TW201630591A - Pharmaceutical emulsified preparation and manufacturing method thereof - Google Patents

Abstract

The present invention provides a pharmaceutical emulsified preparation and manufacturing method thereof. Although the pharmaceutical emulsified preparation is a stable emulsion, it will release the pharmaceutical ingredients in inner aqueous phase after medication for the patient thereby achieving the treatment effect to hepatocellular carcinoma. To solve the problem, there is provided a w/o/w type emulsion preparation, in which its inner aqueous phase is a water solution containing pharmaceuticals and its outer aqueous phase is dispersed with w/o oil drops. The w/o oil drops are formed by containing polyoxyethylene hardened castor oil in oil phase as surfactant, wherein the additive mole number of ethylene oxide of the polyoxyethylene hardened castor oil is more than one and less than nine.

Description

Medical emulsion preparation and preparation method thereof Field of invention

The present invention relates to an emulsified preparation for medicine and a method for producing the same, and more particularly to an emulsified pharmaceutical preparation for medical use for treating hepatocellular carcinoma and a method for producing the same.

Background of the invention

Generally, in the treatment of hepatocellular carcinoma, transcatheter arterial treatment is performed: the oily contrast agent (iodineized poppy oil fatty acid ethyl ester) is stagnated in the tumor site, and the anticancer agent is emulsified in the oily contrast agent. The emulsion is injected into the artery through a microcatheter, and the anticancer agent reaches hepatocellular carcinoma, thereby treating hepatocellular carcinoma.

The w/o/w type in which the emulsion is injected into the artery via a catheter, and the w/o type emulsion or the w/o type emulsion is further dispersed as w/o particles in the outer water phase. Injecting the emulsion into the hepatic artery system has become mainstream in medical institutions: the w/o type emulsion is obtained by emulsifying the anticancer agent aqueous solution w1 in which the water-soluble anticancer agent powder is dissolved in an aqueous solution to the oily contrast agent o (for example, Refer to Patent Document 1).

Advanced technical literature Patent literature

Patent Document 1: Japanese Patent Laid-Open No. Hei 10-158152 (page 2 to page 3, drawing 2)

Summary of invention

However, in the manufacture of various types of w/o/w emulsions, such as Patent Document 1, it is particularly important in the selection of surfactants that the w/o/w type emulsion is the most preferable. The safety of the emulsified state and the safety of the performance by the medical institution, but the status quo has not yet caught up with the most stable internal dispersion of the aqueous phase of the anticancer agent in the oil phase. A suitable choice of surfactant. Specifically, the ethylene oxide addition 40 mol of polyoxyethylene hardened castor oil (HCO40) of the surfactant disclosed in Patent Document 1 has been used for a long time in medical institutions. However, the HLB (Hydrophile-Lipophile Balance) value which is an indicator of hydrophilic hydrophobicity is 12.5, which is hydrophilic, and is not suitable as a surfactant added to the oil phase. Further, when the w/o/w type emulsion is administered to a patient by selecting a surfactant which focuses only on the stability of the w/o/w type emulsion, there is a problem in that a blood vessel Although the w/o particles released inside can be stably retained in the target hepatocellular carcinoma for a long time, the w particles in the w/o particles, that is, the aqueous solution of the anticancer agent are not released to the liver due to the high stability. Cellular cancer does not work.

The present invention has been made in view of such a problem, and an object thereof is to provide an emulsified preparation for medicine and a method for producing the same, which is an emulsified preparation for medicine

Although it is a stable emulsion, it will release the medicinal component of the internal aqueous phase after administration to the patient, and it can be effective against hepatocellular carcinoma.

In order to solve the above problems, the emulsified pharmaceutical preparation of the present invention is a w/o/w type emulsion preparation, characterized in that The water phase in the w/o/w emulsion preparation is an aqueous solution containing a chemical, and w/o oil droplets are dispersed in the outer aqueous phase, and the w/o oil droplets contain polyoxyethylene hardened castor oil in the oil phase. Made as a surfactant; and The addition mole number of the ethylene oxide of the polyoxyethylene hardened castor oil is 1 or more and 9 or less.

According to this feature, by using a polyoxyethylene hardened castor oil having a low molar number of ethylene oxide as an oily surfactant, a molecule due to a difference in addition position and degree of polymerization of ethylene oxide The unevenness of the three-dimensional structure is reduced, and it is possible to form a stable monodisperse w/o/w type emulsion preparation, and at the same time, since the movement of the agent between the outer water phase and the inner water phase through the oil phase is possible, it is cast. After being administered to the body, the medicinal component of the internal aqueous phase can be released.

The characteristic is that the addition mole number of ethylene oxide of the polyoxyethylene hardened castor oil which is the above surfactant is 4 or more and 6 or less.

According to this feature, the polyoxyethylene hardened castor oil having a three-dimensional structure approximation can be added to the surfactant at a plurality of positions where ethylene oxide can be added, or added at a fixed position. It is possible to prepare a more stable monodisperse w/o/w type emulsion preparation and to release the medicinal ingredient of the internal aqueous phase after being administered to the body.

The characteristic is that it comprises 0.1 to 20% by weight of the aforementioned oil phase The aforementioned surfactant.

According to this feature, it is possible to form a monodisperse w/o/w type emulsion preparation in which an oil-based surfactant is sufficiently coated with w particles and w/o particles and is stable for a long period of time.

The characteristic is that the osmotic pressure of the aforementioned inner water phase and the aforementioned outer water phase is slightly balanced, and is less than 1 times the osmotic pressure of the physiological saline solution.

According to this feature, the w/o/w type emulsion preparation released into the blood vessel changes the external water phase into blood, and the solution of the inner water phase having a low osmotic pressure is gradually transferred to the blood through the oil phase, thereby being effective. The aqueous solution containing the drug in the internal aqueous phase is slowly released.

The feature is that the w/o particles of the aforementioned w/o/w type emulsion preparation have a diameter of from 1 μm to 400 μm.

According to this feature, the w/o particles easily pass through the blood vessel, and can be made into a size capable of sufficiently releasing the medicinal ingredient.

The method for producing an emulsified preparation for medical use according to the present invention is a method for producing a w/o/w type emulsion preparation, characterized in that the aqueous phase of the w/o/w type emulsion preparation is an aqueous solution containing a pharmaceutical agent, and W/o oil droplets are dispersed in the outer aqueous phase, and the w/o oil droplets are obtained by containing polyoxyethylene hardened castor oil as a surfactant in the oil phase; and the osmotic pressure of the inner aqueous phase is in the above-mentioned when used The osmotic pressure of the aqueous phase is above.

