JP2013158752A - Capsule production device, medical capsule, and capsule production method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently generate a capsule having accurate size regardless of the properties of a liquid.SOLUTION: A capsule production device includes: a liquid discharge part discharging a first liquid held inside a pressure container a prescribed amount by a prescribed amount by supplying external force into the pressure container; a liquid film holding part holding a second liquid in a film state; and a control part controlling the operation of the liquid discharge part. The control part makes the first liquid be discharged toward the liquid film of the second liquid held in the liquid film holding part from the liquid discharge part to form a core, and makes the second liquid cover the core when the core penetrates the liquid film of the second liquid to form a shell enveloping the core.

Description

  The present invention relates to a capsule manufacturing apparatus, a medical capsule, and a capsule manufacturing method.

  A capsule produced by covering a core substance (core) with a film (shell) is known. Such a capsule can have various functions by appropriately selecting a material for forming the core or shell. For example, it can have a function to protect the core from the external environment and a function to adjust the rate at which the core is released to the external environment, and is expected to be applied to various fields such as food and medicine as a functional material. Has been.

  Various methods have been proposed as capsule generation methods. For example, the shell material that forms the shell of the capsule and the core material that forms the core (both are liquid) are held in a liquid film shape and are arranged so as to overlap each other. Then, bubbles are generated and ruptured near the lower interface of the core material liquid film, and the core material is discharged to the liquid film side of the coating material by the pressure generated when the bubbles burst, and the core material is removed by the coating material. There has been proposed a method for generating microcapsules so as to be wrapped. (For example, patent document 1).

JP 2005-224647 A

  According to the method of Patent Document 1, it becomes easy to generate a capsule having a uniform shell thickness. However, in the method of Patent Document 1, the liquid film of the core material and the liquid film of the shell material are arranged so as to overlap each other. The width of is narrow. In addition, since the core material is discharged by bursting the bubbles, it is difficult to strictly control the particle size of the capsules to be generated. Therefore, it is not suitable when it is desired to accurately generate a capsule having a predetermined size (capacity).

  An object of the present invention is to provide a capsule manufacturing apparatus capable of efficiently producing a capsule having an accurate size regardless of the nature of a liquid.

  A main invention for achieving the above object is that a liquid discharge unit that discharges a predetermined amount of the first liquid held in the pressure vessel by supplying an external force into the pressure vessel, and a second liquid A liquid film holding unit for holding the liquid film and a control unit for controlling the operation of the liquid discharge unit, wherein the control unit applies the liquid film of the second liquid held by the liquid film holding unit to the liquid film holding unit. The core is formed by ejecting the first liquid from the liquid ejecting portion, and when the core penetrates the liquid film of the second liquid, the core is pushed by the second liquid. The capsule manufacturing apparatus is characterized by forming a shell including the core by coating.

  Other features of the present invention will become apparent from the description of the present specification and the accompanying drawings.

It is a conceptual diagram of a capsule. It is a figure which illustrates roughly the operation | movement at the time of a shell being formed. It is the schematic explaining the basic composition of the capsule manufacturing apparatus 1 in 1st Embodiment. 2 is a schematic cross-sectional view of a liquid ejection unit 10. FIG. It is a figure showing the flow of the process of producing | generating a capsule using the capsule manufacturing apparatus 1 in 1st Embodiment. FIG. 6A to FIG. 6C are diagrams for explaining the state in the vicinity of the nozzle outlet when discharging a highly viscous fluid in chronological order. It is explanatory drawing of a sodium alginate. It is explanatory drawing which shows the intermediate | middle aspect which changes from sodium alginate to a calcium alginate gel. It is explanatory drawing of a calcium alginate gel. It is a figure explaining the modification of the capsule manufacturing apparatus. It is the schematic explaining the basic composition of the capsule manufacturing apparatus 2 in 2nd Embodiment. It is the schematic explaining the basic composition of the capsule manufacturing apparatus 3 in 3rd Embodiment. It is a figure explaining roughly the operation | movement at the time of the droplet of a core material penetrating two liquid films.

At least the following matters will become clear from the description of the present specification and the accompanying drawings.
A liquid discharge unit that discharges the first liquid held in the pressure vessel by a predetermined amount by supplying an external force into the pressure vessel; and a liquid film holding unit that holds the second liquid in a film shape And a control unit that controls the operation of the liquid ejection unit, the control unit from the liquid ejection unit toward the liquid film of the second liquid held in the liquid film holding unit. A shell that encloses the core by forming the core by discharging the liquid and covering the core with the second liquid when the core penetrates the liquid film of the second liquid To form a capsule.
According to such a capsule manufacturing apparatus, a capsule having an accurate size can be efficiently generated regardless of the properties of the liquid. For example, it is possible to produce capsules using liquids of various properties from high viscosity liquids to low viscosity liquids, and the amount of liquid discharged is accurately controlled, so that the raw materials are wasted. This makes it easier to produce capsules of a desired size.

In the capsule manufacturing apparatus, the liquid discharge unit discharges the first liquid held in the pressure vessel by supplying compressed air as the external force and pressurizing the pressure vessel. Preferably, the control unit adjusts the amount of the first liquid discharged from the liquid discharge unit by adjusting the amount of the compressed air supplied to the liquid discharge unit.
According to such a capsule manufacturing apparatus, the first liquid can be accurately ejected in a fixed amount. Further, it is possible to stably discharge the liquid without generating heat during the discharging operation.

In this capsule manufacturing apparatus, it is preferable that the shell is cured by bringing the core in a state of being encapsulated by the shell into contact with a third liquid that cures the second liquid.
According to such a capsule manufacturing apparatus, the shell can be gelled by a gelation reaction caused by the contact between the second liquid (shell material) and the third liquid (shell hardener). As a result, it is possible to generate a capsule that is strong against the external environment in which the core is encapsulated by a shell having an appropriate hardness. Further, the hardness of the shell can be adjusted by adjusting the concentration of the third liquid.

