JP5072057B2 - Microcapsule manufacturing method using microchannel structure - Google Patents

Description

The present invention relates to a method for producing microcapsules suitably used in the medical field and various industrial fields.

In recent years, interfacial tension differs using a microchannel structure in which a microchannel having a length of about several cm and a width and depth of sub-μm to several hundreds of μm is formed on a glass substrate of several centimeters square. Research to prepare emulsions composed of two types of liquids has attracted attention. In addition, studies have been conducted to produce microcapsules from the emulsion thus prepared.
For example, in Patent Document 1, Non-Patent Document 1, and the like, a microchannel having a structure in which a microchannel in which one liquid is introduced and circulated and a microchannel in which the other liquid is introduced and circulated merge at a junction. It is described that by using a structure, an emulsion in which uniform fine droplets composed of one liquid are dispersed in one liquid can be prepared. An emulsion refers to a system in which one liquid (dispersed phase) that does not dissolve in each other is dispersed as fine droplets in the other (continuous phase).

Specifically, as shown in FIG. 9, the techniques disclosed in these documents are microscopically formed with a T-shaped flow path 52 formed on one surface of a substrate 51 and a cover body (not shown) joined thereto. The flow path structure 50 is used. The formed flow path 52 includes a continuous phase flow path 54 through which a fluid forming a continuous phase is introduced and distributed, a dispersed phase flow path 55 through which a fluid forming a dispersed phase is introduced and distributed, and a dispersion with the continuous phase flow path 54. The phase channel 55 is joined at the junction 56 and has a discharge channel 57 for discharging the emulsion formed at the junction 56. Further, a continuous phase introduction port 54 a and a dispersed phase introduction port 55 a are respectively formed at the base end portions of the continuous phase flow channel 54 and the dispersed phase flow channel 55, and the emulsion is discharged to the end portion of the discharge flow channel 57. A discharge port 57a is formed.
By using such a microchannel structure 50, the fluid forming the dispersed phase is supplied to the fluid flowing through the continuous phase channel 54 in an intersecting direction. As a result, the fluid forming the dispersed phase is refined by the shearing force of the fluid forming the continuous phase, and the fine droplets composed of the dispersed phase having a diameter smaller than the width of the dispersed phase channel 55 are contained in the fluid forming the continuous phase. An emulsion dispersed in is obtained.

As a method of preparing an emulsion in this way and producing microcapsules from this emulsion, for example, when using a sol solution such as a gelatin solution as a fluid forming a continuous phase, the obtained emulsion is taken out into a container or the like, There is a method of obtaining microcapsules in which fine droplets composed of a dispersed phase become contents and gelatinized film is formed around them by heating and cooling while stirring.
In addition, when a fluid containing a polymerizable substance is used as a fluid forming a continuous phase, the obtained emulsion is not taken out into a container or the like, but polymerized in a discharge channel to form a polymerized film to form a microcapsule. There are also methods.
International Publication WO02 / 068104 Pamphlet Takashi Nishisako et al., “Liquid microdroplet generation in microchannels”, Proceedings of the 4th Chemistry and Microsystem Study Group, 59 pages, 2001

However, in the method in which the obtained emulsion is taken out into a container and heated and cooled while stirring in the container to form a gelled film, the fine droplets may re-divide or coalesce during stirring. There is a problem that the particle size dispersion degree of the obtained microcapsules is deteriorated.
In the method of polymerizing in the discharge channel, the channel may be blocked or the polymerization may not proceed sufficiently. Furthermore, in the obtained microcapsule, the content is fixed inside the polymer film, and the free movement of the content may be hindered, and there is a problem that it is difficult to obtain a high-quality microcapsule.

  The present invention has been made in view of the above problems, and when producing microcapsules from an emulsion, it is an object to provide a method for producing high-quality microcapsules having a uniform particle size and good particle size dispersion. To do.