According to this feature, the solution of the external aqueous phase having a low osmotic pressure is transferred to the inner aqueous phase through the oil phase, and the w particles are expanded to increase the capacity of the aqueous solution containing the drug, thereby increasing the w/o/w released into the blood vessel. The sustained release time of the internal aqueous phase caused by the emulsion preparation.

A method for producing an emulsified pharmaceutical preparation according to the present invention, which is a method for producing a w/o/w type emulsion preparation, and characterized in that the aqueous phase in the w/o/w type emulsion preparation is an aqueous solution containing a pharmaceutical agent, and is externally The w/o oil droplet is dispersed in the water phase, and the w/o oil droplet is obtained by containing polyoxyethylene hardened castor oil as a surfactant in the oil phase; in the manufacturing method, the method for producing the emulsion is as follows: a stopcock for regulating three or more flow paths, wherein a first syringe filled with an oil phase is connected to a flow path a side of the stopcock, and a second syringe filled with an inner water phase is connected to the flow path b side, and the flow is a third syringe filled with an outer aqueous phase is connected to the side of the road c; (1) the oil phase of the first syringe and the second portion are made by moving the plungers of the first syringe and the second syringe a primary emulsion in which the inner aqueous phase of the syringe passes through the flow path a and the flow path b is recovered to the second syringe, and (2) by moving the plungers of the second syringe and the third syringe Making the first emulsion of the second syringe and the aforementioned third syringe The outer aqueous phase is a secondary emulsion through the flow path b and the flow path c, and is capable of connecting the end of the flow path a or the flow path a to the connector of the first syringe and/or capable of A connector that connects the flow path c or the end of the flow path c to the third syringe may be provided with a porous body.

According to this feature, a stopcock capable of regulating three or more flow paths can be used to efficiently form the primary emulsion or the secondary emulsion once by the porous body having the plurality of through holes.

The feature is that the porous system described above forms a structure in which the size of the openable opening is adjacent to the opening of the opening, and the particles are not dried out.

According to this feature, the particles emitted from the openings do not merge with each other, and can be dispersed in the continuous phase.

It is characterized in that the porous body is hydrophilic when the continuous phase of the emulsion produced by the porous body is an aqueous phase, and is hydrophobic when it is an oil phase.

According to this feature, the liquid and the porous body of the porous body repel each other, and the liquid is easily formed into a spherical state in the porous body, and can be dispersed in the continuous phase in a state in which the particles are mutually incompatible with each other, and can be prevented at the same time. The emulsion phase transition.

The feature is that (1) injecting the outer water phase of the third syringe into the flow path c before the production of the emulsion, and the intermediate porous body is previously wetted by the outer water phase while the flow path is performed. Degassing c, (2) injecting the oil phase of the first syringe into the flow path a, and moisturizing the intermediate porous body in advance with the oil phase, while filling the flow path a and the flow with the oil phase The path b, and (3) connects the aforementioned second syringe filled with the inner water phase to the aforementioned flow path b.

According to this feature, the produced emulsion does not mix with air, and each porous body in the flow path can be prevented from being transformed into an emulsion phase by previously wetting the continuous phase of the produced emulsion.

O‧‧‧oil phase (oily contrast agent)

W1‧‧‧ internal aqueous phase (anticancer agent aqueous solution)

w‧‧‧Outer water phase

Wo‧‧‧w/o emulsion

Wow‧‧‧w/o/w emulsion

1, 2, 3 ‧ ‧ injection syringes

P1, P2, P3‧‧‧ plunger

4‧‧‧Three-way stopcock

4a‧‧‧Three-way stopcock male connector

4b, 4c‧‧‧Three-way stopcock concave connector

4d‧‧‧ cock

5‧‧‧Concave-concave embedding device with porous body

5a‧‧‧Emulsion device concave connector

6‧‧‧ convex-concave emulsification device equipped with porous body

6a‧‧‧Emulsion device concave connector

6b‧‧‧Emulsifying device male connector

S1, s2‧‧‧ porous body

A-b‧‧‧one emulsification flow path

B-c‧‧‧ secondary emulsification flow path

Figure 1 is a graph showing a w/o/w emulsion.

Fig. 2 (a) is a configuration diagram of an apparatus for producing a w/o/w type emulsion, and (b) is a view showing a state in which the connections are made.

Fig. 3 (a) is a schematic view showing that the aqueous phase is wetted in advance to deaerate the secondary emulsification channel bc, and (b) is followed by wetting the porous body with an oil phase in advance and filling the oil phase with a single emulsion. A schematic diagram of the flow path ab, (c) is a diagram showing a state in which the degassing in the three-way stopcock is completed and the remaining internal water phase has been connected to the three-way stopcock.

Fig. 4(a) is a view showing a primary emulsification method; (b) is a view showing a secondary emulsification method.

Fig. 5 (a) is a photograph of a w/o type emulsion obtained by adding an oily surfactant of a pharmaceutical additive to an oily contrast agent in an equivalent amount, and (b) after standing for 3 days. Photo.

Figure 6 is a photograph of a microscopic particle size and particle size distribution of a w/o/w emulsion produced by SPG direct film emulsification using various surfactants (a) HCO5 (b) HCO10 (c) HCO40 (d) PGCR.

Figure 7 is a photograph of a microscopic particle size and particle size distribution of a w/o/w emulsion produced by SPG permeable membrane emulsification using various surfactants (a) HCO5(b)HCO10(c)HCO40(d)PGCR.

Detailed description of the preferred embodiment Form for implementing the invention

The form of the pharmaceutical emulsified preparation according to the present invention and a method for producing the same will be described below based on examples.

[Examples]

(1) w/o/w type emulsion

As shown in Fig. 1, the emulsion preparation of the present embodiment is a w/o oil droplet in which the anticancer agent aqueous solution w1 is dispersed in the oil phase o, and is further dispersed in the outer water phase w. o/w type emulsion. The w/o/w type emulsion, especially an emulsified preparation for hepatic artery medicine, is injected into a hepatic artery blood vessel through a microcatheter for the treatment of hepatocellular carcinoma. Further, the w/o/w type emulsion is not limited to use in the treatment of hepatocellular carcinoma, and may be used, for example, in other cancer treatments, and may be administered to the body.

The substance constituting the w/o/w type emulsion will be described. The internal aqueous phase w1 is pharmaceutically acceptable, and is not particularly limited, and a pharmaceutical aqueous solution such as an aqueous solution containing an anticancer agent can be used as a main drug for treating a disease site.

The oil phase o is not particularly limited as long as it is pharmacologically acceptable, and may be appropriately selected depending on the intended use, such as vegetable oil, fatty acid, and paraffin. Further, the oil phase o contains a surfactant.

