 130 μm) was used. The applied voltage to the needle was 17.5 kV, and the flow rate of the first polymer electrolyte solution pushed out from the needle was 0.2 ml / h. The distance from the needle tip to the liquid surface of the second polymer electrolyte solution was 4.5 cm.

  FIG. 2 shows a micrograph of the microcapsules of Example 1 immediately after being produced. Moreover, about 80 particle diameters were measured about the microcapsule of Example 1, and the distribution of the particle diameter was calculated | required. The results are shown graphically in FIG. As shown in FIG. 4, it was confirmed that microcapsules having a uniform particle size could be produced.

  Further, 1 ml of the second polymer electrolyte solution was taken out together with the prepared microcapsules. This was centrifuged and the supernatant was discarded. Then, 1 ml of YPD medium (glucose 2 wt%, peptone 2 wt%, yeast extract 1 wt%) was added and dispersed, then an appropriate amount was taken out and left for 20 hours. A photomicrograph of the microcapsule after 20 hours is shown in FIG. As is clear from the photograph in FIG. 3, it was confirmed that yeast can be grown in the microcapsules.

<Examples 2 to 5>
Next, a polyallylamine hydrochloride (PAH) aqueous solution was used as the first polymer electrolyte solution of Examples 2 to 5. No substance for inclusion in the microcapsules was added to the first polymer electrolyte solution. Further, as the second polymer electrolyte solution, a polystyrene sulfonic acid (PSS) aqueous solution was used. In Examples 6 to 17 described later, the first polymer electrolyte solution and the second polymer electrolyte solution were the same type. In Examples 2 to 17, the concentration of PSS in the second polymer electrolyte solution was all 10 wt%, and the distance from the needle tip to the liquid surface of the second polymer electrolyte solution was all 4.5 cm. .

  The applied voltage to the needle was changed to 15 kV, 17.5 kV, 22 kV, and 24 kV, and other conditions were the same, and about 100 microcapsules of Examples 2 to 5 were produced. Table 1 shows the concentration of PAH in the first polymer electrolyte solution, the diameter of the needle, and the flow rate of the first polymer electrolyte solution. About the microcapsule of each Example, the particle size was measured and the average value of the particle size, the standard deviation value, and the coefficient of variation (relative standard deviation value) were obtained. The results are also shown in Table 1. Moreover, the relationship between the average value and standard deviation value of the particle diameters of the microcapsules of Examples 2 to 5 and the applied voltage is shown in a graph in FIG. In the graph of FIG. 5, the average value of the particle diameter is indicated by a square symbol, and the range of the average value ± standard deviation value is indicated by a straight line. 6 to 9 described later are displayed in the same manner.

  As is clear from FIG. 5 and Table 1, Example 4 with an applied voltage of 22 kV and Example 5 with an applied voltage of 24 kV compare Examples 2 to 4 although the particle size of the microcapsules hardly changes. Then, the higher the voltage applied to the needle, the smaller the particle size of the microcapsules.

<Examples 6 to 10>
Next, the needle inner diameter and outer diameter were changed to the values shown in Table 2, and the other conditions were the same, and about 100 microcapsules of Examples 6 to 10 were produced. Table 2 also shows the concentration of PAH in the first polymer electrolyte solution, the applied voltage, and the flow rate of the first polymer electrolyte solution. About the microcapsule of each Example, the particle size was measured and the average value of the particle size, the standard deviation value, and the coefficient of variation were obtained. The results are also shown in Table 2. Moreover, the relationship between the average value and the standard deviation value of the particle diameters of the microcapsules of Examples 6 to 10 and the inner diameter of the needle is shown in a graph in FIG.

  As is clear from FIG. 6 and Table 2, Example 7 with a needle inner diameter of 130 μm and Example 8 with a needle inner diameter of 190 μm are substantially the same in Examples 6-10, although the particle size of the microcapsules is almost the same. Then, the smaller the inner diameter of the needle, the smaller the particle size of the microcapsule.

