JPH06315617A - Emulsifying method and device - Google Patents

Abstract

PURPOSE:To obtain an emulsion where loss volume has been decreased even for a small quantity and which is uniform and excels in stability by forcibly feeding a liquid for a dispersed phase into a flowing liquid for a continuous phase through a porous member to disperse it. CONSTITUTION:A emulsifying vessel 11 is divided into a chamber for a liquid for a dispersed phase 13 and a chamber for a liquid for a continuous phase 14 by a porous member 12. The porous member is preferably that of 0.1-10 micron average pore diameter and is preferably a porous membrane in the form of a plate or a cylinder. The pressurization of the liquid for a dispersed phase in the liquid chamber 13 is performed through a line 26 communicating with a gas pressurizing source or by a pressurizing member, such as a piston. The liquid for a continuous phase in the liquid chamber 14 is agitated by a rotor 23, etc. In this way, the liquid for a dispersed phase is pressurized even for a small quantity of 1-10ml of the emulsified quantity. And also the liquid chamber 14 is provided with an introducing pipe 39 for the liquid for a continuous phase and an emulsion takeoff port to continuously produce an emulsion little by little. In this case, the liquid chamber 13 is preferably provided with an introducing pipe 32 for the liquid for a dispersed phase.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an emulsification method and an emulsification apparatus therefor, and more particularly to an emulsification method and method capable of producing an extremely stable oil-in-water type, water-in-oil type or water-in-oil-in-water type emulsion. It relates to the emulsifying device. The present invention also relates to an emulsification method and a small emulsification apparatus for producing a small amount of emulsion, and particularly to a monodisperse emulsification method suitable for producing a small amount of emulsion of 1 to 100 ml and a small emulsifier thereof.

[0002]

BACKGROUND OF THE INVENTION Emulsions are made by mechanically treating a continuous phase and a dispersed phase together to disperse the dispersed phase in the continuous phase. As a means for industrially producing an emulsion, a mechanical-physical method such as a high-speed stirring emulsifier, a high-pressure homogenizer, or an ultrasonic emulsifier has been used so far. However, in these production methods, it is difficult to uniformly control the particle size of the emulsion because the destruction of the dispersed phase is not always performed uniformly and reproducibly, and it is not easy to produce a stable and high-quality emulsion.

Therefore, in order to control the particle size uniformly and produce a stable and high-quality emulsion, a new method has been proposed in which a porous glass film having a fine pore size and a uniform size is used as a dispersive element of a dispersed phase. (JP-A-2-95433). The outline of this method is shown in FIG. In this method, when an oil-in-water (O / W) emulsion is produced, the tubular porous glass membrane 1 that is more easily wetted by the water phase than the oil phase is used as the dispersion element. The circumference of the tubular porous glass membrane 1 was filled with the dispersed phase oily liquid 2, the dispersed phase oily liquid was pressed into the porous glass tube by the pressure pump 3, and the continuous phase was circulated by the circulation pump 4. The oily liquid of the dispersed phase is emulsified and dispersed in the aqueous liquid 5 of 1. Therefore, according to this method, it is possible to produce a uniform and stable emulsion (hereinafter, referred to as a monodisperse emulsion), in which the particle size is uniform and the characteristics of the material of the dispersion element are reflected. Also, by changing the size of the pore size of the dispersion element, it is possible to design the emulsion particles suitable for the intended use of the emulsion.

[0004]

However, in this method, the amount of the liquid in the dispersed phase required for emulsification is sufficient to fill the periphery of the tubular dispersing element, the high pressure pipe 6 and the dispersed phase tank 7. In addition, the continuous-phase liquid is used inside the tubular dispersion element, the circulation pipe 8 and the continuous-phase tank 9.
It needs to be sufficient to meet. Therefore, when the emulsion is mass-produced by this method, it is necessary to increase the number of dispersion elements and scale up the dispersed phase tank 7 and the continuous phase tank 9 as appropriate, but there is a limit in producing a small amount of emulsion, The minimum is 100 ml. Further, since the membrane module 10 has a complicated structure, loading and unloading of the dispersion element is complicated, and it is inconvenient to manufacture many types of emulsions. As described above, this method is capable of continuous mass production of emulsions, but it is difficult to produce a small amount of emulsion of several ml to several tens of ml, and its solution is desired.

Particularly, in recent years, in the development of new medical drugs, clinical administration of emulsifying anticancer agents, development of liquid crystal materials using expensive emulsifying raw materials, and research and development of new emulsions using rare surfactants. In the above, there is a need for the production of an emulsion that is small and uniform and excellent in stability, and an emulsification method and an emulsification apparatus for producing such a small amount of emulsion are desired. Therefore,
It is an object of the present invention to solve the problems associated with ross volume when producing a small amount of a uniform and stable emulsion by the conventional emulsification method and device.