The method for producing a microcapsule of the present invention is a first method for preparing an emulsion in which a liquid that forms a continuous phase and a liquid that forms a dispersed phase are merged in a flow path, and the dispersed phase is dispersed in the continuous phase. A second step in which a fluid containing a phase separation inducer is joined to the emulsion in a flow path to form a concentrated phase composed of components in the continuous phase around the dispersed phase, and the concentrated phase. And a third step of preparing a coacervate capsule dispersion in which a coacervate film is formed and a coacervate film is formed around the dispersed phase.
As the third step, a method of forming a coacervate film by gelling the concentrated phase is suitable. In that case, the second step is preferably performed at a temperature higher than the gelation temperature. Furthermore, it is preferable to implement the 4th process which cools, after stirring the said dispersion liquid under a heating after the said 3rd process .

  According to the present invention, it is possible to produce a high-quality microcapsule having a uniform particle size and good particle size dispersion.

Hereinafter, the present invention will be described in detail with reference to the drawings.
In the method for producing microcapsules of the present invention, a liquid that forms a continuous phase (hereinafter referred to as a continuous phase liquid) and a liquid that forms a dispersed phase (hereinafter referred to as a dispersed phase liquid) are combined in a flow path. A first step of preparing an emulsion in which a dispersed phase is dispersed in droplets in a continuous phase, and a fluid containing a phase separation inducer is joined in the flow path to the prepared emulsion to form a droplet-shaped dispersed phase. A second step of forming a concentrated phase consisting of components in the continuous phase around the periphery, and a coacervate capsule dispersion in which the concentrated phase formed in the second step is converted into a coacervate film and a coacervate film is formed around the dispersed phase. A third step of preparation.

FIG. 1 shows an example of a manufacturing system suitably used in the method for manufacturing a microcapsule of the present invention, and includes a microchannel structure 10A for performing the first step.
As shown in FIGS. 2 and 3, the microchannel structure 10 </ b> A of this example has a channel 12 formed on one surface of a glass substrate 11, and a glass cover body 13 bonded to the surface. The integrated flow path 12 includes a continuous phase flow path 14 through which a continuous phase liquid is introduced and circulated, a dispersed phase flow path 15 through which a dispersed phase liquid is introduced and circulated, and a continuous phase flow path 14. The dispersed phase flow path 15 is composed of a discharge flow path 17 formed by merging at the merging portion 16, and these have a Y-shaped shape communicating with each other.
In this example, each of the continuous phase flow path 14, the dispersed phase flow path 15 and the discharge flow path 17 is a micro flow path (micro channel) having a width of 500 μm or less and a depth of 300 μm or less.
Further, the continuous phase flow path 14, the dispersed phase flow path 15 and the discharge flow path 17 are all formed by etching, and the bottom surface and the wall surface of the flow path are curved surfaces as shown in FIGS. 3 (b) and 3 (c). Connected to the shape.

  Small holes are formed in portions of the cover body 13 corresponding to the base end portions of the continuous phase flow path 14 and the dispersed phase flow path 15 to form a continuous phase introduction port 14a and a dispersed phase introduction port 15a, respectively. The dispersed phase liquid can be introduced from the outside and fed. Further, a small hole is formed in a portion corresponding to the end portion of the discharge channel 17 to form a discharge port 17a, and the emulsion generated in the microchannel structure 10A is discharged from here. .

Microsyringes 20 and 21 and microsyringe pumps 22 and 23 are connected to the continuous phase introduction port 14a and the dispersed phase introduction port 15a through pipes 18 and 19, respectively. The liquid is fed at a flow rate of. In this way, by connecting a constant liquid feeding means including the microsyringes 20 and 21 and the microsyringe pumps 22 and 23 to the continuous phase introduction port 14a and the dispersed phase introduction port 15a, the continuous phase liquid and the dispersed phase liquid can be obtained. Even if it is a trace amount, these can be stably introduced into the continuous phase flow path 14 and the dispersed phase flow path 15 and fed.
On the other hand, the discharge port 17a is connected to the collection container 25 by a pipe 24, and a joint portion 26 having a three-way joint is provided in the middle of the pipe 24, where a fluid containing a phase separation inducing agent is provided. The pipe 27 to which the gas is supplied is joined. A microsyringe 28 and a microsyringe pump 29 for introducing a fluid containing a phase separation inducer into the pipe 27 are connected to the upstream side of the pipe 27. That is, the emulsion generated in the microchannel structure 10A and discharged from the discharge port 17a merges with the fluid containing the phase separation inducer at the joint portion 26. As a result, the emulsion in the continuous phase around the dispersed phase. A concentrated phase composed of components is formed and collected in the collection container 25.