The surfactant added to the oil phase o contains the polyoxyethylene hardened castor oil (hereinafter, simply referred to as "HCO") having the structure shown in the following Chemical Formula 1. The number of the successive HCO refers to the molar number of ethylene oxide addition, and the value of the addition mole number is represented by x+y+z+l+m+n, for example, when ethylene oxide is added to the molar number. At 5 o'clock, it is HCO5.

Since HCO is not a food additive and is a pharmaceutical additive, it is safe as a surfactant used for a w/o/w emulsion to be administered to a patient. Further, the addition molar number of the HCO is more than 0 and less than 10, and is preferably 1 or more and 9 or less from the viewpoint that the reaction product is not excessively reacted with HCO. Thus, by using an HCO having a low molar number of ethylene oxide added as an oily surfactant, the heterogeneous change of the molecular three-dimensional structure due to the difference in the addition position and polymerization degree of ethylene oxide is used. It is possible to produce a stable monodisperse w/o/w type emulsion preparation, and it is possible to move the agent between the outer water phase w and the inner water phase w1 through the oil phase o, after being administered to the body, The medicinal component of the inner aqueous phase w1 can be released slowly.

Further, the molar number of addition of ethylene oxide of the preferred HCO is 4 or more and 6 or less. In this range, polyoxyethylene hardened castor oil can be obtained by approximating the addition of a plurality of positions at which ethylene oxide can be added or by adding a surfactant at a fixed position. And can make a more stable monodisperse w/o/w emulsion preparation, and is being cast After being administered to the body, the medicinal component of the internal aqueous phase w1 can be released.

The surfactant added to the oil phase o can be appropriately changed depending on the oil phase o to be used, and the monodisperse w/o which can sufficiently coat the w particles and the w/o particles for a long period of time can be formed as an oily surfactant. From the viewpoint of the /w type emulsion preparation, it is preferred to contain 0.1 to 20% by weight of the oil phase o.

The external aqueous phase w is not particularly limited, and may be appropriately selected depending on the application, and may be distilled water for injection, nutrient, physiological saline or glucose injection.

The osmotic pressure adjusting agent to be added to the inner aqueous phase w1 and the outer aqueous phase w may be pharmacologically acceptable, and the w/o/w type emulsion may be stably maintained, for example, salt: Glucose, sugars such as lactose and sucrose, glycerin, etc.

The surfactant added to the external aqueous phase w is not only when the w/o particles dispersed in the external aqueous phase w are left for a long time, but when the w/o/w emulsion is used for use, it is immediately administered. It can also be used as needed. The surfactant is not particularly limited as a pharmaceutical emulsifier, and is not particularly limited as long as it is pharmacologically acceptable. For example, polyoxyethylene sorbitol surfactants and polycondensation agents are exemplified. Oxyethylene-hardened castor oil-based surfactant, lecithin, poloxamer-based surfactant, and the like.

The diameter of the w/o particles of the w/o/w type emulsion preparation is from 1 μm to 400 μm. Within this range, the w/o particles easily pass through the blood vessel, and can be made to have a size that can sufficiently release the medicinal ingredient. In addition, the diameter of the w/o particle is preferably 30 μm to 300 μm from the viewpoint of requiring a certain degree of size so as not to flow back due to the backflow, and it is preferable from the viewpoint of smooth passage. It is preferably in the range of 30 μm to 80 μm, and can smoothly pass through the blood vessel and easily reach the affected part.

(2) Ideal w/o/w emulsion preparation

In the case of describing an ideal w/o/w type emulsion preparation, when a pharmaceutical product having pharmacological effects at a main therapeutic target is used in the internal aqueous phase w1, it is desirable to have a mechanism in which it is dispersed. In the w/o particles of the outer aqueous phase w, the inner aqueous phase w1 enclosed in the particles at a high concentration is administered to the target site after the preparation is administered, and the inner aqueous phase w1 is first permeated through the oil phase o. It works for the diseased area. In this case, it is expected that the therapeutic effect of the sustained release property of the internal aqueous phase w1 can be utilized. On the other hand, in the case of producing a w/o/w type emulsion, the ideal in-line water phase w1 does not bleed out to the outer water phase w side.

The movement of the solution of the inner aqueous phase w1 and the outer aqueous phase w easily passes through the formulation of the oil phase o, which is largely due to the oily surfactant contained in the oil phase o, in order to make the w/o/w emulsion as described above. The pharmacodynamic mechanism of the formulation acts and requires the inclusion of a specific oily surfactant in the oil phase o.

Furthermore, after the preparation of the w/o/w type emulsion preparation and the administration of the patient, the internal water phase w1 which is expected to have pharmacodynamic effect will ooze out to the outer water phase w side, especially when it is used. When it is regarded as a blood vessel equivalent to the osmotic pressure of physiological saline, the ideal state is that the movement of the solution of the aqueous phase w1 and the outer aqueous phase w in the w/o/w type emulsion ends, and the inner water phase w1 and the outer phase The aqueous phase w becomes an osmotic pressure whose osmotic pressure balance is lower than that of physiological saline.

This means that if the osmotic pressure of the aqueous phase w1 and the external aqueous phase w in the w/o/w emulsion is made lower than the osmotic pressure of the physiological saline solution. In the state of physiological saline (for example, in blood), the external aqueous phase w of the w/o/w type emulsion is diluted by systemic blood flow after administration, and w/o particles become present in In the blood, or in the tissue, the inner water phase w1 of the w/o particles is easy to move to the outer phase side, that is, it is easy to release.

As above, it is desirable that the osmotic pressure of the aqueous phase w1 in the w/o/w type emulsion (before emulsification) is higher than the osmotic pressure of the outer aqueous phase w when it is used, when the w/o/w type emulsion is administered ( After emulsification, the osmotic pressure of the inner aqueous phase w1 and the outer aqueous phase w is slightly balanced and is less than 1 times the osmotic pressure of the physiological saline. By doing so, the solution of the outer aqueous phase w having a low osmotic pressure is transferred to the inner aqueous phase w1 through the oil phase o, and the w1 particles are expanded to increase the capacity of the aqueous solution containing the drug, so that the release can be released into the blood vessel. The sustained release time of the aqueous phase w1 is increased by the w/o/w emulsion preparation. Further, the w/o/w type emulsion preparation which is released into the blood vessel is changed into blood by the external water phase w, and the solution of the inner water phase w1 having a low osmotic pressure is gradually passed through the oil phase o to the blood. The (outer phase) transfer can efficiently release the aqueous solution containing the drug in the inner aqueous phase w1.