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an emulsification method and an apparatus for producing the same, which can easily produce a uniform and stable emulsion even in a small amount. There is. That is, the present invention, the liquid for the dispersed phase in a stationary state, under pressure by the pressurizing body,
The emulsification method is characterized in that the liquid of the disperse phase is dispersed into the liquid of the continuous phase by press-fitting into the liquid of the continuous phase flowing through the fine pores of the porous member. Further, according to the present invention, the inside of the emulsification container is partitioned by a perforated plate having uniform pores having an average pore diameter of 0.1 to 10 microns, and a chamber for the liquid for a dispersed phase is formed on one side and another on the other side. A chamber for forming an emulsion is formed, the chamber for the liquid for dispersed phase has an opening communicating with a gas pressurizing source at the end opposite to the porous plate, and the chamber for forming the emulsion is formed. ,
The emulsification device is characterized in that a rotor for stirring is provided and a liquid supply pipe for a continuous phase is connected to the emulsification device. The present invention also provides an emulsification container having an average of 0.1 to 10 microns. It is partitioned by a perforated plate having pores of uniform pore size, a chamber for the dispersed phase liquid is formed on one side, and a chamber for emulsion formation is formed on the other side, and the chamber for the dispersed phase liquid is a cylinder. The emulsification device is characterized in that a reciprocating member that is formed in a cylindrical shape and that is in liquid-tight contact with the inner wall surface of the cylinder is reciprocally movable. Further, according to the present invention, the inside of the emulsification container is partitioned by a porous cylinder having uniform pores having an average pore diameter of 0.1 to 10 microns, and the inside of the liquid for the dispersed phase is divided through the cylinder. A chamber is formed, a chamber for emulsion formation is formed on the outside, the chamber for the dispersed phase liquid is in communication with a dispersed phase container connected to a gas pressurizing source, and the chamber for emulsion formation is Is an emulsification device characterized in that a rotor for stirring is provided and a liquid supply pipe for a continuous phase is connected, and the present invention is an emulsification container, in which the both end portions are provided. There is a cylindrical member with a thread groove inside,
Inside each of the thread grooves of the cylindrical member, an inward flange is provided, and on the outside of each inward flange,
The O-rings are respectively arranged in contact with the flange surfaces, and the inner ring surface of the O-rings provides 0.1 to 10
A porous cylinder in which pores having an average pore diameter of micron are uniformly formed is held, and a dispersed phase supply pipe is connected to a space formed between the porous cylinder and the cylinder. It is in an emulsifying device.

In the present invention, in order to reduce the loss volume, the liquid for the dispersed phase is pressurized by a gas, a liquid which is not easily dissolved in the liquid for the dispersed phase, or a pressure member such as a piston. As the gas for pressurization, it is sufficient that it is inert to the liquid for the dispersed phase, and air, nitrogen, or other inert gas can be used. In the present invention, the liquid for the dispersed phase is pressurized and passes through the fine pores of the porous member such as a perforated plate, and is stirred to be dispersed in the liquid for the continuous phase in a fluid state to form an emulsion. In this case, the pore size of the porous member is 0.1 to 10 μm in average pore size.
m is preferable.

In the present invention, the porous member is preferably porous. In particular, if the porous member has a uniform pore diameter, the particle size of the emulsion to be formed can be formed uniformly, so it is more preferable to make the pore diameter of the porous member uniform. In the present invention, a plate-shaped porous member, a cylindrical porous member, a porous plate-shaped membrane and a porous cylindrical membrane can be used as the porous member. In the present invention, as such a porous member, _CaO-B 2 _{O 3}
-SiO ₂ -Al ₂ O ₃ based porous glass, CaO-B
_{2 O 3 -SiO 2 -Al 2 O} 3 -Na 2 O -based porous glass and _CaO-B 2 _O of 3 -SiO ₂ -Al ₂ O 3 -N
porous material with a formed like porous glass a 2 _O-MgO-based in a plate shape or a cylindrical shape, for example, to use a plate-shaped or cylindrical porous membrane preferably.

In the present invention, it is preferable that the surface of the porous member is formed to have a property of being hard to be wet by an oily liquid and / or an aqueous liquid which is a dispersed phase. In particular, in order to disperse the droplets of the dispersed phase having a uniform particle size, the surfaces of the plate-shaped and cylindrical porous bodies and the plate-shaped and cylindrical porous membranes are hard to be wet by the liquid serving as the dispersed phase. Is preferred. In the present invention, a surfactant is used to stably disperse the dispersed phase liquid in the continuous phase liquid. Addition of surfactant
It is the liquid side that is the continuous phase and / or the liquid side that is the dispersed phase. By using this surfactant, it is possible to prevent the droplets of the dispersed phase that were once generated from contacting each other and forming new droplets. can do.

In the present invention, in order to bring the liquid serving as the dispersed phase and the liquid serving as the continuous phase into contact with a porous member such as a porous membrane while reducing the loss volume, the inside of the emulsification container is porous. It is formed by being divided into a liquid chamber which is a dispersed phase and a liquid chamber which is a continuous phase through the membrane. The liquid chamber serving as the dispersed phase, that is, the liquid chamber for the dispersed phase faces the porous member on one side, contains the liquid serving as the dispersed phase, that is, the liquid for the dispersed phase, and stores the liquid for the dispersed phase. Pressurizing means for applying pressure is provided. The continuous-phase liquid chamber, that is, the continuous-phase liquid chamber, faces the porous plate on one side and contains the continuous-phase liquid, that is, the liquid for the continuous phase, and the continuous phase is passed through the porous plate. A rotor or a stirring device is provided to uniformly disperse the droplets of the dispersed phase pressed into the liquid. One chamber wall is formed in the perforated plate, and the bottom and peripheral side walls are formed in a sealed state.