In this example, Teflon (registered trademark) tubes having an inner diameter of 2 mm are used for the pipes 18, 19, 24 and 27. 1 is a holder made of a pair of plate-like bodies, and the microchannel structure 10A is stably held and fixed by the holder 30. Reference numeral 31 in FIG. 1 is a fillet joint. is there.
Moreover, the part enclosed with the broken line in FIG. 1 is stored in the thermostat, and the part outside the broken line is hold | maintained at room temperature lower than it.

  In the first step of this example, an emulsion in which the continuous phase liquid and the dispersed phase liquid are merged in the flow path of the microchannel structure 10A, and the dispersed phase is dispersed in the form of droplets in the continuous phase. To prepare. Specifically, the microsyringe 20 and 21 are filled with the continuous phase liquid and the dispersed phase liquid, respectively, and introduced into the continuous phase channel 14 and the dispersed phase channel 15 at a predetermined flow rate by the microsyringe pumps 22 and 23, An emulsion in which the dispersed phase is dispersed in the continuous phase in the form of droplets of a uniform size at a certain interval by being merged in the flow channel (the confluence portion 16 in this example) of the microchannel structure 10A. Can be prepared and can be circulated in the discharge channel 17.

  The dispersed phase liquid used here is dispersed in the form of droplets in the emulsion as described above, whereas the continuous phase liquid is a solution surrounding the periphery of the droplet-shaped dispersed phase composed of the dispersed phase liquid. is there. Therefore, the dispersed phase liquid and the continuous phase liquid need to be liquids that are not compatible with each other. For example, when one of the dispersed phase liquid or the continuous phase liquid is an aqueous phase, the other is an organic phase (oil phase) that is substantially insoluble in water.

The dispersed phase liquid eventually becomes the contents (core substance) of the obtained microcapsules, and the continuous phase liquid surrounds the contents and forms a film that separates the contents from the outside.
Therefore, the dispersed phase liquid is not particularly limited as long as it can be accommodated in a film formed from components in the continuous phase liquid. However, since the dispersed phase flow channel 15 is preferably a micro flow channel (micro channel) having a width of 500 μm or less and a depth of 300 μm or less because of the ease of forming an emulsion, What can distribute | circulate such a microchannel is preferable.

  Furthermore, the dispersed phase liquid may be a slurry containing solids such as fine particles or a mixed liquid composed of a plurality of liquids, and the plurality of liquids may circulate in a laminar flow. Also good. In particular, when a slurry containing solids such as fine particles is used as the dispersed phase liquid, even if there is a difference in specific gravity between the fine particles in the slurry and the liquid, the continuous phase liquid and the dispersed phase liquid in the flow path. According to the first step, the particles are joined in the flow path to form an emulsion, so that the fine particles are prevented from being detached from the dispersed phase, and the fine particles can be effectively taken into the dispersed phase. This is because the influence of gravity is smaller than the influence of interfacial tension and viscous force in the flow channel, particularly in the micro flow channel. In addition, as described later, in the present invention, a fluid containing a phase separation inducer is joined in the flow path to the emulsion thus prepared, and a concentrated phase composed of components in the continuous phase around the dispersed phase. And the third step of preparing a coacervate capsule dispersion in which a concentrated phase is formed into a coacervate film and a coacervate film is formed around the dispersed phase, so that the fine particles in the dispersed phase are coacervated. Incorporation into the film and fixing can also be suppressed.

  On the other hand, as a continuous phase liquid, a concentrated phase is formed around the dispersed phase by contact with a fluid containing a phase separation inducer, and further, the contents can be confined by forming a coacervate film by a method of gelling the concentrated phase. It is necessary to have a component. Examples of such a solution include a solution in which a dispersant such as polyvinyl alcohol is dissolved in an appropriate solvent, a liquid containing a surfactant such as sodium dodecyl sulfate, and a pH-adjusted cross-linking agent as necessary. Examples thereof include sol solutions containing gelatin and the like (for example, gelatin-gum arabic aqueous solution).