The capsule manufacturing apparatus includes a spray unit that sprays the third liquid in a mist shape, and sprays the third liquid from the spray unit in a moving direction of the core enclosed by the shell. By doing so, it is desirable that the second liquid and the third liquid are brought into contact with each other.
According to such a capsule manufacturing apparatus, the second liquid (shell) containing the core is uniformly brought into contact with the mist-like third liquid (shell hardener), thereby having a uniform hardness shell. Capsules can be generated. In addition, since capsules are generated in the gas phase, the completed capsules can be easily collected.

The capsule manufacturing apparatus includes a liquid film holding unit that holds the third liquid in a film shape, and the core in a state of being encapsulated by the shell passes through the liquid film of the third liquid. It is desirable that the second liquid and the third liquid are brought into contact with each other by covering the shell with the third liquid.
According to such a capsule manufacturing apparatus, the amount of the third liquid (shell hardening material) used at the time of capsule generation can be saved, and the configuration of the apparatus can be simplified, so that the capsule manufacturing cost can be kept low. . Further, the shell can be adjusted to a desired hardness by changing the concentration and thickness of the liquid film formed by the shell curing material.

In such a capsule manufacturing apparatus, the second liquid is an aqueous solution containing polysaccharides or proteins, the third liquid is an aqueous solution containing a polyvalent metal salt, the second liquid and the third liquid It is desirable to cure the shell by bringing it into contact with a liquid to cause a chemical reaction.
According to such a capsule manufacturing apparatus, a capsule that is harmless to the human body and highly applicable to the medical field or the like can be generated. Moreover, since it is possible to form a shell made of a hydrophilic gel, it is possible to produce a capsule having high water retention performance and easy adjustment of osmotic pressure through a film between the external environment and the capsule. it can.

Moreover, the medical capsule manufactured with this capsule manufacturing apparatus becomes clear.
According to such a medical capsule, after having been ingested by the body using a capsule with a core containing a drug enclosed by a shell, it can reach the affected area without being absorbed or decomposed on the way It can be applied to a DDS (Drug Delivery System) etc. in which a drug is released.

  Forming a core by discharging a first liquid from a liquid discharge unit that discharges a predetermined amount of liquid held in the pressure container by supplying an external force into the pressure container; Forming a shell enclosing the core by covering the core with the second liquid when the core penetrates the liquid film of the second liquid held in the form of a film. The capsule manufacturing method is revealed.

=== Overview ===
<What is a capsule?>
In FIG. 1, the conceptual diagram of the capsule produced | generated by this embodiment is shown. The capsule in this embodiment is comprised by the "core" (inclusion) and the "shell" (film | membrane) which covers it as shown in the figure, and has a spherical external shape. The core material forming the “core” includes those in which the active ingredient is dissolved, those in which the active ingredient is dispersed, and those in which the active ingredient is present in solid or gaseous form. Such capsules are used in various fields such as foods, quasi-drugs, and pharmaceuticals, and the size of capsules (capacity of inclusions) and the thickness of shells vary depending on the application. .

<Capsule production method>
An outline of a method for generating a capsule having a core and a shell as described above will be briefly described. In the present embodiment, capsules are generated using a plurality of types of liquids as raw materials. It is assumed that the first liquid is used as the core material that forms the core, and the second liquid is used as the shell material that forms the shell. As the first liquid and the second liquid, optimum liquid materials are selected according to the function and application of the capsule to be generated.

  When the capsule is generated, the core material (first liquid) that becomes the core of the capsule is used for the shell material (which is a liquid film of the second liquid, also referred to as a liquid film) held in a thin film shape. Drop the liquid. And when a core material penetrates a liquid film, a shell is formed by covering so that a shell material may wrap the whole core material.

  FIG. 2 is a diagram schematically illustrating the operation when the shell is formed. (A)-(D) of a figure represents the mode at the time of a chronological order when a core material penetrates a liquid film. In the figure, it is assumed that the core material enters vertically from the vertically upward direction with respect to the liquid film (shaded portion) held horizontally. Note that the direction in which the core material enters the liquid film of the shell material is not limited to the vertical direction, and may be made to enter the liquid film in an oblique direction from above.

  (A) First, the core formed by the droplets of the core material (first liquid) has a predetermined speed (speed that can penetrate the liquid film) in the liquid film formed by the shell material (second liquid). Rush in. (B) The core in contact with the liquid film continues straight ahead and tries to penetrate the liquid film. On the other hand, the liquid film is deformed so as to wrap around the core. In addition, if the core material and the shell material are combined with liquids having different properties such as composition, specific gravity, viscosity, and surface tension, they are not immediately mixed even when they are in contact with each other. For example, a combination of liquids that form an interface such as an oily liquid with respect to an aqueous liquid is conceivable. (C) The core continues straight while being wrapped in the liquid film of the shell material. At the stage where the core passes through the initial position of the liquid film, most of the core is covered with the liquid film (shell material). In addition, the liquid film in the part where the core has passed is in a state where a hole is opened, but when the shell material moves from around the hole, the liquid film is blocked to return to the state without the hole. To do. (D) When the core completely penetrates the liquid film of the shell material, the entire core is covered with the shell material, and a shell including the core is formed. Moreover, the hole opened in the liquid film when the core penetrates is closed by the shell material.

  Through such an operation, a capsule having a structure in which a core is covered with a shell is generated.

  In the state shown in FIG. 2D, the capsule shell remains liquid (second liquid). For this reason, the shell may be very unstable with respect to the external environment, and the shell may be destroyed by simply touching the generated capsule. Therefore, in the present embodiment, the formed shell (second liquid) is brought into contact with the third liquid as a shell curing material to cause a chemical reaction. Capsules that are strong against the external environment are produced by making the shells adequately hardened by chemical reaction. Details of the chemical reaction between the second liquid and the third liquid will be described later.