(3) Appliances used in the manufacture of w/o/w emulsions

As shown in Fig. 2 (a), the device used for the production of the w/o/w emulsion is a medical three-way stopcock 4; a concave-concave emulsification device 5 equipped with a porous body; and a convex body on which a porous body is mounted - A concave emulsifying device 6; and injection syringes 1, 2, and 3. The three-way stopcock 4 is composed of a three-way stopcock connector 4a, three-way stopcock connectors 4b, 4c, and a cock 4d. The concave-concave emulsifying device 5 on which the porous body is mounted is provided with the porous body s1 at the center of the embedding device female connectors 5a and 5a, and the emulsifying device female connectors 5a and 5a can be connected to the injection syringes 1, 2. 3 and three-way stopcock male connector 4a. The convex-concave emulsifying device 6 on which the porous body is mounted is provided with the porous body s2 at the center of the emulsifying device female connector 6a and the emulsifying device male connector 6b, and the emulsifying device female connector 6a can be connected to the injection syringes 1, 2 3, the emulsifying device male connector 6b is connectable to the three-way stopcock female connectors 4b, 4c. The injection syringes 1, 2, and 3 can accommodate a liquid having a capacity of 10 cc and can be connected to the three-way stopcock recessed connectors 4b, 4c, the emulsifying device female connector 5a or the emulsifying device female connector 6a.

The state in which the three-way stopcock 4, the concave-concave emulsification device 5 on which the porous body is mounted, the convex-concave emulsification device 6 on which the porous body is mounted, and the injection syringes 1, 2, and 3 are respectively connected is shown in Fig. 2(b). In this connected state, the plungers P1, P2, and P3 of the syringes 1, 2, and 3 for injection (hereinafter referred to as "pumping") are pulled and pulled by the three-way stopcock 4 The cock 4d and one of the three flow paths of the three-way stopcock 4 are stopped, and the liquid becomes able to reciprocate in the remaining two flow paths and the flow path in the injection syringe. In addition, the porous body s1 of the concave-concave emulsification device 5 in which the porous body is mounted and the porous body s2 of the convex-concave emulsification device 6 in which the porous body is mounted are accommodated by the liquid in the injection syringes 1, 2, and 3 The emulsions of the injection syringes of different phases are emulsified to produce the emulsion immediately.

The porous bodies s1 and s2 are designed such that the conductive tubes having the same diameter and the same diameter are bundled, or a plurality of conductive tubes formed by the three-dimensional entangled structure are formed as in the case of the SPG porous body; For example, glass, ceramics, metal, wood, resin, etc. are mentioned, and the molded body may be a sintered body, a porous film by a glass phase separation method, or the like.

In the so-called porous glass film formed by the glass phase separation method, as the phase-separated porous glass body, there is a well-known porous material composed of Na ₂ OB ₂ O ₃ —SiO ₂ as a base glass and composed of a skeleton SiO 2 . Glass, a porous glass composed of Na ₂ OB ₂ O ₃ -SiO ₂ -GeO ₂ as a base glass and having a skeleton of SiO ₂ -GeO _{2 ,} composed of CaO-B ₂ O ₃ -TiO ₂ -SiO ₂ -based glass And a porous glass composed of a skeleton TiO ₂ -SiO ₂ , a porous glass composed of Na ₂ OB ₂ O ₃ -ZrO ₂ -SiO ₂ as a base glass and having a skeleton ZrO ₂ -SiO ₂ , and CaO-B ₂ O ₃ -Al ₂ O ₃ -SiO ₂ is a porous glass having a basic glass composition and having a skeleton of Al ₂ O ₃ -SiO ₂ , but preferably CaO-B ₂ O ₃ -SiO ₂ -Al ₂ O ₃ Porous glass, CaO-B ₂ O ₃ -SiO ₂ -Al ₂ O ₃ -Na ₂ O based porous glass and CaO-B ₂ O ₃ -SiO ₂ -Al ₂ O ₃ -Na ₂ O-MgO system The porous glass or the like is suitably molded in accordance with the shape of the connecting tube.

Among these porous glasses, it is particularly preferable to use a value obtained by dividing the pore diameter when the pore volume accounts for 10% of the total pore volume by the pore diameter when the pore volume accounts for 90% of the total in the relative cumulative pore distribution curve. A microporous membrane that is substantially in the range of 1 to 1.5. Such a film, which is particularly uniform in pores, is suitable for film emulsification. In the porous glass film suitable for film emulsification, there is a Shirasu Porous Glass (hereinafter referred to as "SPG") film, and it is preferable to use it. In the manufacture of the w/o/w type emulsion preparation, based on the porous bodies s1 and s2 of the SPG film, the size of the opening and the distance adjacent to the openings are adjusted so as to pass through the porous bodies s1 and s2, respectively. The particles produced in the continuous phase do not dry out each other, and the particles emitted from the openings are not aligned with each other, and can be dispersed in the continuous phase. Furthermore, since the pore diameter of the porous body is made 5 μm or more, the solute is emulsified during pumping emulsification. The trapping does not cause clogging in the porous body, and the liquid can smoothly pass through and can be easily emulsified by manual operation.

(4) Preparation for w/o/w emulsion manufacturing

The preparation for the manufacture of the w/o/w type emulsion will be described using FIG. 3. First, each of the injection syringes 1, 2, and 3 to be connected to the three-way stopcock 4 houses an inner water phase w1, an oil phase o, and an outer water phase w (not shown). Next, as shown in (a), the three-way stopcock concave connector 4c is coupled to the injection syringe 3 through the convex-concave emulsification device 6 on which the porous body is mounted. The cock 4d of the three-way stopcock 4 is switched to the side of the three-way stopcock 4a, and the plunger P3 is pressed in the direction of the arrow to press the outer water phase w in the injection syringe 3, and the porous body s2 is wetted by the outer water phase w. At least the degassing of the flow path in the three-way stopcock connector 4c of the secondary emulsification flow path bc is completed. In addition, the secondary emulsification flow path bc is a flow path in the three-way stopcock connector 4b, a flow path in the three-way stopcock connector 4c, and a flow in the convex-concave emulsification device 6 in which the porous body is mounted. Road composition.

Next, as shown in (b), the cock 4d is switched to the side of the three-way stopcock 4c, and the injection syringe 2 in which the oil phase o is accommodated is connected to the three-way stopcock through the concave-concave emulsification device 5 on which the porous body is mounted. The device 4a is connected. The plunger P2 is pressed in the direction of the arrow to press the oil phase o in the injection syringe 2, and the porous body s1 is wetted by the oil phase o, and the degassing of the primary emulsification channel a-b is completed and the oil phase o is filled. In addition, the primary emulsification flow path ab is a flow path in the three-way stopcock connector 4a, a flow path in the three-way stopcock connector 4b, and a flow path in the concave-concave emulsification device 5 on which the porous body is mounted. Composition.