Further, the flow path 12 included in the micro flow path structure 10A is formed in a direction in which the dispersed phase flow path 15 intersects the continuous phase flow path 14, and as a result, the dispersed phase liquid is absorbed by the shearing force of the continuous phase liquid. There is no particular limitation as long as it is formed so as to obtain a finely divided emulsion in which droplet-like dispersed phases having a diameter smaller than the width of the dispersed phase channel 15 are dispersed.
For example, in addition to the Y-shape as in the example of FIG. 1, a T-shape as in FIG. 9 may be used. The depth and width of each of the flow paths 14, 15, and 17 can be set as appropriate. Further, two or more dispersed phase flow paths 15 may be formed so that two or more kinds of liquids can be supplied as the dispersed phase. When the dispersed phase is a mixture of a plurality of substances, A junction for preparing the mixture may be separately provided on the upstream side of the junction 16 with the continuous phase flow path 14.

However, as already described above, at least the dispersed phase flow channel 15 is preferably a micro flow channel (micro channel) having a width of 500 μm or less and a depth of 300 μm or less from the viewpoint of easy formation of an emulsion.
Further, if the width and depth of the discharge channel 17 are made wider than those of the continuous phase channel 14 and the dispersed phase channel 15, the influence from the wall surface can be reduced, and the droplets in the emulsion formed at the merging portion 16 can be reduced. It has the effect of avoiding re-division more. In that case, the width and depth of the discharge flow path 17 are gradually increased so that the flow rate of the emulsion does not decrease rapidly as it goes forward, or the discharge flow path 17 is immediately after the junction 16. It is preferable to widen the width and depth of the liquid droplets so that the droplets composed of the dispersed phase flow alternately to the left and right with respect to the traveling direction. In this way, in the discharge channel 17, the flow velocity of the front droplet rapidly decreases and the rear droplet catches up and collides with this, thereby reducing the possibility that the droplets coalesce. Can do. Note that the ease of coalescence and re-division of the droplets is greatly affected by the emulsion feed speed in the discharge channel 17 and the type of the continuous phase liquid and the dispersed phase liquid. It is preferable to set.

The droplet size of the dispersed phase in the emulsion formed in the first step is the shape of each flow path 14, 15, 17 and the viscosity and interfacial tension of the continuous phase liquid and the dispersed phase liquid to be fed, It is controlled according to various conditions such as liquid feeding speed. The tip of the dispersed phase liquid that has moved in the dispersed phase flow path 15 as a liquid column is dispersed at a constant interval in the continuous phase at the junction 16 according to these various conditions, and has a uniform size. For example, if the liquid feeding speed of the continuous phase liquid flowing in the flow path is larger than the liquid feeding speed of the dispersed phase liquid, an emulsion having a good particle size dispersion can be stably formed. This is preferable from the point of view.
Here, if the wettability between the continuous phase liquid and the continuous phase flow path 14 is made larger than the wettability between the dispersed phase liquid and the dispersed phase flow path 15, droplets of a uniform size can be obtained. This is preferable because it is easy to produce and the amount of the dispersed phase liquid fed can be increased.

In the second step, a fluid containing a phase separation inducer is joined to the emulsion prepared in the first step in the flow path, and a concentrated phase composed of components in the continuous phase is formed around each dispersed phase.
Specifically, the microsyringe 28 is filled with a fluid containing a phase separation inducer, supplied at a predetermined flow rate by the microsyringe pump 29, and merged in the flow path (in this example, the joint portion 26). As a result, so-called coacervate occurs in which a concentrated phase composed of components in the continuous phase is formed around the dispersed phase.
Here, if a fluid containing a phase separation inducer is added not to the flow path but to the collection container 25 downstream of the fluid, there are many non-nucleated rich phases that do not surround the periphery of the dispersed phase. On the other hand, phenomena such as the formation of a dispersed phase in which a concentrated phase surrounds a plurality of dispersed phases to form a double nucleus, and a concentrated phase is not formed in the surroundings are observed. As a result, the microcapsules obtained by coagulating the concentrated phase by a method such as gelation described later are easy to aggregate, and are non-nuclear without the contents, or conversely, with multi-nuclei, There is a tendency that the content ratio of an insufficient film is increased.
Therefore, as in the example of FIG. 1, the flow path (in this example, the pipe 27) through which the fluid containing the phase separation inducer intersects and merges with the flow path in which the emulsion is fed, It is important to join the fluid containing the phase separation inducer to the emulsion in the flow path from the viewpoint of producing good quality microcapsules having a uniform particle size, good particle size dispersion, and no aggregation.