=== First Embodiment ===
As an embodiment of a capsule manufacturing apparatus for carrying out the invention, a capsule manufacturing apparatus 1 using a liquid ejection apparatus will be described as an example.
In the capsule manufacturing apparatus 1, a core material is discharged using a liquid fixed amount discharge apparatus to form droplets (core). The formed core is covered with the shell material when penetrating the liquid film of the shell material, and a capsule composed of the core and the shell is generated. By adjusting the size of the core and the thickness of the shell, capsules of a desired size can be generated.

<Configuration of capsule manufacturing apparatus 1>
FIG. 3 is a schematic diagram illustrating a basic configuration of the capsule manufacturing apparatus 1 according to the first embodiment. The capsule manufacturing apparatus 1 includes a liquid ejection unit 10, a liquid film holding unit 30, and a liquid contact unit 50.
For the sake of explanation, as shown in FIG. 3, a coordinate axis composed of an X axis, a Y axis, and a Z axis is set. The Z axis is a vertical direction (a downward direction in FIG. 3), the X axis is a direction perpendicular to the Z axis, and the Y axis is a direction perpendicular to the Z axis and the X axis. In FIG. 3, the liquid discharge unit 10, the liquid film holding unit 30, and the liquid contact unit 50 are arranged in a straight line along the Z-axis direction, but the positional relationship thereof can be changed. It is.

(Liquid ejection unit 10)
The liquid discharge unit 10 is a liquid fixed amount discharge device (hereinafter also referred to as a dispenser) capable of discharging a first liquid (core material) by a predetermined amount. The liquid discharge unit 10 includes a barrel 11, a nozzle 12, a plunger 13, an adapter 14, and a control unit 15. FIG. 4 shows a schematic cross-sectional view of the liquid ejection unit 10. The liquid discharge unit 10 shown in FIG. 4 is a type of dispenser that discharges liquid when compressed air is supplied as an external force.

  The barrel 11 is a cylindrical pressure vessel and holds the first liquid (core material) inside. A nozzle 12 is provided at the lower end portion (Z-axis direction side) of the barrel 11, and a plunger 13 is inserted from the upper end side, and liquid is held therebetween. In FIG. 4, the first liquid is held in the area indicated by the hatched portion. And when the plunger 13 moves downward, the inside of the barrel 11 is pressurized, and the first liquid is discharged from the nozzle 12. Therefore, the barrel 11 is made of a material and shape that can withstand the pressure applied during pressurization. A control valve (not shown) that can control the liquid discharge amount may be provided between the barrel 11 and the nozzle 12. The installation position is fixed by the barrel 11 being supported by a stand (not shown).

  The nozzle 12 is a liquid discharge port of the dispenser, and discharges the liquid (first liquid) from the tip. The nozzle 12 can be removed from the barrel 11 and replaced, and the nozzle having the optimum diameter is selected according to the size of the capsule to be formed (that is, the liquid discharge amount).

  The plunger 13 is a pressurizing portion of the dispenser, and pressurizes the liquid (shaded portion in FIG. 4) held inside the barrel 11 by moving in the Z-axis direction inside the barrel 11. The barrel 13 is formed of a resin such as polyethylene in accordance with the inner diameter of the barrel 11 and appropriately pressurizes the liquid inside when discharging the liquid.

  The adapter 14 connects the control unit 15 and the barrel 11 and supplies an external force (compressed air in the example of FIG. 4). The compressed air sent from the control unit 15 is supplied to the barrel 11 (plunger 13) via the tube portion of the adapter 14, and moves the plunger 13 in the Z-axis direction by a predetermined amount. Thereby, the inside of the barrel 11 is pressurized, and the first liquid is discharged from the nozzle 12.

  The control unit 15 is a control unit of the dispenser and controls the liquid discharge amount. The discharge flow rate is controlled, for example, by adjusting the amount of compressed air supplied to the barrel 11 (plunger 13). In this case, a method of supplying compressed air for moving the plunger 13 by a predetermined amount to directly pressurize the liquid in the barrel 11 or pressurizing the inside of the barrel 11 in advance, and controlling the control valve as described above. There is a method of controlling the discharge amount by controlling. Alternatively, the plunger 13 may be operated so that an amount of liquid to be discharged for each liquid discharge operation is taken into the barrel 11 from the outside, and the liquid is discharged by the taken amount.

  In the dispenser of FIG. 4, the plunger 13 is operated by supplying compressed air as an external force. However, the operation of the plunger is controlled using the rotational force of an electric motor. May be.

(Liquid film holding unit 30)
The liquid film holding unit 30 has a liquid film holding frame 31. The liquid film holding frame 31 is a frame that holds the second liquid (shell material), which is a raw material for forming the shell, in a thin film shape. The second liquid (shell material) is surrounded by the liquid film holding frame 31 to form a liquid film having the liquid film holding frame 31 as an outer edge. The liquid film holding frame 31 can be made of any material as long as it can hold the liquid film. In the present embodiment, the liquid film holding frame 31 is made of metal (for example, stainless steel, aluminum, copper, gold, silver, brass, titanium, carbon steel, white steel). Etc.) or a liquid film holding frame made of resin (for example, acrylic, polyurethane, silicon resin, epoxy resin, melamine resin, phenol resin, polyethylene, polypropylene, polystyrene, polyvinyl chloride, nylon, etc.) can be used. Moreover, as long as it can hold | maintain a liquid film, a shape is also free, and shapes other than a square like FIG. 3 may be sufficient. The thickness of the liquid film holding frame 31 is determined in consideration of the thickness of the liquid film to be held.

  The liquid film of the second liquid is formed using, for example, a liquid film forming mechanism (not shown). The liquid film forming mechanism includes, for example, a second liquid tank that stores the second liquid, a brush-shaped application unit having a width (length) that is equal to or larger than the width of one side of the liquid film holding frame 31, and the like. And it can be set as the mechanism which forms a liquid film by apply | coating the 2nd liquid stored in the 2nd liquid tank to the liquid film holding frame 31 using this application part. According to such a liquid film forming mechanism, even when the liquid film is damaged (the liquid film is broken) during the capsule generating operation (details will be described later), the liquid film can be immediately re-formed. .