Finally, as shown in (c), the injection syringe 1 in which the internal water phase w1 is accommodated is coupled to the three-way stopcock concave connector 4b. Here, when the w/o/w type emulsion is produced, when the porous bodies s1 and s2 are used, since the surface properties of the porous body are greatly affected, the very important porous body s1 is made hydrophobic and porous. The body s2 is made hydrophilic. For example, in order to produce a w/o emulsion, if the porous body is hydrophilic, there is a possibility that the emulsion phase is transformed to become an o/w emulsion and the defects are caused. On the other hand, in order to manufacture an o/w emulsion, if the porous body is hydrophobic, there is a possibility that the emulsion phase transformation becomes a w/o emulsion and the failure is caused. As a result, the original w/o/w emulsion was not formed at all. Further, by making the porous body s1 hydrophobic, the porous body s2 is made hydrophilic, and the liquid and the porous body of the porous body repel each other, and the liquid is easily formed into a spherical state in the porous body, and the particles can be emitted in an unconformable manner. The particles are dispersed in the continuous phase separately. In addition, for example, even if the porous body s1 is hydrophilic, in order to produce a w/o emulsion, the porous body s1 can be conditioned by the oil phase o which is a continuous phase, and the porous body s1 can be made hydrophobic from hydrophilicity. Sexuality, which is important in either case, first harmonizes the porous bodies with a continuous phase prior to emulsification.

Further, by filling the flow path in the three-way stopcock 4 with the liquid in the injection syringe by the above-described procedure, air is not mixed in the produced emulsion. Further, each of the porous bodies s1 and s2 in the flow path is previously wetted by the continuous phase of the produced emulsion, and the desired phase w/o/w emulsion can be reliably produced by preventing the emulsion phase transition.

(5) Method for producing w/o/w type emulsion

Next, using FIG. 4 to describe the manufacturing method of the w/o/w type emulsion Bright. First, in the state in which the cock 4d of the three-way stopcock 4 is switched to the injection syringe 3 side, the plunger P2 is pressed to store the inner water phase w1 and the oil phase o in the injection syringe 1 in the state of (a). At this time, by oscillating the injection syringe 1, the internal water phase w1 and the oil phase o are roughly mixed beforehand, and then the plungers P1 and P2 of the injection syringes 1 and 2 are alternately reciprocated. The first emulsification flow path a-b of the liquid flow arrow is emulsified by pumping through the porous body s1 (hereinafter referred to as "pumping emulsification") to produce a w/o type emulsion wo of a primary emulsion. In order to obtain the target primary emulsion, the number of pumping times can be appropriately adjusted, for example, by passing the porous body s1 about 10 times to 30 times (the so-called "one pass" system is called to pass through the flow path once. ) The desired primary emulsion can be produced. Further, the manufactured w/o type emulsion was first stored in the injection syringe 1.

Then, in the state in which the cock 4d of the three-way stopcock 4 is switched to the injection syringe 2 side as in (b), the plunger P3 is pressed to store the w/o type emulsion wo and the outer aqueous phase w in the injection syringe 1 Inside. At this time, the w/o type emulsion wo is roughly mixed with the outer water phase w by the oscillation injection syringe 1, and the plungers P1 and P3 of the injection syringes 1, 3 are alternately reciprocated. The secondary emulsification flow path b-c of the liquid flow arrow is pumped and emulsified through the porous body s2 to produce a w/o/w type emulsion wow of the secondary emulsion. In order to obtain the target secondary emulsion, the number of pumping times can be appropriately adjusted. For example, the desired secondary emulsion can be produced by passing the porous body s2 about 3 times to 5 times. When the emulsion is produced by using the three-way stopcock 4, the porous bodies s1 and s2 can be used to efficiently form the primary emulsion once by using the porous bodies s1 and s2 having a plurality of through holes. And secondary emulsion. Further, since the three-way stopcock 4 and the injection syringes 1, 2, and 3 are used, it is possible to adjust the use of the emulsion in the hand, and it is sterilized aseptically immediately before being administered to the patient, and thereafter the storage unit may be used. The syringe for injection of the obtained emulsion was attached to the catheter as it was, and it was immediately administered.

Further, the pumping emulsification method in one emulsification and second emulsification is an emulsification method in which a permeable membrane emulsification method is carried out by repeatedly mixing a dispersed phase and a continuous phase in advance, and permeating the porous body s1. S2 The dispersed phase droplets which have been coarsely dispersed in the continuous phase are granulated, and by performing this pumping a plurality of times, the emulsion of the target particle diameter can be produced.

In addition, in the method of manufacturing the w/o/w type emulsion wow without using the three-way stopcock 4, it is conceivable to use an injection in which a concave-concave emulsification apparatus 5 (porous body is hydrophobic) in which a porous body is mounted is used. The w/o type emulsion wo, which is a primary emulsion, is produced by the syringe 1 and the injection syringe 2, and is stored in the injection syringe 1, and then the injection syringe 1 is removed from the concave-concave emulsification device 5 on which the porous body is mounted, and The injection syringe 1 is an injection syringe 3 in which a concave-concave emulsification device 5 (a porous body is hydrophilic) in which another porous body is placed, and a w/o/w emulsion wow which is a secondary emulsion is produced. . When the w/o/w type emulsion is produced by using the three-way stopcock 4 as described above, the concave-concave emulsification device 5 to which the porous body is attached and the three-way stopcock 4 in which the convex-concave emulsification device 6 of the porous body is mounted are prepared in advance. The w/o/w type emulsion manufacturer can sequentially connect all of the injection syringes 1, 2, and 3 to be used to the three-way stopcock 4, so that the injection syringes 1 and 3 can be easily attached or detached from the three-way stopcock 4, and the preparation is easy. Pumping emulsification.

(6) Surfactant for oil phase used in w/o/w type emulsion Evaluation

Next, in the oil phase of the w/o/w type emulsion preparation of the present invention, No. 3, 4, 5, 7, 8 which is regarded as a pharmaceutical additive in the surfactant shown in Table 1 was used. 9, the stability and monodispersity of the w/o/w emulsion were evaluated.

No. 1 to 8 in Table 1 show a list of oil-based surfactants, and HCO 40 of No. 9 is recommended as an oil-based surfactant of w/o/w type emulsion described in Patent Document 1, but HCO 40 is water-soluble. Sexuality, and the HLB value showing hydrophilic hydrophobicity is also clear. The HLB value is a value indicating the degree of affinity of the surfactant to water and oil (water-insoluble organic compound), and the HLB value is about 9 or less. Generally, it can be used for emulsification of a w/o emulsion, and the HLB value is higher. Near 0, the lipophilicity becomes higher.