In the present invention, the chamber for the dispersed phase liquid is provided on one side of the porous plate, the chamber for the continuous phase liquid is provided on the other side of the porous plate, and the area of the porous plate is reduced. The emulsifying device can be easily downsized, and a small amount of emulsion can be easily formed. Further, in the present invention, in order to avoid the formation of loss volume, that is,
To avoid the amount of liquid that does not contribute to the formation of the emulsion,
The dispersed phase liquid chamber and the continuous phase liquid chamber formed through the perforated plate can approximate the amount of liquid used to form the emulsion. Therefore, in the present invention,
The amount of liquid for the dispersed phase and the amount of liquid for the continuous phase can be the required amount of the emulsion to be produced, and are used depending on the amount of the target emulsion.

In the present invention, in order to reduce the loss volume during emulsification, the chamber for the liquid for the dispersed phase has one chamber wall formed of a perforated plate, and the bottom and the surrounding side walls are sealed. It is formed. In the present invention, the liquid for the disperse phase, which penetrates by pressure into the chamber of the liquid for continuous phase, that is, the chamber of the liquid for emulsion formation, through the holes of the perforated plate is forced into the liquid for continuous phase. In order to uniformly disperse the liquid in the emulsion, a rotor or a stirring device for stirring is provided in the liquid chamber for forming the emulsion. The rotor may be of a type that rotates magnetically, and a rotary blade is attached to the rotary shaft, and the rotary shaft is inserted into the liquid chamber for emulsion formation from outside in a liquid-tight and rotatably manner, The rotor can be rotated by external power.

In the present invention, in order to efficiently press the dispersed phase liquid into the continuous phase liquid through the perforated plate, it is possible to remove bubbles adhering to the surface of the perforated plate under the pressure of the dispersed phase liquid. It is preferable to open a channel for removing bubbles in the wall of the continuous phase liquid chamber adjacent to the peripheral edge of the porous plate. In the present invention, the liquid chamber for emulsion formation may be provided with an inlet for the continuous-phase liquid and an outlet for the emulsion to continuously produce a small amount. In this case, it is preferable to provide a liquid inlet for the dispersed phase in the liquid chamber for the dispersed phase. In the present invention, the chamber for the liquid for the dispersed phase is provided for pressure control of the liquid for the dispersed phase and is connected to a gas supply source or a liquid supply source which is not easily dissolved in the liquid for the dispersed phase so that the pressure can be adjusted. To be When a piston or the like is used as the pressurizing body, the liquid chamber for the dispersed phase can be formed in the piston cylinder, and the piston rod or the plunger as the pressurizing body can be provided in the liquid chamber.

[0014]

In the present invention, the liquid for the dispersed phase is pressurized under gas pressure,
Through the fine pores of the perforated plate, it is pressed into the flowing continuous phase liquid to disperse the dispersed phase liquid in the continuous phase,
Even if the emulsified amount is as small as 1 to 100 ml, the liquid in the dispersed phase can be pressurized, and a uniform and uniform monodisperse emulsion can be easily produced. Therefore, according to the present invention, not only single emulsions such as oil-in-water (O / W) emulsions and water-in-oil (W / O) emulsions, but also double emulsions such as W / O / W emulsions are similarly small in amount. However, a uniform emulsion can be obtained. Further, according to the present invention, the size of the liquid droplets formed through the perforated plate is much larger than the diameter of the holes through which the perforated plate passes, for example, several times larger, because the size of the droplets swells during the formation process. By selecting according to the target particle size, the particle design of the emulsion can be performed.

According to the present invention, it is possible to easily produce a high-performance emulsion that is homogeneous and excellent in stability in a small amount of various kinds. Therefore, such an emulsion is required in a field or for a dispersed phase which is a raw material of an emulsion. It is effective when the above liquid, the liquid for the continuous phase, or the surfactant or stabilizer added thereto is very expensive or extremely rare. For example, strict particle design is required for emulsified anti-cancer agents, which have been attracting attention due to the significant reduction in side effects, and for effective expression of drug efficacy, but it is required for actual clinical administration. Although it is only 5 to 10 ml at the most, it is possible to easily and easily produce such a small amount of emulsion and to prepare a necessary amount without waste.

[0016]

EXAMPLES Hereinafter, embodiments of the present invention will be described with reference to examples, but the present invention is not limited to the contents of the following examples and explanations. 1 is a schematic side sectional view for explaining an embodiment of the present invention.
FIG. 2 is a schematic configuration diagram illustrating an emulsification device configured by incorporating the embodiment of FIG. 1. FIG. 3 is a schematic side sectional view showing another embodiment of the present invention, and FIG. 4 is a further side embodiment showing a case where the liquid chamber of the dispersed phase is located below. FIG. 5 is a side sectional view showing one embodiment of the horizontal type of the present invention. FIG. 6 is a view showing another embodiment of the present invention different from the embodiment of the present invention shown in FIGS. 1 to 5, and shows an example of emulsifying a liquid in a dispersed phase from the inside to the outside of a porous cylinder. It is a sectional side view. FIG. 7 is a view showing an embodiment constructed in a relationship opposite to that of FIG. 6, and is a side sectional view showing an example of emulsifying the liquid of the dispersed phase from the outer side to the inner side of the porous cylinder. In the drawings showing these examples, the same reference numerals are given to corresponding parts.

In the embodiment shown in FIGS. 1 and 2,
The emulsifying device 11 uses a disk-shaped porous glass film 12. The porous glass film 12 is held between the dispersed phase tank 13 and the continuous phase tank 14 by the upper and lower two O-rings 15 and 16 so as to be liquid-tight from above and below. In this example, the continuous phase tank 14 has a step 17 formed therein,
The disperse phase tank 13 is placed in a nest in this, and the disperse phase tank 13 is transformed into the continuous phase tank 14 by tightening with a cap nut 18 so that the periphery of the porous glass membrane 12 is pressed by the upper and lower two O-rings 15 and 16. Crimp.