  However, the liquid film forming mechanism is not an essential configuration for the capsule manufacturing apparatus 1, and it is sufficient that the liquid film holding unit 30 holds the liquid film of the second liquid when the capsule is generated. For example, the liquid film of the second liquid may be formed by another external device and held in the liquid film holding frame 31.

(Liquid contact part 50)
The liquid contact part 50 stores the third liquid (shell hardener) in a liquid state, and causes the second liquid (shell hardener) to contact the third liquid (shell hardener) to cause a chemical reaction. .

  The liquid contact part 50 has a liquid storage tank 51. The liquid storage tank 51 is a container that can store a liquid. In the present embodiment, as shown in FIG. 3, the third liquid is stored in a liquid state to form a liquid phase (shaded portion of the liquid storage tank 51). The upper part of the liquid storage tank 51 is an opening, and the capsule enters the liquid phase in the liquid storage tank 51 from the opening and is brought into contact with the third liquid stored in the liquid storage tank 51.

  In the present embodiment, the core (first liquid droplet) covered with the shell material (second liquid) by penetrating the liquid film holding unit 30 is in the shell hardening material (third liquid). Enter. And when a shell material (2nd liquid) contacts with a shell hardening material (3rd liquid), a chemical reaction will arise in the liquid storage tank 51, and it will become appropriate hardness.

  Moreover, the liquid storage tank 51 has a function as a capsule collection | recovery part which collect | recovers the capsules after contacting a 3rd liquid. When recovering the capsule, the completed capsule is recovered from the third liquid by a method such as a filtration method or a centrifugal separation method.

<About capsule generation operation>
Next, a specific operation when generating a capsule using the capsule manufacturing apparatus 1 will be described. FIG. 5 is a diagram illustrating a flow of a process of generating a capsule using the capsule manufacturing apparatus 1 in the first embodiment. In this embodiment, a capsule is produced | generated by three processes, a core formation process (S101), a shell formation process (S102), and a shell hardening process (S103).

S101: Core Formation Step First, a capsule core is formed by droplets (dots) of the core material (first liquid) ejected from the liquid ejection unit 10.

  As shown in FIG. 3, when discharging the core material, the core material is discharged by a predetermined amount toward the liquid film of the shell material held by the liquid film holding unit 30. In the present embodiment, the liquid discharge unit 10 is provided vertically above the liquid film holding unit 30, and the core material is discharged in the Z-axis direction. That is, the core material is discharged from a direction perpendicular to the liquid film of the shell material held parallel to the XY plane. However, the core material does not necessarily have to be discharged in a direction perpendicular to the liquid film of the shell material. The discharged core material is deformed into a spherical shape (droplet) by surface tension while flying in the atmosphere to form a core.

  As the core material forming the core, a substance (aqueous solution) containing an active ingredient (for example, hydroquinone, ceramide, bovine serum albumin, γ-globulin, lipiodol, bifidobacteria, vitamins, hyaluronic acid, IPS cells, etc.) is used. . In the present embodiment, since a dispenser is used as the liquid ejection device, many liquid materials can be selected as a core material from a low viscosity liquid to a high viscosity liquid. For example, in the dispenser of FIG. 4, the liquid is discharged by pressurizing the inside of the barrel by the operation of the plunger. Therefore, it is easy to accurately discharge a fixed amount of liquid even when the viscosity of the discharged liquid is high. In addition, since no large heat is generated during the discharging operation, even if the first liquid contains a biological material (cells or the like), there is a risk of causing denaturation due to heat. And can be safely ejected as droplets.

  However, care must be taken when using a liquid having a high viscosity as the core material. FIG. 6A to FIG. 6C are diagrams for explaining the state in the vicinity of the nozzle outlet when discharging a highly viscous fluid in chronological order. When the viscosity of the core material is high, the liquid immediately after being ejected from the nozzle portion of the liquid ejecting portion 10 is elongated in the vertically downward direction (the ejected direction) to form a teardrop shape as shown in FIG. 6A. Such a state in which the liquid extends so as to have a tail is called “tailing” of the discharged fluid. The length of the tailing varies depending on the properties of the liquid (viscosity, molecular weight, etc.) and the ejection conditions (e.g., ejection speed). Divided into parts. At this time, the length from the nozzle outlet to the lower end of the droplet is assumed to be h. Then, as shown in FIG. 6C, the divided droplet-like portion moves as it is vertically downward, and the ridge-like portion returns into the nozzle so as to be sucked. The droplet-like portion is accelerated to a predetermined speed, and then continues to move at a constant speed due to balance with air resistance.

  In the present embodiment, a liquid film holding unit 30 is provided below the liquid discharge unit 10 (see FIG. 3). Therefore, it is necessary to install each device so that the distance H in the Z-axis direction from the nozzle outlet to the shell material liquid film is longer than h (see FIG. 6B). When the distance H from the nozzle outlet to the shell material liquid film is h or less (H ≦ h), the core material (first liquid) and the shell material (in the state shown in FIG. 6A before the droplet is formed) This is because it becomes difficult to produce a capsule having an appropriate shape.

  Moreover, in order to shorten the distance h in which the tailing occurs as much as possible, a configuration in which the core material in which the tailing occurs can be forcibly cut may be provided. For example, when the core material has a high viscosity and a long tail is likely to occur, an air blower is provided in the vicinity of the nozzle outlet, and air is blown from the blower to cut the tail portion, thereby forming a spherical liquid. Drops can be easily formed.

  The liquid discharge amount when discharging the core material is determined according to the size (capacity) of the core of the capsule to be generated. This is because in the present embodiment, the droplets of the discharged core material (first liquid) become the core as it is. In other words, the size of the capsule to be generated (core size) can be freely set by controlling the amount of the core material discharged.