  In addition, before and after the flow path for joining the fluid containing the phase separation inducer to the emulsion, various known mechanisms may be provided as necessary so that a concentrated phase is easily formed around the dispersed phase. . As such a mechanism, a mechanism for classifying droplets composed of dispersed phases in an emulsion by utilizing a phenomenon that a fluid moves along a flow along a streamline in the channel, Examples include a mechanism for forming irregularities and developing a stirring action.

The fluid containing the phase separation inducer is not particularly limited as long as it contains a phase separation inducer that induces coacervate and is compatible with the continuous phase liquid. Examples of the phase separation inducer include water for dilution, acids such as sulfuric acid, acetic acid and hydrochloric acid for pH adjustment, alkalis such as sodium hydroxide, methanol, ethanol, acetone, dioxane which are poor solvents, sulfuric acid Examples include salts such as sodium. Since such a phase separation inducer needs to be used in the form of a fluid that is compatible with the continuous phase liquid, an appropriate solvent or the like is used as necessary.
Moreover, although the liquid feeding speed of the fluid containing a phase separation inducer can be set as appropriate, it is preferable to add at a flow speed that does not break the emulsion formed upstream.

Next, in the third step, the liquid material obtained in the second step (liquid material containing a concentrated phase composed of components in the continuous phase formed around each dispersed phase) is collected in the collection container 25. After the collection, a third step of forming the concentrated phase into a coacervate film is performed by a method according to the type of the continuous phase liquid used. As a result, a dispersion of coacervate capsules (microcapsules) in which the content of the dispersed phase is covered with a coacervate film can be obtained.
As a specific method for forming a concentrated phase into a coacervate film, when the continuous phase liquid is a sol solution capable of forming a gel, the liquid in the collection vessel 25 is subjected to the gelation temperature (hereinafter referred to as gelation). It is referred to as temperature.) A coacervate film can be prepared by forming a coacervate film by cooling to the following and gelling the concentrated phase, and forming a coacervate film around the dispersed phase. In that case, by performing the second step described above at a temperature higher than the gelation temperature, the continuous phase liquid does not gel in the second step, and a dense phase is formed well. In the example of FIG. 1, the joint part 26 in which the second step is performed is warmed to a temperature higher than the gelling temperature by being housed in a thermostatic bath, while the collection container 25 in which the third step is performed is room temperature. And below the gelation temperature.
In this specification, the concentrated phase is formed into a coacervate film by gelation or the like, and the content of the dispersed phase is covered with a coacervate film, which is called a coacervate capsule. This coacervate capsule is also one of the microcapsules. is there.

  In addition, when the continuous phase liquid is a sol solution that can form a gel, the coacervate capsule dispersion prepared in the third step is heated again to the gelling temperature or higher if necessary, and then cooled again. Then, by performing the fourth step of gelling, it is possible to produce a high quality coacervate capsule with a uniform particle size and less aggregation. That is, in order to carry out stirring under heating in the fourth step, the fluidity of the coacervate membrane is increased to protect the contents, and the coacervate capsules are coalesced and split while suppressing the destruction of the coacervate capsules. Can reduce aggregation. In addition, according to such a fourth step, there is also an advantage that mononuclear microcapsules having a single droplet-like dispersed phase as contents are easily generated.

By performing the first to third steps as described above, and performing the fourth step as necessary, the coacervate capsules are obtained in a state of being dispersed in the dispersion liquid. It can also be taken out as a powdery microcapsule by performing the fifth step of removing the solvent.
Specific methods of the fifth step include various known methods, for example, a method in which the coacervate film is crosslinked and cured, and then dehydrated, and further washed and filtered. Examples of the crosslinking method include a method in which a crosslinking agent such as an aqueous formaldehyde solution is added to the dispersion, and the pH is adjusted with an alkaline aqueous solution as necessary, followed by heating and stirring.