(Experimental Example 1) Evaluation of Stability of Primary Emulsification of Pharmaceutical Additive Oily Surfactant

In order to use No. 4, 5, 7, and 8 of Table 1 as the oil phase of the w/o/w type emulsion, the emulsion stability was first confirmed by the primary emulsified w/o type emulsion. The emulsified content is 3 ml of a 20% lactose aqueous solution in the internal aqueous phase, and the iodine poppy oil fatty acid ethyl ester (medicinal name "Iodized oil": Guerbet Japan) is used as a pharmaceutical oily contrast agent. 5 ml of the iodized oil") was used for the oil phase oil and fat, and 0.5 ml of 10 wt% was added to the surfactant with respect to 5 ml of the above-mentioned fats and oils. The emulsification method was easily evaluated by stirring at 900 rpm and stirring for 3 minutes. As a result, as shown in the photograph of Fig. 5, it can be seen that the w/o type emulsion is uniformly obtained after the emulsification of (a), but as shown in (b) after standing for 3 days, It was also confirmed by visual observation that No. 4 (SL-10), No. 5 (SO-10V), and No. 8 (HCO10) were separated as two layers, and the emulsion stability was poor. With respect to these, No. 7 (HCO5) obtained a w/o type emulsion in which separation layer stability did not occur after 3 days, and it was easily confirmed under the microscope that fine w particles of 1 to 3 μm were obtained. Thus, it is understood that even if the oily surfactant of the pharmaceutical additive is excellent in the stability of the primary emulsified w/o emulsion which is important for the formation of the w/o/w emulsion, even the same polyoxyethylene hardened castor oil system HCO10 has no stability, while HCO5 has. Also, it is confirmed that HCO10 will be separated by 2 layers, and for HCO20 and HCO30. In addition, it was confirmed that it was separated into two layers in the same manner as HCO10. In the case of primary emulsified w/o emulsion formation, HCO20 and HCO30 can be said to have the same properties as HCO10.

Further, even if the HLB value is less than 6.0 of HCO5 and the hydrophobicity is high, the HLB value of 4.3 is SO-10V. From the experimental results, it is understood that the emulsification of the primary emulsified w/o type emulsion of the w/o/w type emulsion is Not suitable. That is, the emulsion stability of the w/o type emulsion could not be judged only by the HLB value. Although the SO15MV of No. 3 is also small in HLB value and high in hydrophobicity, it is not suitable at all in the emulsification of the w/o type emulsion which forms the w/o/w type emulsion of the present invention.

(Experimental Example 2) Evaluation of w/o/w type emulsion formation by addition of polyoxyethylene hardened castor oil system

In order to produce a w/o/w type emulsion preparation, for the iodized oil in the oil phase, No. 7, 8, and 9 of Table 1 are used as the polyoxyethylene hardened castor oil type HCO5, HCO10, HCO40, and Polyglycerin condensed ricinoleic acid ester (trade name "CR-310" for the oily surfactant which exhibits excellent stability and monodispersity in the w/o/w type emulsion described in Patent Document 1. "The monodispersity of the Sakamoto Pharmaceutical Industry Co., Ltd., hereinafter referred to as "PGCR" only) was evaluated by comparative experiment. The results are shown in Experimental Example 2, Comparative Example 21, Comparative Example 22, and Comparative Example 23 of Table 2, respectively.

For the emulsification method for producing a w/o/w type emulsion, the emulsification method using a porous glass film (Japanese Patent Laid-Open No. Hei 2-95433), which is exemplified in Patent Document 1, is a once-emulsified w/o. The type emulsion slowly takes time to pass through the porous glass film to be dispersed in the aqueous phase which is dispersed into the outer aqueous phase. The method of producing a w/o/w type emulsion was carried out by using a so-called direct film emulsification method as a possible SPG filter kit (manufactured by SPG Technology Co., Ltd.) of 20 μm hydrophilicity. In the SPG direct film emulsification method, a particle diameter of about 3 to 5 times the pore diameter is produced, and in this case, monodisperse particles having a main system of about 60 μm to 100 μm are obtained in the w/o particle diameter. The micrograph and particle size distribution of the separately produced w/o/w type emulsion particles are shown in Fig. 6. The internal aqueous phase is a 20% aqueous solution of lactose in the aqueous phase of the above experimental example, and contains only an aqueous solution of an anticancer agent, epirubicin hydrochloride (trade name "Farmorubicin for injection": Pfizer (stock), the following , is only called "Farmorubicin aqueous solution"). The external aqueous phase was added with 0.4% NaCl as an osmotic pressure adjusting agent and 0.7% HCO60 (manufactured by Daylight Chemicals Co., Ltd.) as an aqueous solution of a surfactant. A 20% aqueous solution of lactose, approximately equivalent to the osmotic pressure of 1.8% NaCl.

For this result, w/o/w type emulsions of HCO5, HCO40, and PGCR were used. As can be seen from Table 2 and Fig. 6, the distribution amount was accumulated from the particle diameter to be 50. The particle diameter of the relative particle amount is 50% D. For the w/o/w type emulsion using HCO5, HCO40, and PGCR, the 50% D system can obtain about 89 μm, 82 μm, 86 μm, and single. Dispersion of the target particle diameter emulsion, but using 50% D of the particle size distribution of the HCO10 w/o/w type emulsion, about 43 μm, the result of the direct SPG direct film emulsification method cannot be obtained, further at 10% The D is about 16 μm, and the distribution also extends to the vicinity of the fine particles of 10 μm and tends to be polydisperse. That is, it can be said that HCO10 is not suitable for forming a w/o/w type emulsion.

Moreover, this w/o/w type emulsion preparation is also used as a target for injection preparation, especially in the case of vascular injection, from the viewpoint of DDS therapy, it cannot be used for the target particle diameter. The so-called polydispersity in which the particle diameter distribution is wide, especially in the case of extremely fine particles, it is possible to cause the vascularization of the blood vessels other than the blood vessel to be targeted, and cause clogging of the microvascular or peripheral blood vessels. The possibility of exposing the body to a dangerous state due to incomplete blood flow. For example, in the w/o/w type emulsion preparation which is injected into the hepatic artery for the treatment of hepatocellular carcinoma, it is considered to have an ideal particle diameter distribution of 30 μm or more, and in order to obtain the target particle diameter by the SPG direct membrane emulsification method, From the particle size distribution of the w/o/w type emulsion with HCO10 and the cumulative map of Fig. 6(b), the particle diameter is 30% or less, which is as much as about 30%. It can be said that HCO10 is injected into the liver for the treatment of hepatocellular carcinoma. The w/o/w emulsion of the artery is not suitable.