  In particular, in the present embodiment, by appropriately selecting the nozzle diameter of the dispenser, various droplets can be used depending on the application, from a microcapsule having a droplet diameter of nanometer (nm) order to a relatively large capsule having millimeter order (mm). Capsules of any size can be generated. For example, when producing a capsule used for medical treatment, there is a case where it is desired to use a liquid containing cellular tissue or the like as a core material. The capsule generated in this case needs to secure an area (capacity) that allows the cell tissue to survive. Therefore, by adjusting the diameter of the droplet according to the cell tissue (for example, about φ30 μm) (for example, forming a droplet of about φ300 μm), it becomes easy to generate a capsule utilizing the material characteristics.

  The amount of the core material (first liquid) discharged from the liquid discharge unit 10 is controlled by the control unit 15. In the example of FIG. 4, the discharge amount of the core material can be accurately controlled by the amount of compressed air supplied into the barrel 11. According to this method, the yield of the core material (first liquid) when producing capsules can be made extremely high. That is, since the discharged core material droplets directly form the core, the core material is hardly wasted. Therefore, the raw material cost of the capsule can be reduced. In particular, it is very effective when a very expensive substance has to be used as the core material (for example, when a medical material is used as a core when producing a capsule used for medical treatment). Further, since the amount of liquid used can be optimized, the amount of liquid discarded is small, which is also effective from the viewpoint of environmental protection. Further, not only medical capsules but also cosmetic capsules and food capsules can optimize the amount of liquid used as described above.

  The liquid discharge speed at the time of discharging the core material is set to a speed that can penetrate the liquid film of the shell material in the next shell formation step (S102). That is, the discharged droplets of the core material are set so as to have a momentum large enough to penetrate the liquid film of the shell material. The liquid discharge speed of the core material depends on the thickness of the liquid film to penetrate, the viscosity of the liquid film material (shell material), the surface tension of the liquid film, the discharge amount and density of the core material (first liquid), etc. Different. The conditions also differ depending on the positional relationship (distance) between the liquid ejection unit 10 and the liquid film holding unit 30. Therefore, it is preferable to conduct an experiment in advance under the conditions under which capsules are actually generated, and to examine the minimum core material discharge speed that can penetrate the liquid film of the shell material. For example, a discharge speed threshold is set for each size of the core to be generated and each liquid material to be used, and by controlling the operation of the plunger with reference to the threshold, the first liquid is discharged at a predetermined speed or higher. Let

S102: Shell Formation Step The core formed in S101 enters the liquid film of the shell material held by the liquid film holding unit 30. When the core penetrates the liquid film, the shell is formed by covering the core with a shell material (second liquid) (see FIG. 2).

  In the present embodiment, polysaccharides or proteins (for example, sodium alginate, calcium alginate, potassium alginate, ammonium alginate, ethyl cellulose, methyl cellulose, pectin, gellan gum, chitosan, collagen, etc.) are used as the shell material (second liquid). The contained substance (aqueous solution) is used. Alginates are almost harmless to the human body, and the range of applicability of capsules is widened by using them as capsule shell materials. As described above, the shell material (second liquid) and the core material (first liquid) are selected as liquids that are difficult to mix with each other. In other words, each liquid material is selected so that the first liquid and the second liquid form an interface for a certain period of time and can maintain a separated state.

  The liquid film holding unit 30 is installed horizontally (on the XY plane in FIG. 3), and the position is adjusted so that droplets of the core material (first liquid) discharged from the liquid discharge unit 10 land on the liquid film. Is done. By allowing the core to enter perpendicularly to the liquid film, it becomes easy to form a uniform shell with little thickness unevenness. However, as long as the shell can be held, it is possible to form a shell that covers the core even if the liquid film holding unit 30 is inclined with respect to the horizontal plane.

  In the present embodiment, the shell of the capsule is formed using the shell material (second liquid) as a raw material. Therefore, it is conceivable that the second liquid is consumed while the capsule generating operation is repeated, and the liquid film becomes thin. In this case, there is a possibility that the thickness of the formed shell cannot be kept uniform, or the liquid film itself is easily broken. Further, while the capsule generating operation is repeated, impurities (for example, core material residue, satellites, bubbles, etc.) may be mixed into the liquid film.

  Therefore, the liquid film state is prevented from changing by re-forming the liquid film or changing the liquid film together with the liquid film holding frame 31 at a predetermined timing during the capsule generating operation. Thereby, the shell of the capsule produced | generated can be maintained at high quality. The timing for exchanging the liquid film is determined based on, for example, the duration of the capsule generating operation, the total discharge amount of the core material by the liquid discharge unit 10, and the like.

S103: Shell curing step After the shell covering the core is formed in S102, the shell is cured at the liquid contact portion 50. In this embodiment, the liquid storage tank 51 of the liquid contact part 50 is installed below the liquid discharge part 10 and the liquid film holding | maintenance part 30 (refer FIG. 3), and was discharged to the Z-axis direction (vertical downward direction). The core material (first liquid) penetrates the liquid film of the shell material (second liquid) and then enters the liquid storage tank 51 as it is. The shell hardening material (third liquid) stored in the liquid storage tank 51 comes into contact with the shell material (second liquid) to cause a chemical reaction, and the shell (second liquid) is hardened. .

  The distance between the liquid film holding unit 30 and the liquid storage tank 51 (distance in the Z-axis direction) is greatly related to droplet evaporation and the speed of entry into the third liquid, and is a microcapsule having a diameter of less than 100 μm. 0.1 to 100 mm, particularly 0.1 to 50 mm is preferable, and 0.1 to 15 cm, particularly 0.1 to 10 cm is preferable when generating microcapsules having a diameter of 100 μm to 1000 μm. . This is because the shell material (second liquid) evaporates during movement if the capsule travel distance from the liquid film holding unit 30 to the liquid storage tank 51 is too long. It should be noted that a windless environment is desirable during the drop descent in order to prevent evaporation and drop in landing accuracy. Furthermore, in order to suppress evaporation, it is desirable that the droplet flight environment is humid.