  In addition, when it is desired to make the formed microcapsule film thicker, the microcapsules obtained in the third step and thereafter may be used as capsule nuclei, and a film may be formed on the outside thereof. Specifically, the liquid containing the microcapsules obtained in the third and subsequent steps is stirred to such an extent that the microcapsules are not destroyed, and is subjected to a phase separation method, a submerged drying method, an in-situ polymerization method, or the like. do it. By such a method, a stronger microcapsule can be obtained while maintaining the shape, dispersibility, particle size uniformity and the like of the microcapsule obtained first.

  The microcapsules produced in this way are, for example, high-performance liquid chromatography column packing, pressure measurement film, carbonless (pressure-sensitive copying) paper, toner, thermal expansion agent, heat medium, light control glass, gap Agent (spacer), thermochromic (thermosensitive liquid crystal, thermosensitive dye), magnetophoresis capsule, pesticide, artificial feed, artificial seed, fragrance, massage cream, lipstick, vitamins capsule, activated carbon, enzyme-containing capsule, DDS (drug) It can be used for applications such as delivery systems.

  In the above description, the fine channel structure 10A included in the manufacturing system of FIG. 1 is exemplified by a glass substrate 11 joined and integrated with a glass substrate 11. The material of the substrate 11 and the cover body 13 is not limited to glass as long as it can form the flow path 12 and has excellent chemical resistance and moderate rigidity. Examples of such a material include quartz, ceramic, and silicon, and other materials such as metal and resin may be used. Examples of the method for joining and integrating the substrate 11 and the cover body 13 include a joining method by heat treatment (thermal joining), an adhesion method using an adhesive such as a thermosetting resin, and the like. Moreover, although there is no limitation in particular also about the magnitude | size and shape of the board | substrate 11 and the cover body 13, it is desirable for thickness to be about several mm or less. The size and shape of the continuous phase introduction port 14a, the dispersed phase introduction port 15a, and the discharge port 17a formed in the cover body 13 are not particularly limited. For example, a small hole having a diameter of about several hundred mm to several mm is used. It is desirable to be. Various chemical means, mechanical means, and the like can be applied to the processing of the small holes, and specifically, laser irradiation, ion etching, or the like may be performed.

In addition, as the quantitative liquid feeding means, those composed of the microsyringes 20, 21, 28 and the microsyringe pumps 22, 23, 29 are illustrated, but not limited thereto, in addition to various mechanical means, physical Means and the like can be used as appropriate.
Moreover, in this example, although the 3rd process is performed in the collection container 25, as long as the 3rd process can be performed, it is not limited to a container shape, A tube etc. may be used.

  Furthermore, in the present invention, a microchannel structure 10B as shown in FIGS. 4 and 5 can also be suitably used. This microchannel structure 10B is configured such that a phase separation inducing agent channel 32 into which a fluid containing a phase separation inducing agent is introduced and circulates is joined in the middle of the discharge channel 17. In 10B, not only the first step but also the second step can be performed. In the figure, reference numeral 32a denotes a phase separation inducer inlet into which a fluid containing the phase separation inducer is introduced. By using such a microchannel structure 10B, the fluid containing the phase separation inducing agent is merged with the emulsion generated in the merging portion 16 in the channel (merging portion 33 in this example). A dense phase composed of components in the continuous phase is formed around the dispersed phase. In the microchannel structure 10B, the substrate 11 is cut out to form each channel, and the covers 13 and 13 'are laminated on both surfaces of the substrate 11. Moreover, when this microchannel structure 10B is used, the third and subsequent steps may be performed in the same manner as in FIG.