In this example, the continuous-phase tank 14 is provided with a small liquid passage port 19 connected to the liquid supply line for the continuous phase, and a small opening 20 for taking out the produced emulsion. ing. The opening 20 is provided with a plug 21, and the plug 21 is removed from the opening 20 to take out the emulsion from the opening 20. The size of the opening 20 of the continuous phase tank 14 is determined by the residence time of the continuous phase liquid in the continuous phase tank 14. On the bottom 22 of the continuous-phase tank 14, a rotor 23 of a magnetic stirrer is placed. This rotor 23
Drives the magnetic stirrer to rotate it.
A ventilation port 27 is provided in the upper portion of the dispersed phase tank 14 to which a pipe line 26 that connects to a pressurized nitrogen gas cylinder via a precision pressure regulator is connected.

Since this example is constructed as described above,
In the case of producing a monodisperse oil-in-water emulsion, that is, a 0 / W emulsion, first, the rotor 23 is placed in the continuous phase tank 14. At this time, the plug 21 of the emulsion sampling opening 20 provided at the lower part of the side wall of the continuous phase tank 14 is removed, and the emulsion withdrawing pipe is connected to leave the open state. The porous glass membrane 12 is placed on the O-ring 16 mounted on the step portion 17 of the continuous phase tank 14, another O-ring 15 is mounted thereon, the dispersed phase tank 13 is placed, and The disk-shaped porous glass membrane 12 is fixed between the dispersed phase tank 13 and the continuous phase tank 14 by tightening the nut 18.

In this example, the vent 27 of the dispersed phase tank 13 is for introducing the gas for pressurization and is also the liquid inlet for the dispersed phase, and the vent 27 is formed before the emulsion is formed.
From the oil 30 in which a predetermined amount of oil or a surfactant is dissolved
Is injected. After the liquid of the dispersed phase is introduced into the dispersed phase tank 13, the pipe line 26 is connected to a precision pressure controller, and the inside of the dispersed phase tank 13 is connected to a nitrogen gas cylinder for pressurization through the precision pressure controller to pressurize. Is ready. Therefore, in the continuous phase tank 14 below the dispersed phase tank 13, an aqueous solution 28 in which continuous phase water or a surfactant or a dispersion aid is dissolved
Is poured until the liquid surface comes into contact with the film surface of the disk-shaped porous glass film 12.

When emulsification is started, first, the continuous aqueous phase 28 in the continuous phase tank 14 is magnetically stirred.
Is stirred. Then, the dispersed oil phase 30 in the dispersed phase tank 13 is pressurized using a nitrogen gas cylinder. Here, if the pressure is raised to the critical pressure or more, the dispersed oil phase 30 permeates the disk-shaped porous glass membrane 12, and oil droplets of uniform size are formed in the continuous aqueous phase 28. During the emulsification operation, the produced monodisperse emulsion overflows from the collection port 20 and is collected from the collection tube by the amount of the oil to be injected.

In this example, the liquid passage port 19 provided in the continuous phase tank 14 and the ventilation port 27 provided in the dispersed phase tank are provided for each one, but it is possible to provide more liquid passage ports and ventilation ports. it can. In this case, different operations can be performed. For example, if the liquid passage port 19 is connected to the emulsion collection port 20 via a pump, the dilute emulsion may be connected via the liquid passage port 19 to the continuous phase tank 1
4 can be introduced into the emulsion to give an emulsion having a predetermined concentration, or the emulsion can be continuously prepared. Further, by providing the precision pressure regulator, the pressure can be accurately controlled.

FIG. 2 is a layout view showing an example of the automatic emulsification device. In FIG. 2, the emulsifying device 11 is a continuous phase tank 1
It is provided on the magnetic stirrer 31 in order to rotate the rotor 23 of the magnetic stirrer 31 contained in the motor. A liquid supply pipe 32 for the dispersed phase is connected to the dispersed phase tank 13 of the emulsifying device 11, and the liquid supply pipe 32 for the dispersed phase is a three-way solenoid valve 33.
Connected to the path 34. One end 35 of the branch flow path of the three-way solenoid valve 33 is immersed in a liquid container 36 for the dispersed phase liquid, and the remaining end 37 is connected to a cylinder pump 38 for the dispersed phase.

The liquid supply pipe 39 for the liquid for the continuous phase, which is connected to the continuous phase tank 14 of the emulsifying device 11, has a three-way solenoid valve 40.
It is connected to the path 41. One end 42 of the branch flow path of the three-way solenoid valve 40 is immersed in the liquid container 43 of the liquid for the dispersed phase, and the remaining one end 44 is connected to the cylinder pump 45 for the continuous phase. In addition, the continuous phase tank 14
An overflow pipe 46 is provided near the perforated plate 12.
The conduit 26 extending from the vent 27 of the dispersed phase tank 13 of the emulsifying device 11 is connected to a nitrogen gas source (not shown) via a pressure gauge 47, a pressure adjusting valve 48 and a solenoid valve 49.