  On the other hand, when a capsule of a relatively large size having a diameter of 1000 μm or more is generated, the liquid discharge amount is large and it is difficult to evaporate, so that the distance between the liquid film holding unit 30 and the liquid storage tank 51 is increased. You can also.

  In the present embodiment, a polyvalent metal salt having a gelation-inducing factor (for example, calcium chloride, calcium acetate, calcium nitrate, calcium citrate, calcium lactate, calcium carbonate, etc.) as the shell hardening material (third liquid) Containing calcium salts, aluminum salts such as aluminum chloride, aluminum nitrate, aluminum sulfate, aluminum acetate, aluminum phosphate, manganese salts such as manganese chloride, manganese nitrate, manganese acetate, manganese sulfate, magnesium chloride, magnesium nitrate, A substance (aqueous solution) containing a magnesium salt such as magnesium acetate or magnesium sulfate, or an iron salt such as ferrous phosphate or ferric phosphate) is used.

  Moreover, as a shell hardening material (3rd liquid), the substance (aqueous solution) containing enzymes, such as thrombin, can also be used. Fibrinogen can be gelled by enzymatic reaction with thrombin.

  In the shell curing step (S103), the shell material (second liquid) comes into contact with the shell cured material (third liquid) to cause a chemical reaction such as a crosslinking reaction, a polymerization reaction, or an enzyme reaction, thereby curing the shell material. (Gelation). Here, “curing (gelation)” includes a state in which the viscosity increases.

<About chemical reaction>
As a specific example of the reaction when the shell is cured (gelled), it occurs when an aqueous sodium alginate solution is used as the shell material (second liquid) and an aqueous calcium chloride solution is used as the shell hardening material (third liquid). The chemical reaction will be described. FIG. 7 is an explanatory diagram of sodium alginate. FIG. 8 is an explanatory diagram showing an intermediate state of changing from sodium alginate to calcium alginate gel. FIG. 9 is an explanatory diagram of a calcium alginate gel.

As shown in FIG. 7, sodium alginate (C ₆ H ₇ O ₆ Na) has monovalent sodium ions bonded to alginic acid. When this sodium alginate comes into contact with an aqueous solution of calcium chloride (CaCl ₂ ), divalent calcium ions (Ca ²⁺ ) are replaced with sodium ions (Na ⁺ ) of sodium alginate, so that gelation proceeds (FIG. 8). At this time, the sodium ion (Na ⁺ ) is monovalent and the calcium ion (Ca ²⁺ ) is divalent, and therefore one calcium ion (Ca ²⁺ ) with respect to two sodium ions (Na ⁺ ). Is replaced. At this time, in the sodium alginate, two sodium ions (Na ⁺ ) are eliminated between the two sodium alginate and are replaced with one calcium ion (Ca ²⁺ ) which is a divalent metal ion (FIG. 9). . Then, cross-linking condensation that bridges the two alginic acids occurs and gels (hardens). Such a chemical reaction is also called a crosslinking reaction.

  Incidentally, FIG. 9 shows a region surrounded by a broken line. In the calcium alginate gel, water molecules move from the inside of the gel to the outside through the region surrounded by the broken line, or the water molecules move from the outside to the inside. Thus, the elastic gel is realized by the presence of water molecules in the region surrounded by the broken line. The inflow and outflow of water molecules in the gel are balanced. In the present embodiment, by forming a gel-like shell having hydrophilicity, a capsule having high biocompatibility can be produced when ingested by the human body. Moreover, since it is a hydrophilic shell, there also exists an advantage that adjustment of the osmotic pressure through this shell becomes easy between a core and an external environment.

Moreover, the thickness of the shell formed and the hardness of the gel can be freely adjusted by adjusting the concentration of the shell material or the shell hardening material. Thereby, the capsule corresponding to various uses can be generated. For example, when applying capsules to the medical field, it is possible to select the time from when the shell is broken until the internal substance (core) is exposed by adjusting the strength (hardness) of the shell. become able to. Specifically, when a capsule composed of a core made of a drug and a shell covering the core is generated, the drug (core) reaches the affected part without being absorbed or decomposed in the middle after being ingested by the human body. . When the shell is broken and the drug is released when it reaches the affected area, it can be applied to a DDS (drug delivery system).
The capsule in which the shell is cured is collected from the liquid contact part 50.

<Effects of First Embodiment>
In the capsule manufacturing apparatus of the present embodiment, the first liquid (core material) is discharged from the liquid discharge unit 10 toward the liquid film of the second liquid (shell material) held in the liquid film holding unit 30. Form the core. Then, when the core penetrates the liquid film, the shell is formed by covering the core with the second liquid (shell material). And a shell is hardened by making it contact with the 3rd liquid (shell hardening material) stored in the liquid contact part 50, and producing a chemical reaction, and produces | generates a capsule.

  According to the capsule manufacturing apparatus of the present embodiment, by adjusting the discharge amount of the first liquid (core material) and the liquid film thickness of the second liquid (shell material), a capsule having a desired size can be accurately obtained. Can be generated. And since the discharged 1st liquid forms a core as it is, the yield of a core material is very high, and it is advantageous also in terms of cost.

  Moreover, the selectivity of the capsule material is wide, and various liquids can be combined. In particular, since the core material droplets are discharged using a dispenser, it is possible to accurately discharge the core material regardless of the discharge amount or the viscosity. In particular, it is possible to accurately eject a large droplet having a diameter of the order of millimeters. Further, since heating is not required during the liquid discharging operation, even a liquid containing a biological material such as a cell can be used as the core material without destroying the biological tissue. On the other hand, as long as the second liquid (shell material) forming the shell can be held as a liquid film in the liquid film holding unit 30 and can be cured by the liquid contact unit 50, various kinds of liquids can be used. Liquid can be used. Therefore, it becomes easy to efficiently produce a capsule having an accurate size regardless of the nature of the liquid.

<Modification>
In the capsule manufacturing apparatus 1 shown in FIG. 3, only one dispenser is disposed as the liquid ejection unit 10 with respect to the liquid film holding unit 30, but the present invention is not limited to this. That is, a plurality of dispensers may be arranged above the liquid film holding unit 30. FIG. 10 is a view for explaining a modification of the capsule manufacturing apparatus 1.