On the other hand, from the w/o/w type emulsion particle size distribution using other HCO5, HCO40, and PGCR, and the cumulative diagram of FIG. 6, it is understood that the particle diameter is 30 μm or less with respect to the target particle diameter, and it is possible to use SPG. The direct film emulsification method produces a target particle diameter of 60 to 100 μm in a single dispersion, and can be used safely.

From the above, in the pharmaceutical w/o/w emulsion preparation, the surfactant contained in the oil phase is an oily interface of the polyoxyethylene hardened castor oil which is a pharmaceutical additive. The active agent, HCO10, becomes unsuitable for stability and monodispersity.

(Experimental Example 3) Evaluation of the pharmacodynamic mechanism of w/o/w emulsion

Then, if the pharmacodynamic mechanism is explained, the inner seal is sealed at a high concentration. A w/o/w type emulsion preparation having a medicinal internal aqueous phase, in order to achieve high accuracy at a target site, as described above, an ideal system: in the case of emulsion production, the internal water phase does not Exuding to the outer aqueous phase side, and in the case of administration, for example, in the blood or in the affected tissue, the internal aqueous phase of the w/o particles is exuded toward the outer phase side, that is, it must be w/ The movement of the solution of the aqueous phase and the external aqueous phase within the o/w emulsion formulation is an oily surfactant that occurs significantly. In short, if the w/o particle diameter is enlarged from the manufacture of the w/o/w emulsion or from the time of manufacture until the imminent administration, the inner aqueous phase can be swollen by absorbing the solution of the outer aqueous phase. For this reason, the movement of the solution of the inner water phase and the outer water phase can occur on both sides, and it can be said that it is the above-mentioned ideal w/o/w type emulsion.

Then, the w/o/w type emulsion produced in the above Experimental Example 2, Comparative Example 22, and Comparative Example 23 was followed-up, and the change in the w/o particle diameter (50% D: medium diameter) was respectively Table 3 is shown in Experimental Example 3, Comparative Example 32, and Comparative Example 33. As a result, it is clear that there is almost no expansion of w/o particles relative to the w/o/w type emulsion when HCO40 is used, and w/o/w type emulsion when HCO5 (or PGCR) is used. The w/o particles, which significantly show the tendency to expand, are oily surfactants that are prone to the movement of the solution of the inner and outer aqueous phases.

In fact, if the w/o/w emulsion is first placed in a vial, the w/o/w emulsion caused by HCO40 has fluidity for a long time and the w/o particle system is dispersed. In the state of the outer aqueous phase, the w/o/w type emulsion caused by HCO5 (or PGCR) exhibits emulsion viscosity from the second day or so, and the fluidity is deteriorated. This is due to the w/o particle size on the day of manufacture. When it is swelled, the closest filling ratio of the w/o particles to the total volume of the w/o/w type emulsion becomes 74% by volume or more, and the viscosity of the entire emulsion becomes high.

Here, as shown in Table 2, if the internal water phase and the external water phase are first made to have a predetermined osmotic pressure and respective capacities, the inner water phase and the outer water phase occur after the w/o/w type emulsion is produced. The solution moves, the osmotic pressure of both sides becomes the osmotic pressure in the equilibrium state, and the osmotic pressure of the aqueous phase in the system is equivalent to 1.8% NaCl system 3 ml and external water phase osmotic pressure 0.4% NaCl system 7.5 ml, so the following formula is used. When it is derived, it is equivalent to 0.8% NaCl, and it can be made to be lower than the osmotic pressure of 0.9% NaCl equivalent to physiological saline or blood.

(1.8% NaCl × 3ml + 0.4% NaCl × 7.5ml) / (3ml + 7.5ml) = equivalent 0.8% NaCl

Thus, when the w/o particle of the w/o/w type emulsion is expanded when HCO5 (or PGCR) is used, the solution of the inner aqueous phase and the outer aqueous phase moves due to the osmotic pressure difference, that is, In this case, due to the solution of the external aqueous phase It is absorbed to the inner water phase side to expand the w/o particles, and if the HCO5 is used for the oil phase surfactant, the main medicinal inner water phase will not be formed in the emulsion production. It is easy to move to the outer water phase side, that is, it will not leak, and in the blood or in the affected tissue after administration, the formulation design of the medicinal inner water phase can be used. The capacity of each phase and the osmotic pressure are adjusted to be freely controlled.

In contrast, when the w/o/w type emulsion preparation using HCO40 is used, as in the case of the experimental example, even if the formulation makes the osmotic pressure of the inner water phase higher than the osmotic pressure of the outer water phase, w/o particles It is not as good as the use of HCO5. It is difficult to cause the movement of the solution of the inner and outer water phases. Even if the internal phase of the medicinal water is not oozing out of the water phase, it is lucky. There is also a condition in which the inner water phase does not ooze out to the outer phase in the blood or in the affected tissue, and it becomes impossible to expect the effect to be effective.

That is, the surfactant which can induce the pharmacodynamic mechanism of the w/o/w type emulsion preparation produced by monodisperse is a pharmaceutical additive, and further, in the polyoxyethylene hardened castor oil system, the addition of ethylene oxide is not The number of ears is 5, HCO5. This is because, by using HCO having a low molar number of ethylene oxide added to HCO, the heterogeneity of the molecular three-dimensional structure due to the difference in the addition position and polymerization degree of ethylene oxide is small. A stable monodisperse w/o/w emulsion formulation can be prepared. This mechanism can be considered to be due to the fact that, as already explained in the general chemical formula of the aforementioned HCO, the value of the addition mole number of HCO is represented by x+y+z+l+m+n, combined The HCO system of any of the six addition positions may be added evenly, or may be added at a fixed position to form a polyoxyethylene hardened castor oil having the same three-dimensional structure or an approximate structure. By By using a surfactant having such a structure, the hydrophilic groups of the surfactant in the oil phase adsorb each other to form a lamella structure, which can effectively serve as the outer water phase and the inner layer. The movement of the aqueous solution of the aqueous phase acts as a possible pathway.

(Experimental Example 4) Evaluation of the formation of w/o/w emulsion by the tripartite method

The above experimental example is also a static direct membrane emulsification method in the SPG membrane emulsification, that is, a surfactant for the oil phase is carried out by injecting the dispersed phase w/o emulsion into the continuous phase side through the SPG membrane. evaluation of. On the other hand, in the experimental example, the method of using the three-way stopcock shown in FIG. 2 to FIG. 4 (hereinafter referred to as "three-way stopcock method") is used as follows: In order to emulsify the SPG film, it is also a dynamic permeable membrane emulsification method, which is a so-called pre-coarse mixed dispersion phase and a continuous phase, and the dispersed phase which is coarsely dispersed in the continuous phase is droplets, and then granulated through the SPG film. Method (for the experimental example, the aforementioned pumping emulsification method). In the experimental example, the SPG film for primary emulsification of the emulsification device 5 is 50 μm hydrophobic, and the SPG film for secondary emulsification mounted on the emulsification device 6 is 100 μm hydrophilic each SPG film porous body. The evaluation of the oil phase surfactant for forming the w/o/w type emulsion obtained by the three-way stopcock method according to the present invention was carried out.