<Examples 11 to 13>
Next, the flow rate of the first polymer electrolyte solution extruded from the needle was changed to 0.05 ml / h, 0.1 ml / h, and 0.2 ml / h, and the other conditions were the same, and Examples 11 to 13 were used. About 100 microcapsules were prepared. Table 3 shows the concentration of PAH, applied voltage, and needle diameter in the first polymer electrolyte solution. About the microcapsule of each Example, the particle size was measured and the average value of the particle size, the standard deviation value, and the coefficient of variation were obtained. The results are also shown in Table 3. Moreover, the relationship between the average value and the standard deviation value of the particle diameters of the microcapsules of Examples 11 to 13 and the flow rate of the first polymer electrolyte solution is shown in a graph in FIG.

  As apparent from FIG. 7 and Table 3, the smaller the flow rate of the first polymer electrolyte solution pushed out from the needle, the smaller the particle size of the microcapsules.

<Examples 14 to 17>
Next, the concentration of PAH (first polymer electrolyte) in the first polymer electrolyte solution was changed to 1 wt%, 3 wt%, 5 wt%, 10 wt%, and the other conditions were all the same. About 100 microcapsules of ˜17 were prepared. Table 4 shows the applied voltage, the diameter of the needle, and the flow rate of the first polymer electrolyte solution. About the microcapsule of each Example, the particle size was measured and the average value of the particle size, the standard deviation value, and the coefficient of variation were obtained. The results are also shown in Table 4. Moreover, the relationship between the average value and the standard deviation value of the particle size of the microcapsules of Examples 14 to 17 and the concentration of the first polymer electrolyte is shown in a graph in FIG.

  The microcapsules of Example 14 produced at a concentration of 1 wt% were flat rather than spherical, and were more fragile than the microcapsules of other Examples. Comparing Examples 15 to 17 excluding Example 14, as is apparent from FIG. 8 and Table 4, it can be seen that the lower the concentration of the first polymer electrolyte, the smaller the particle size of the microcapsules.

DESCRIPTION OF SYMBOLS 1 Microcapsule manufacturing apparatus 2 Needle 3 Cylinder 4 Electrode plate 5 Power supply part 6 Stirrer 7 Container 8 1st polymer electrolyte solution 9 2nd polymer electrolyte solution

Claims (6)

Extruding a first polymer electrolyte solution in which the first polymer electrolyte is dissolved from a needle;
Applying a voltage to the needle to charge the first polymer electrolyte solution to be pushed out and eject it as fine droplets;
By contacting the ejected microdroplets with the second polymer electrolyte solution in which the second polymer electrolyte is dissolved to form a spherical interface composed of the polymer electrolyte complex, Manufacturing process;
A method for producing microcapsules, comprising:   An electrode is arranged facing the needle so that the charged micro droplet ejected from the needle is directed to the second polymer electrolyte solution, and an electric field is formed between the needle and the electrode. The method for producing microcapsules according to claim 1, wherein:   The microcapsule manufacturing method according to claim 1 or 2, wherein the polyion of the first polymer electrolyte and the polyion of the second polymer electrolyte have opposite charges.   The microcapsule having the predetermined substance inside the interface is manufactured by adding a predetermined substance in advance to the first polymer electrolyte solution extruded from the needle. 4. The method for producing a microcapsule according to any one of 3 above.   The predetermined substance includes at least one of a cell, a protein, a nucleic acid, a polysaccharide, a dye, a catalyst, a physiologically active substance, a nutrient, a drug, a fragrance component, a pigment, and an adsorbing substance. The microcapsule manufacturing method according to claim 4.   At least among the voltage applied to the needle, the inner diameter of the needle, the flow rate of the first polymer electrolyte solution pushed out from the needle, and the concentration of the first polymer electrolyte in the first polymer electrolyte solution The microcapsule manufacturing method according to claim 1, wherein the particle size of the microcapsules is controlled by controlling one.