  As shown in the figure, droplets of the core material (first liquid) are discharged from a plurality of dispensers toward the liquid film of the shell material (second liquid). The plurality of discharged droplets (cores) are respectively covered with the shell material by penetrating the liquid film of the shell material, and a plurality of capsules are formed. The shells of the plurality of formed capsules are cured by the liquid contact portion 50.

  By providing a plurality of dispensers as the liquid ejection unit 10 and increasing the number of droplets (cores) that can be ejected at the same timing, a plurality of capsules can be generated simultaneously, and capsule generation efficiency can be further increased. .

=== Second Embodiment ===
In the second embodiment, capsules are manufactured using the capsule manufacturing apparatus 2 having a configuration of the liquid contact portion 50 different from that of the first embodiment. In FIG. 11, the schematic explaining the basic structure of the capsule manufacturing apparatus 2 in 2nd Embodiment is shown. In the capsule manufacturing apparatus 2, the liquid discharge unit 10 and the liquid film holding unit 30 have the same configuration as that of the capsule manufacturing apparatus 1. In the present embodiment, the liquid ejection unit 10 may have a plurality of dispensers as in the case of FIG. 10 described above.
Hereinafter, the liquid contact portion 50 will be mainly described.

<Liquid contact part 50>
The liquid contact unit 50 according to the present embodiment includes a spray unit 55 and a capsule collection unit 56.
The spraying unit 55 sprays the shell hardener (third liquid) in a mist to spray the shell hardener over a predetermined region in the atmosphere as shown in FIG. In other words, an atmosphere (hereinafter also referred to as a shell curing material atmosphere) of fine particles of the shell curing material is formed in a predetermined region in the atmosphere. The spray unit 55 includes, for example, a spray nozzle, and discharges the shell curing material (third liquid) in a mist form.

  The capsule collection unit 56 is a container that collects the completed capsule, and is arranged on the most downstream side in the moving direction of the capsule (core) (the direction in which the first liquid is discharged).

<Capsule generation operation>
The capsule generating operation in the second embodiment is basically the same as that in the first embodiment (see FIG. 5), except that the shell is cured in the gas phase in the shell curing step (S103).

  The core (capsule) in a state of being covered with the shell material by penetrating the liquid film of the shell material (second liquid) is a shell hardening material atmosphere formed in the middle of the moving direction (Z-axis direction in FIG. 11) When it passes through, it comes into contact with the fine particles of the shell hardener (third liquid). Thereby, a chemical reaction arises in the part which the shell material and the shell hardening material contacted on the shell surface, and the said contact part becomes hard. For example, when an aqueous solution containing alginate is used as the shell material (second liquid) and an aqueous solution containing calcium chloride is used as the shell hardener (third liquid), a crosslinking reaction occurs at the contact portion, and the shell Harden. In addition, by distributing the fine particles of the shell curing material uniformly in the gas phase, the shell curing material can be in uniform contact with the shell material, and the chemical reaction can proceed uniformly over the entire surface (shell) of the capsule. That is, unevenness is hardly generated in the hardness of the gel on the capsule surface.

  Therefore, by maintaining an appropriate concentration of the shell curing material in the shell curing material atmosphere, it is possible to generate a capsule in which the shell has an appropriate hardness. Note that the capsule with the hardened shell moves in the moving direction as it is and is collected by the capsule collecting unit 56.

<Effects of Second Embodiment>
In the second embodiment, the shell is hardened in the gas phase and settles as it is in the recovery container 56 and is recovered as a capsule. Therefore, compared with recovering the capsule from the liquid phase, the labor required for the recovery operation is reduced. Can be omitted. For example, in the first embodiment, the capsule is recovered from the shell hardened material liquid stored in the liquid contact portion 50 by a filtration method or a centrifugal separation method, but such a recovery method is not necessary in the present embodiment. Further, since the shell can be brought into uniform contact with the shell curing material, capsules with less unevenness in shell hardness can be generated.

=== Third Embodiment ===
In 3rd Embodiment, a capsule is manufactured using the capsule manufacturing apparatus 3 which hardens a shell with the shell hardening material hold | maintained at the liquid film form. In FIG. 12, the schematic explaining the basic structure of the capsule manufacturing apparatus 3 in 3rd Embodiment is shown.

  In the capsule manufacturing apparatus 3, the liquid ejection unit 10, the liquid film holding unit 30 (referred to as the first liquid film holding unit 30 in this embodiment), the second liquid film holding unit 40, and the capsule collection unit 56 are provided. Prepare. The configuration other than the second liquid film holding unit 40 is the same as that of the second embodiment.

(Second liquid film holding unit 40)
The second liquid film holding unit 40 has a liquid film holding frame 41. The liquid film holding frame 41 is the same frame as the liquid film holding frame 31 described above, and holds the third liquid (shell hardener) in a thin film shape in this embodiment. The liquid film of the shell hardening material is held in a position below the first liquid film holding unit 30 in parallel with the liquid film of the shell material (see FIG. 12).

<Capsule generation operation>
In the third embodiment, a capsule is generated by a droplet of a core material continuously penetrating a liquid film of a shell material and a liquid film of a shell hardening material. FIG. 13 is a diagram schematically illustrating an operation when a droplet of the core material penetrates two liquid films. (A)-(F) of a figure represent the mode when a core material penetrates a liquid film in time series order.