Since this example is constructed as described above,
The branch flow path 37 of the three-way solenoid valve 33 is connected to 35, the cylinder pump 38 for the dispersed phase is operated to the suction side, the liquid for the dispersed phase is discharged from the liquid container 36, and the liquid for the dispersed phase is used for the dispersed phase. It is sucked and collected in the cylinder pump 38. Therefore,
By switching the three-way solenoid valve 33, the branch flow passage 37 of the three-way solenoid valve 33 is communicated with the branch flow passage 34, and the cylinder pump 38 for the dispersed phase is operated to the discharge side so that the cylinder pump 38 for the dispersed phase is provided. The sucked liquid for dispersed phase is supplied into the dispersed phase tank 13 from the liquid supply pipe 32 for dispersed phase.

The branch flow passage 44 of the three-way solenoid valve 40 is connected to 42, and the cylinder pump 45 for the continuous phase is operated to the suction side to transfer the liquid for the continuous phase from the liquid container 43 to the liquid for the continuous phase. It is sucked and collected in the cylinder pump 45 for the continuous phase. Therefore, the three-way solenoid valve 40 is switched so that the branch flow passage 44 of the three-way solenoid valve 40 communicates with the branch flow passage 41, and the continuous-phase cylinder pump 45 is operated to the discharge side, so that the continuous-phase cylinder pump 40. The liquid for the continuous phase sucked inside is supplied into the continuous phase tank 14 from the liquid supply pipe 39 for the continuous phase. Therefore, the operation of the magnetic stirrer 31 and the rotation operation of the rotor 23 are started in order to stir the liquid of the continuous phase so that the liquid of the dispersed phase is uniformly dispersed in the liquid of the continuous phase.

The pressure adjusting valve 48 is adjusted to adjust the pressure in the dispersed phase tank 13 within a predetermined range. When the inside of the dispersed phase tank 13 exceeds a predetermined pressure (critical pressure), the liquid 30 for the dispersed phase passes through the porous plate 12 and the continuous phase tank 14
It is pressed in. With the start of the emulsification, the emulsion overflows from the overflow pipe 46 into which the liquid for the dispersed phase has been press-fitted and flows out into the liquid container 43 for the continuous phase. Below the liquid container 43 for the continuous phase, a weight scale (not shown) is provided, and the total amount of the liquid for the dispersed phase is stored in the continuous phase tank 14
It can be detected that it has been press-fitted in.

The embodiment shown in FIG. 3 is an apparatus for producing an emulsion of the type in which pressure is applied by a piston instead of pressurization by gas. In this example, the porous glass film 12
In the same manner as in the embodiment of FIG. 1, the peripheral portion is liquid-tightly held and held by the O-rings 15 and 16 between the dispersed phase tank 13 and the continuous phase tank 14. In this example, the stepped portion 17 of the continuous phase tank 14 is provided with an opening 51 of a flow passage 55 for removing bubbles adhering to the perforated plate to the outside. In this example, the flow path 55 for removing air bubbles is provided so as to also serve as an overflow flow path. Of course,
It is also possible to separately provide the overflow channel and the bubble removal channel.
The continuous phase tank 14 is provided with a rotor so that the dispersed phase liquid is uniformly dispersed in the continuous phase liquid, as in the embodiment of FIGS. 1 and 2. The rotor operates the magnetic stirrer 31, rotates the rotor, and stirs the continuous phase liquid. In this example, a piston 52 is attached to the dispersed phase tank 13 to pressurize the liquid for the dispersed phase, and the piston 52 is moved downward to pressurize the liquid 30 in the dispersed phase. It can be carried out.

In this example, the dispersed phase tank 13 is provided with a conduit 32 for introducing the dispersed phase liquid. Pipeline 3
An opening / closing valve 54 is provided at 2 to form a closed container that is closed after the bubbles are removed during the formation of the emulsion and that is pressurized. In this example, it is possible to avoid bubbles from adhering around the porous glass film 12 as much as possible,
Emulsion formation efficiency increases.

The embodiment shown in FIG. 4 is an example in which the dispersed phase tank 13 is formed below the continuous phase tank 14, and in order to stir the liquid of the continuous phase, the stirring blade 53 is provided on the stirring rotary shaft. An agitator 56 with an upper continuous phase tank 14
It is provided inside. The porous glass film 12 is liquid-tightly sandwiched and held between the dispersed phase tank 13 and the continuous phase tank 14 by O-rings 15 and 16. In this example, a dispersed phase liquid supply pipe 32 is connected to the dispersed phase tank 13, and a continuous phase liquid supply pipe 1 is connected to the continuous phase tank 14.
9 is provided. The flow path for bubble removal and the overflow flow path 50 is
The flow passage / overflow passage 55 for removing air bubbles is formed in the step portion 17 of the dispersed phase tank 13, and is formed in the step portion 17 of the continuous phase tank 14. The embodiment shown in FIG. 5 is formed horizontally, and the porous glass membrane 12 is vertically stretched between the dispersed phase tank 13 and the continuous phase tank 14 by O-rings 15 and 16. And is held in a liquid tight manner. A piston 52 is provided as a pressurizing means in the dispersed phase tank 13, and the continuous phase tank 14 has an upper wall 57.
A stirring device 56 including a stirring blade 53 similar to that of the embodiment of FIG.
Is provided. In the present example, the dispersion phase liquid supply pipe 32 and the bubble removal channel 50 are formed in the upper wall 58 of the dispersed phase tank 13, and the continuous phase liquid supply is provided in the upper wall 57 of the continuous phase tank 14. A pipe 19 and a flow path 55 for removing bubbles are formed.