Hereinafter, the present invention will be specifically described with reference to examples.
[Example 1]
The first to third steps were performed using the manufacturing system having the configuration shown in FIG. 1 to obtain a coacervate capsule dispersion.
The substrate 11 of the microchannel structure 10A includes a continuous phase channel 14 having a width of 136 μm and a depth of 48 μm, a dispersed phase channel 15 corresponding to a microchannel having a width of 106 μm and a depth of 48 μm, a width of 136 μm, and a depth. A Pyrex (registered trademark) glass substrate of 70 mm × 20 mm × 1 mm (thickness) in which a Y-shaped flow channel 12 composed of a discharge flow channel 17 having a length of 48 μm and a length of 40 mm was formed on one side was used. Note that the continuous phase flow path 14 and the dispersed phase flow path 15 intersect and merge at the merge portion 16 at an angle of α = 44 ° in FIG. The channel 12 was formed by general photolithography and wet etching.
As the cover body 13, a glass plate of 70 mm × 20 mm × 1 mm (thickness) was used and thermally bonded to the surface of the substrate 11 on the side where the flow path 12 is formed. Note that three small holes with a diameter of 1.2 mm were previously formed in the cover body 13 by mechanical processing means as the continuous phase inlet 14a, the dispersed phase inlet 15a, and the outlet 17a.
Further, Teflon (registered trademark) tubes having an inner diameter of 2 mm were used for the pipes 18, 19, 24, and 27, and the three-way joint of the joint part 26 was used that joined at three crossing angles of 120 °. . As the collection container 25, a glass beaker was used.
And the part enclosed with the broken line in FIG. 1 was stored in the thermostat, and it heated at 50 degreeC. On the other hand, the part outside the broken line was kept at a lower room temperature.

The first to third steps were performed using such a manufacturing system.
As the dispersed phase liquid, a mixture of dodecane and Oil Blue N was used, and as the continuous phase liquid, an aqueous solution in which 1 wt% of gelatin and 1 wt% of gum arabic were mixed was used. In addition, a 1% aqueous solution of acetic acid was used as the fluid containing the phase separation inducer.
The dispersed phase liquid, the continuous phase liquid, and the fluid containing the phase separation inducer are put into the microsyringes 20, 21, and 28, respectively, and the microsyringe pumps 22, 23, and 29 are operated, and the dispersed phase liquid is continuously 2 μl / min. The phase liquid was supplied at 125 μl / min, and the phase separation inducer was supplied at a flow rate (flow rate) of 5 μl / min.
Since the downstream end of the pipe 24 and the collection container 25 are at room temperature and are lower than the gelation temperature (40 ° C.) of the continuous phase liquid, gelation occurs in the vicinity of the downstream end of the pipe 24 and in the collection container 25. As a result, a dispersion of coacervate capsules in which a coacervate film in which a continuous phase liquid was gelled was collected around the dodecane solution was collected in the collection container 25.
When the dispersion was observed, the obtained coacervate capsule was a microcapsule having a uniform core as shown in FIG. 6 having an average particle diameter of the core of the capsule of 98 μm and a degree of particle size dispersion of 3.5%. there were.
As described above, according to Example 1, a coacervate film was formed on the surface, and uniform microcapsules with good particle size dispersion in which coalescence and splitting were suppressed could be obtained.

[Comparative Example 1]
The same process as in Example 1 was performed except that the fluid containing the phase separation inducer was not directly joined to the emulsion from the joint portion 26 but directly added to the emulsion collected in the collection container 25. As the fluid containing the dispersed phase liquid, the continuous phase liquid, and the phase separation inducer, the same fluids as in Example 1 are used, and the liquid feeding speed of the dispersed phase liquid and the liquid feeding speed of the continuous phase liquid are the same as in Example 1. I made it. In addition, 0.2 ml of fluid (1% acetic acid aqueous solution) containing a phase separation inducer was added to 5 ml of the collected emulsion.
In the merging portion 16, it was confirmed that the emulsion was generated in a stable state. However, when the dispersion liquid collected in the collection container 25 was observed, as shown in FIG. Gel), capsules having nuclei but agglomerated, and liquid droplets in which a coacervate film was not formed.
As described above, when the fluid containing the phase separation inducer is added to the collection container 25 that collects the emulsion, not in the flow path, and is brought into contact with the emulsion, Aggregated capsules, and further droplets in which the coacervate film is not formed, are generated, and the yield of high-quality coacervate capsules is reduced.