  (A) First, the core formed by the droplets of the core material (first liquid) has a predetermined speed (speed that can penetrate the liquid film) in the liquid film formed by the shell material (second liquid). Rush in. (B) The core that has come into contact with the liquid film of the shell material continues to advance straight and tries to penetrate the liquid film. In contrast, the liquid film of the shell material is deformed so as to wrap the core. The core material and the shell material are liquids having different properties such as composition, specific gravity, viscosity, and surface tension (for example, a combination of an aqueous liquid and a liquid that forms a strong interface such as an oily liquid). Even in contact, it is not immediately mixed. (C) The core continues straight while being wrapped in the liquid film of the shell material. At the stage where the core passes the position of the initial liquid film, most of the core is covered with the shell material liquid film. In the portion where the core has passed, the shell material liquid film has a hole, but the shell material moves from around the hole so that the shell material liquid film is blocked and there is no hole. Try to return to the state. (D) When the core completely penetrates the shell material liquid film, the entire core is covered with the shell material (second liquid), and a shell including the core is formed. The hole opened in the shell material liquid film after the core penetrates is closed by the shell material. The core covered with the shell directly enters the liquid film of the shell hardening material. (E) The core that has entered the shell hardened material liquid film (the core covered with the shell) is covered with the shell hardened material (third liquid). (F) When the shell hardening material liquid film is completely penetrated, the entire core covered with the shell is covered with the shell hardening material. At this time, when the shell material and the shell curing material come into contact with each other, the gelation reaction proceeds on the surface of the shell (the contact surface between the shell material and the shell curing material), and the shell is cured. This produces a capsule with a shell of suitable hardness.

<Effect of the third embodiment>
In 3rd Embodiment, a core is produced | generated when a core penetrates continuously the liquid film of a shell material, and the liquid film of a shell hardening material. Since the shell hardener is held as a liquid film, the amount of shell hardener used can be reduced. In addition, since the device itself has a simple configuration of a liquid film holding frame, the capsule manufacturing cost can be kept low. Moreover, the shell hardener liquid film can be easily replaced during the capsule generating operation. For example, various types of capsules can be generated depending on the application while adjusting the hardness of the shell by changing the concentration of the shell hardening material or changing the thickness of the liquid film.

=== Other Embodiments ===
Although the capsule manufacturing apparatus as one embodiment has been described, the above-described embodiment is for facilitating understanding of the present invention, and is not intended to limit the present invention. The present invention can be changed and improved without departing from the gist thereof, and it is needless to say that the present invention includes equivalents thereof. Even the embodiments described below are included in the present invention.

<About the liquid ejection part>
In each of the above-described embodiments, the dispenser that discharges the liquid held in the pressure vessel by the external force (for example, compressed air) applied to the plunger has been described as the liquid discharge unit. However, the present invention is not limited to this example as long as the liquid can be discharged in a fixed amount. For example, it is also possible to use a discharge device such as a tube pump that discharges the liquid held in the tube by sequentially operating a plurality of fingers.

<About capsule generation materials>
In the above-described embodiments, specific examples are illustrated for the first liquid to the third liquid, respectively, but capsules can be generated using capsule generating materials other than those illustrated.

<About device layout>
In each of the above-described embodiments, the liquid discharge unit, the liquid film holding unit, and the liquid contact unit are arranged so as to be linearly arranged along the vertical direction, but the arrangement of the devices is not limited to this. For example, when the core (first liquid) is discharged in an oblique direction with respect to the vertical by the liquid discharge unit, each device may be arranged along the moving direction (path) of the core. .

1, 2 capsule manufacturing equipment,
10 liquid ejector, 11 barrel, 12 nozzle, 13 plunger,
14 adapter, 15 controller,
30 liquid film holding part (first liquid film holding part), 31 liquid film holding frame,
40 second liquid film holding part, 41 liquid film holding frame,
50 liquid contact part, 51 liquid storage tank, 55 spraying part, 56 capsule collection part,
111 nozzles, 112 liquid supply passages, 114 nozzle communication passages, 116 elastic plates,
PZT Piezo element

Claims (8)

A liquid discharge unit that discharges the first liquid held in the pressure vessel by a predetermined amount by supplying an external force into the pressure vessel;
A liquid film holding unit for holding the second liquid in a film shape;
A control unit for controlling the operation of the liquid discharge unit,
The control unit discharges the first liquid from the liquid discharge unit toward the liquid film of the second liquid held in the liquid film holding unit, thereby forming a core.
When the core penetrates the liquid film of the second liquid, the core is covered with the second liquid to form a shell that encloses the core. The capsule manufacturing apparatus according to claim 1,
The liquid discharge unit discharges the first liquid held in the pressure vessel by supplying compressed air as the external force and pressurizing the pressure vessel.
Capsule manufacturing, wherein the controller adjusts the amount of the first liquid discharged from the liquid discharger by adjusting the amount of the compressed air supplied to the liquid discharger apparatus. The capsule manufacturing apparatus according to claim 1 or 2,
The capsule manufacturing apparatus, wherein the shell is cured by bringing the core encapsulated by the shell into contact with a third liquid that cures the second liquid. The capsule manufacturing apparatus according to claim 3,
Having a spraying section for spraying the third liquid in a mist form;
The second liquid and the third liquid are brought into contact with each other by spraying the third liquid from the spray section in the moving direction of the core in a state of being enclosed by the shell. Capsule manufacturing equipment. The capsule manufacturing apparatus according to claim 3,
A liquid film holding unit for holding the third liquid in a film shape;
When the core encapsulated by the shell penetrates the liquid film of the third liquid, the second liquid and the third liquid are covered by covering the shell with the third liquid. And a capsule manufacturing apparatus. It is a capsule manufacturing apparatus in any one of Claims 3-5,
The second liquid is an aqueous solution containing polysaccharides or proteins,
The third liquid is an aqueous solution containing a polyvalent metal salt;
The capsule manufacturing apparatus, wherein the shell is cured by bringing the second liquid and the third liquid into contact with each other to cause a chemical reaction.   The capsule for medical manufacture manufactured with the capsule manufacturing apparatus in any one of Claims 1-6. Forming a core by discharging a first liquid from a liquid discharge unit that discharges the liquid held in the pressure container by a predetermined amount by supplying an external force into the pressure container;
Forming a shell enclosing the core by covering the core with the second liquid when the core penetrates the liquid film of the second liquid held in the form of a film;
A method for producing capsules.