In the embodiment shown in FIG. 6, a window 60 is formed at the end of a hollow pipe 59 which communicates with the bottom of the dispersed phase tank 13, and an outward flange portion 61 is provided above and below the window 60. And 62 are formed, and the outward flange portion 61 is formed.
Outside the and 62, a cylindrical porous glass membrane 12 'is
In this case, the O-ring 16 is crimped by the holding nut 63 and the holding bolt 64 to be liquid-tightly fixed. In this example, the cylindrical porous glass membrane 12 '
The inside of the cylinder is formed so that the dispersed phase liquid 30 can be filled from the dispersed phase tank 13 and the dispersed phase liquid 30 can be pressurized. In this example, the cylindrical porous glass membrane 12 ′ is filled with the liquid 2 in the continuous phase tank 14.
8 and the liquid 28 in the continuous phase is rotated and stirred by the magnetic stirrer 31 by the rotor 23 while pressurizing the dispersed phase tank 13 at a predetermined pressure, thereby the liquid 30 in the dispersed phase is cylindrical porous glass. It is formed so that it can be dispersed and emulsified in the continuous phase liquid 28 through the membrane 12 ′.

In the embodiment shown in FIG. 7, the cylindrical porous glass membrane 12 'has an outer cylindrical surface 65 whose upper surface O- is clamped by an upper flange portion 67 of a cylindrical structure 66 and an upper pressing bolt 68. Ring 16 and cylindrical structure 6
6 is liquid-tightly fixed to the cylindrical structure 66 by the lower O-ring 16 which is pressure-bonded with the lower flange portion 69 of 6 and the pressing nut 70. The cylindrical structure 66 and the cylindrical porous glass membrane 12 In this example, the space 71 between the space and the space is connected to the dispersed phase tank 13. In the present example, when the outside of the cylinder of the cylindrical porous glass membrane 12 'is filled with the liquid 30 in the dispersed phase, a bubble removal channel 50 is formed to prevent bubbles from remaining on the membrane surface. . In this example, the cylindrical structure 66 to which the cylindrical porous glass membrane 12 ′ is fixed is arranged so as to be completely submerged below the liquid surface by the continuous phase liquid 28, and further fixed to the cylindrical structure 68 by the rotor 23. The continuous-phase liquid 28 is formed so as to circulate and flow inside the formed porous glass film.

When a monodisperse water-in-oil emulsion (hereinafter referred to as W / O emulsion) is produced by the apparatus shown in the above example, a disk-shaped or cylindrical porous material is prepared in advance. The porous glass membrane is hydrophobized by surface chemical modification, then sufficiently wetted with a continuous oil phase, and attached to a small emulsifier. The disperse phase and the continuous phase are arranged in the completely opposite kind of liquid as compared with the case of producing an O / W emulsion, but basically the emulsification may be performed in the same way.

In the case of producing a monodisperse water-in-oil-in-water emulsion (hereinafter referred to as W / O / W emulsion), the W / O emulsion is first prepared by the above method or a conventional homogenizer. It is prepared using an ultrasonic emulsifying machine and loaded in the dispersed phase tank 13. Water or an aqueous solution in which a surfactant or a dispersion aid is dissolved is added to the continuous phase side, and a hydrophilic porous glass film is used as a dispersion element to emulsify the dispersion element.

An example of producing an emulsion using the apparatus shown in FIGS. 1 and 2 is shown below. An emulsion can be similarly produced by the apparatus shown in FIGS. 3 to 7.

Example 1 Production of Monodisperse O / W Emulsion by Small Emulsifier A monodisperse O / W emulsion was prepared by using the small emulsifier shown in FIG. The decomposed oil phase is an iodized poppy oil fatty acid ethyl ester (lipiodol Ultra-Flu manufactured by Laboratoire Guerbet Co., Ltd.) as a clinical oily contrast agent.
5 ml of tetraglycerin-condensed ricinoleic acid ester (CR-310 manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), which was an oil-soluble surfactant, was added thereto to a concentration of 5% by weight. 1% by weight of Pluronic F68 manufactured by Midori Jushi Pharmaceutical Co., Ltd.
5 ml of an aqueous solution adjusted to have a glucose concentration of 5% by weight. These were set in a small emulsifier according to the procedure described above. Disc-shaped porous glass membrane used (Ise Chemical Industry Co., Ltd. outer diameter 35 mm, thickness 1 mm)
Had a pore diameter of 1.4 μm. A pressure of about 50 kPa was applied, and after about 30 minutes, 10 ml of a monodisperse O / W emulsion having an average particle size of 9.0 μm was obtained.

Example 2 Production of Monodisperse W / O Emulsion by Small Emulsifier Disk-shaped porous glass membrane synthesized by the inventors (outer diameter 35 m)
m, thickness 1 mm, heat treatment conditions: 775 ° C. for 4 hours) with a silicone resin (KP-18 manufactured by Shin-Etsu Chemical Co., Ltd.).
It was surface coated with C) and made hydrophobic. Using this hydrophobized membrane and the same small emulsifier as in Example 1, 10 m of monodispersed W / O emulsion having an average particle diameter of 7.1 μm was used.
1 was produced. The dispersed aqueous phase was carboplatin (John Matthey Pa
RAPLATIN) 1.4% by weight and 2.7% by weight sodium chloride, and the continuous oil phase was prepared by adding tetraglycerin-condensed ricinoleic acid ester to iodinated poppy seed oil fatty acid ethyl ester to a concentration of 2% by weight. I used one. The pressure was about 80 kPa and the emulsification time was about 1 hour.