[Example 2]
The same as Example 1 except that the liquid feeding speed of the dispersed phase liquid, the liquid feeding speed of the continuous phase liquid, and the liquid feeding speed of the fluid containing the phase separation inducer were 10 μl / min, 125 μl / min, and 5 μl / min, respectively. Then, the first to third steps were performed, and the coacervate capsule dispersion liquid was collected in the collection container 25.
In the obtained dispersion, the coacervate capsules were agglomerated, and therefore, the following fourth step was performed. That is, using a hot stirrer and a star-shaped head stirrer, the collection container 25 is placed in a hot water bath heated to 50 ° C. and stirred at 950 rpm for 10 minutes, and then the hot water bath is kept stirring. Ice was added to 10 ° C. and cooled for 30 minutes.
Thus, when the dispersion liquid which passed through the 4th process was observed, as shown in FIG. 8, the coacervate film | membrane which the continuous phase liquid gelatinized was formed around the dodecane solution as shown in FIG. The average particle size of the nuclei was 97 μm, the particle size dispersion was 2.1%, and it was a mononuclear microcapsule containing uniform nuclei.
In this way, by further implementing the fourth step of stirring the dispersion obtained in the third step and then cooling it, a coacervate film is formed on the surface, and coalescence, splitting, and aggregation are greatly suppressed. As a result, it was possible to obtain high-quality mononuclear microcapsules with very good particle size dispersion.
This is because the agitation was carried out under heating in the fourth step, thereby increasing the fluidity of the coacervate membrane to protect the contents and suppressing the destruction of the coacervate capsules, This is probably because aggregation could be reduced.

It is a schematic block diagram which shows an example of the manufacturing system used with the manufacturing method of the microcapsule of this invention. It is a perspective view of the microchannel structure with which the manufacturing system of FIG. 1 is provided. FIG. 2A is a plan view schematically showing the shapes of the flow channels and the respective inlets and discharge ports provided in the micro flow channel structure of FIG. 2, and FIG. ) Is a cross-sectional view (c) showing a cross section of the dispersed phase flow path. It is a perspective view which shows another example of the microchannel structure used with the manufacturing method of the microcapsule of this invention. FIG. 4A is a plan view schematically showing the shapes of the flow channels and the respective inlets and discharge ports provided in the micro flow channel structure of FIG. 4, and FIG. 5B is a cross-sectional view showing the cross sections of the continuous phase flow channels and the discharge channels. ), A cross-sectional view (c) showing the cross section of the dispersed phase flow path, and a cross sectional view (d) showing the cross section of the phase separation inducer flow path. 2 is an optical micrograph showing the microcapsules obtained in Example 1. FIG. 2 is an optical micrograph showing the microcapsules obtained in Comparative Example 1. 2 is an optical micrograph showing the microcapsules obtained in Example 2. FIG. Plan view (a) schematically showing the shape of the flow path and each inlet and outlet provided in the conventional micro flow path structure, and cross-sectional view showing the cross section of the continuous phase flow path and the dispersed phase flow path (b) ).

Explanation of symbols

10A, 10B Microchannel structure 11 Substrate 12 Channel 14 Continuous phase channel 15 Dispersed phase channel 16 Junction portion 17 Discharge channel

Claims (4)

A first step in which a liquid that forms a continuous phase and a liquid that forms a dispersed phase are merged in a flow path to prepare an emulsion in which the dispersed phase is dispersed in the continuous phase;
A second step in which a fluid containing a phase separation inducer is joined to the emulsion in a flow path to form a concentrated phase composed of components in the continuous phase around the dispersed phase;
And a third step of preparing a coacervate capsule dispersion in which the concentrated phase is converted into a coacervate film and a coacervate film is formed around the dispersed phase.   The method for producing a microcapsule according to claim 1, wherein in the third step, the concentrated phase is gelled to form a coacervate film.   The method for producing a microcapsule according to claim 2, wherein the second step is performed at a temperature higher than the gelation temperature.   The method for producing microcapsules according to claim 2 or 3, further comprising a fourth step of stirring the dispersion under heating and then cooling after the third step.

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