Example 3 Production of Monodisperse W / O / W Emulsion by Small Emulsifier An aqueous solution containing 5% by weight of carboplatin and 0.75% by weight of sodium chloride in a dispersed aqueous phase (inner aqueous phase) and a continuous oil phase. 5% by weight of tetraglycerin condensed ricinoleic acid ester
Using iodized poppy oil fatty acid ethyl ester containing,
Ultrasonic Emulsifier (Nippon Seiki Seisakusho Co., Ltd. US-15)
0), all particles have a W / O size of 1 μm or less.
The emulsion was prepared beforehand. Ultrasonic wave is 20kH
Irradiated with z for 10 minutes. Next, using a small emulsifier, the W / O emulsion was placed in a dispersed phase tank and the external water phase was placed in a continuous phase tank to obtain a monodispersed W / O / W emulsion by membrane emulsification. The outer aqueous phase is an aqueous solution containing 2% by weight of Pluronic F68 and 5.8% by weight of glucose, and has two kinds of disc-shaped porous glass membranes (Ise Chemical Industry Co., Ltd.) having pore diameters of 1.4 μm and 4.2 μm. An outer diameter of 35 mm and a thickness of 1 mm manufactured by K.K. were used.

As a result, when the pore diameter is 1.4 μm, about 50
Monodisperse W / O with an average particle size of 9.0 μm at a pressure of kPa
/ W emulsion was obtained, and at 4.2 μm, about 20 k
It was possible to produce 10 cc of a monodisperse W / O / W emulsion having an average particle diameter of 25.3 μm at Pa. At this time,
The volume ratio of the inner water phase, the oil phase and the outer water phase was 1: 2: 7.

Under the same conditions as above, an aqueous solution containing 0.2% by weight of epirubicin hydrochloride (Farmitolia Carlo Erba's Farmorubicin), which is an antineoplastic agent, and 5.8% by weight of glucose was used as an inner aqueous phase to form a monodisperse W A / O / W emulsion was produced. Similar to the above example, when the pore size is 1.4 μm, the average particle size is 9.0 μm and 4.
At 2 μm, a 23.9 μm monodisperse W / O / W emulsion was obtained, and it succeeded in encapsulating almost 100% of the inner aqueous phase. Further, these emulsions were so stable that their morphology hardly changed even after 1 week or more.

[0041]

INDUSTRIAL APPLICABILITY According to the present invention, a liquid for a dispersed phase in a stationary state is pressed into a flowing continuous phase liquid through fine pores of a perforated plate under pressure of a pressure body such as gas. Since the liquid for the dispersed phase is dispersed in the liquid for the continuous phase, the emulsification amount is 1
It is possible to produce a uniform and even monodisperse emulsion, which is a very small amount of 100 to 100 ml as compared with the conventional method. Further, similar to the conventional method, not only single emulsion such as O / W emulsion and W / O emulsion but also double emulsion such as W / O / W emulsion can be designed.

This means that various types of small amounts, homogeneous and high-performance emulsions with high stability are required, or a liquid for a dispersed phase or a liquid for a continuous phase which is a raw material of an emulsion and added to these. It exhibits excellent efficacy when the surface active agent or stabilizer is very expensive or extremely rare.

According to the present invention, the liquid in the dispersed phase is kept stationary,
Since the liquid for the dispersed phase is pressurized by a gas or a pressurizing body such as a piston to disperse the liquid for the dispersed phase in the liquid for the continuous phase through the porous plate, the amount of the liquid for the dispersed phase can be reduced. Correspondingly, the amount of continuous phase liquid is also reduced.
Therefore, the volumes of the dispersion phase liquid chamber and the continuous phase liquid chamber can be reduced, which facilitates downsizing of the emulsifying apparatus.

For example, an emulsified anti-cancer drug, which has been attracting attention due to the drastic reduction of side effects, requires strict particle design for stability and effective expression of drug effect, but in actual clinical administration At most 5 to 1
Only 0 ml. When this is manufactured with a conventional emulsification device, at least 100 ml must be manufactured, and the excess of 90 ml or more must be discarded. This method is not economically acceptable in view of the fact that the anticancer drug used as the raw material of the emulsion is generally expensive. According to the present invention, a necessary amount can be prepared without waste, so that it is possible to provide an effective cancer treatment at low cost in a medical field.

In the present invention, since the emulsification device has a simple structure, it is possible to mass-produce the parts by die processing and to reduce the cost of the emulsification device as compared with the conventional emulsification device. Further, in the present invention, since the device can be easily assembled and disassembled and the parts can be easily washed and sterilized, it is possible to efficiently prepare various kinds of emulsions. Furthermore, the emulsifying apparatus of the present invention is simpler to handle than conventional emulsifying apparatuses, does not require a high degree of knowledge and skill, and by using transparent plastic in the container on the continuous phase side. The emulsification status can be monitored in real time.

[Brief description of drawings]

FIG. 1 is a schematic side sectional view for explaining an embodiment of the present invention.

FIG. 2 is a schematic configuration diagram illustrating an emulsification device configured by incorporating the embodiment of FIG.

FIG. 3 is a schematic side sectional view showing another embodiment of the present invention.

FIG. 4 is a side sectional view showing still another embodiment of the present invention, showing a case where the liquid chamber of the dispersed phase is located below.

FIG. 5 is a side sectional view showing an example of a horizontal type of the present invention.

FIG. 6 is a view showing another embodiment of the present invention different from the embodiment of the present invention shown in FIGS. 1 to 5, showing an example of emulsifying a liquid in a dispersed phase from the inside to the outside of a porous cylinder. It is a sectional side view.

FIG. 7 is a view showing an embodiment constructed in a relationship opposite to that of FIG. 6, and is a side sectional view showing an example of emulsifying a dispersed phase liquid from the outside to the inside of a porous cylinder.

FIG. 8 is a schematic explanatory diagram of a conventional method.

[Explanation of symbols]

1 Porous Glass Membrane 2 Oily Liquid of Dispersed Phase 3 Pressurizing Pump 4 Circulation Pump 5 Aqueous Liquid of Continuous Phase 6 High Pressure Piping 7 Dispersed Phase Tank 8 Circulation Piping 9 Continuous Phase Tank 10 Membrane Module 11 Emulsifier 12 Porous Glass membrane 12 'Cylindrical porous glass membrane 13 Dispersed phase tank 14 Continuous phase tank 15, 16 O-ring 17 Step part 18 Cap nut 19 Liquid inlet port 20 Opening 21 Plug body 22 Bottom part 23 Rotor 26 Pipe line 27 Vent port 28 Continuous Phase water or surfactant or dispersion liquid 30 Dispersed oil phase 31 Magnetic stirrer 32 Liquid supply pipe for dispersed phase 33, 40 Three-way solenoid valve 34, 35, 37, 41, 42, 44 Branch flow path 36 For dispersed phase Liquid container 38, 45 Cylinder pump 39 Liquid supply pipe for continuous phase 43 Liquid container for continuous phase 46 Overflow pipe 47 Pressure gauge 48 Pressure adjustment Valve 49 Solenoid valve 50, 55 Bubble removal channel / overflow channel 51 Opening 52 Piston 53 Stirring blade 54 Open / close valve 56 Stirrer 57 Upper wall of continuous phase tank 58 Upper wall of dispersed phase tank 59 Hollow pipe 60 Window 61, 62 flange part 63 pressing nut 64, 68, 70 pressing bolt 65 cylindrical outer surface of cylindrical porous glass film 66 cylindrical structure 67 upper flange part 69 lower flange part 71 between cylindrical structure and cylindrical porous glass film space

[Procedure amendment]

[Submission date] November 24, 1993

[Procedure Amendment 1]

[Document name to be corrected] Drawing

[Name of item to be corrected] Figure 5

[Correction method] Change

[Correction content]

[Figure 5]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshihiko Iwasaki 6163-3 Totoro-cho, Nobeoka-shi, Miyazaki Kiyomoto Iron Works Co., Ltd. (72) Kenji Fujimoto 6163-3 Totoro-cho, Nobeoka, Miyazaki Prefecture Kiyomoto Inside the Iron Works Co., Ltd.

Claims (6)

[Claims] 1. A stationary phase liquid for a dispersed phase is pressed into a flowing continuous phase liquid through fine pores of a porous member under pressure by a pressure body, and the dispersed phase liquid is aforesaid. An emulsification method characterized by dispersing in a continuous phase liquid. 2. The inside of the emulsification container is partitioned by a perforated plate having uniform pores having an average pore diameter of 0.1 to 10 microns, a chamber for a dispersed phase liquid is formed on one side, and an emulsion on the other side. A chamber for formation is formed, the chamber for the liquid for the dispersed phase is formed with an opening communicating with a gas pressurizing source at an end opposite to the porous plate, and the chamber for forming the emulsion, An emulsification device characterized in that a rotor for stirring is provided and a liquid supply pipe for continuous phase is connected. 3. The inside of the emulsification container is partitioned by a perforated plate having uniform pores with an average pore diameter of 0.1 to 10 microns, a chamber for the dispersed phase is formed on one side, and an emulsion is formed on the other side. A chamber for liquid is formed, and the chamber for the liquid for the dispersed phase is formed in a cylindrical shape, and a reciprocating element that comes into liquid-tight contact with the inner wall surface of the cylindrical shape is reciprocally provided. An emulsification device characterized by the above. 4. The emulsifying apparatus according to claim 2, wherein the chamber for the dispersed phase is provided with a conduit for supplying a liquid for the dispersed phase. 5. The inside of the emulsification container is partitioned by a porous cylindrical body having pores having an average pore diameter of 0.1 to 10 microns uniformly, and the dispersed phase is provided on either side through the cylindrical body. The chamber for the liquid for use is formed, and the chamber for forming the emulsion is formed on the other side, and the chamber for the liquid for the dispersed phase is
It is in communication with a dispersed phase container connected to a gas pressure source, the emulsion forming chamber is provided with a rotor for stirring and a liquid supply pipe for continuous phase is connected. Emulsifying equipment. 6. Inside the emulsification container, cylindrical members having threaded grooves on both ends are provided inside, and inward flanges are provided on the inside of each of the threaded grooves of the cylindrical member. , O-rings are arranged outside the respective inward flanges so as to be in contact with the flange surfaces, and the inner ring surface of the O-rings makes holes having an average hole diameter of 0.1 to 10 microns uniform. An emulsification device characterized in that the formed porous cylinder is held, and a dispersed phase supply pipe is connected to a space formed between the porous cylinder and the cylinder.