First, in order to manufacture the w/o/w type emulsion according to the present invention, the polyoxyethylene hardened castor oil type HCO5 which is No. 7, 8, and 9 of Table 1 was used for the iodized oil in the oil phase. HCO10 and HCO40 exhibit excellent stability and stability in order to form a w/o/w emulsion as described in the above Patent Document 1. The monodispersity of the PGCR of the monodisperse oily surfactant was evaluated by comparative experiments. Experimental Example 4, Comparative Example 41, Comparative Example 42, and Comparative Example 43 of Table 4 are shown.

In this experimental example, the three internal water phases w1, the oil phase o, and the outer water phase w shown in Fig. 2 were respectively filled in a 10 cc injection syringe so as to pass through the one shown in Fig. 4(a). The number of pumping of the emulsification flow path ab was 30, and the number of pumping by the secondary emulsification flow path bc shown in FIG. 4(b) was three times. Further, especially in the case of secondary emulsification, it is needless to say that the w/o particle diameter of the target w/o/w type emulsion can be controlled by the number of pumping times.

As a result, as in Comparative Example 41 of Table 4, here, in HCO10, monodispersity was not obtained at all, and the polydispersity particle size distribution of the two peaks was obtained. Further, in the case of the three-way stopcock method according to the present invention, the HCO10 system is not suitable for the w/o/w type emulsion formation as in the comparative example 21 described above. Further, in the HCO 40 of Comparative Example 42 of Table 4, the monodispersity of the w/o/w type emulsion as described in Patent Document 1 was not obtained, and the polydispersity particle size distribution of the two peaks was obtained, and fine particles were remarkably present. In the case of the three-way stopcock method of the present invention, HCO40 also becomes an unsuitable result; in the polyoxyethylene hardened castor oil system, HCO5 is the most suitable result for the w/o/w type emulsion formation system.

This is because HCO10, HCO20, HCO30, and HCO40 cannot be uniformly refined in the production of the once-emulsified w/o emulsion, and the dispersibility of the w1 particles is poor and cohesively visible, and is encapsulated in the second emulsion. In the case of the step in the drop, it becomes a biased encapsulation behavior, which makes it more difficult to form a w/o/w type emulsion.

In contrast, the w/o/w type emulsion obtained by HCO5, firstly in the case of the w/o type emulsion obtained by one emulsification, can make the inner aqueous phase droplets in the oil phase to be formed under the microscope. In the state of the uniform particle diameter and the dispersibility of about 1 to 3 μm, the emulsification stability which was carried out in the above-mentioned Experimental Example 1 was also confirmed, and it became so that it became uniform in the following secondary emulsification. The ground is enclosed in oil droplets, which is related to the formation of a stable w/o/w emulsion. In addition, by using HCO having a low molar number of ethylene oxide added to HCO, the heterogeneity of the molecular three-dimensional structure due to the difference in the addition position and polymerization degree of ethylene oxide can be reduced. A stable monodisperse w/o/w emulsion formulation. The addition mole number of ethylene oxide greatly affects the stability and monodispersity of the prepared w/o/w emulsion preparation. It is also compatible with HCO10 and HCO20 in the polyoxyethylene hardened castor oil system. , HCO30, HCO40, etc., more than 10 addition moles, when a single digit, that is, 1 or more and 9 or less ethylene oxide addition moles, in the manufacture of w / o / w type emulsion Said to be the ideal surfactant. This is considered to have been described in the general chemical formula of the aforementioned HCO: the value of the addition of the molar number of HCO is represented by x+y+z+l+m+n, and is combined to 6 additions. The HCO system of any of the positions may be added evenly or added to a fixed position to form a polyoxyethylene hardened castor oil having the same three-dimensional structure or an approximate structure. By using a surfactant having such a stable structure, the surfactant can effectively function at the interface between the oil phase and the internal water phase or the interface between the oil layer and the external water phase.

(Experimental Example 5) Evaluation of HCO5 1

Following the previous experimental example, the evaluation of the formulation of the internal water phase was carried out. The results of the price are shown in Table 5. When the internal aqueous phase is made into a 20% aqueous solution of lactose, HCO5 and PGCR can be used without problems in the formation of the w/o/w emulsion, and a stable monodisperse w/o/w emulsion can be obtained. On the other hand, in the same manner as the HCO 40 of the above-mentioned Comparative Example 42, the HCO 10 and the HCO 40 had a two-peak polydisperse particle size distribution, which was a result of being unsuitable as a surfactant added to the oil phase.

(Experimental Example 6) Evaluation of HCO5 2

Further, the evaluation was carried out when a boronic acid (BSH: borocaptate) aqueous solution of a boron compound was used in the internal aqueous phase, and the results are shown in Table 6. Although it was carried out by the static membrane emulsification method of the SPG direct film emulsification method similar to that of Experimental Example 1, even if the polyoxyethylene hardened castor oil system, if the formulation of the internal aqueous phase changes, a large amount of fine particles will be produced. It was confirmed that HCO40 is not suitable as a surfactant added to the oil phase. In contrast, HCO5 will achieve the ideal stable monodisperse w/o/w emulsion.

The embodiments of the present invention have been described above with reference to the drawings, but the specific configuration is not limited to the embodiments, and modifications and additions are also included in the present invention without departing from the scope of the invention.

For example, in the foregoing examples, the experimental examples in which the surfactant is used alone using only HCO5 are shown, but HCO5 and other surfactants may be mixed and used.

For example, in the foregoing embodiment, it is directed to the use of a three-way stopcock A method of producing a w/o/w type emulsion by regulating three flow paths is shown, but it is also possible to use a multi-linker or the like to manufacture a w/o/w type emulsion.

For example, in the above-described embodiment, the concave-concave emulsification device 5 that can be connected to the injection syringe 2 and the end portion of the flow path a and the injection syringe 2 are used to pass the porous body, but it is also possible to pass through the porous body. The porous body is mounted in the three-way stopcock male connector 4a, and the injection syringe 2 is directly connected to the three-way stopcock male connector 4a, and the porous body is also mounted in the three-way stopcock concave connector 4c, and the injection is performed. The syringe 3 is directly connected to the three-way stopcock female connector 4c.

O‧‧‧oil phase (oily contrast agent)

W1‧‧‧ internal aqueous phase (anticancer agent aqueous solution)

w‧‧‧Outer water phase

Claims (10)

An emulsified preparation for medicine, which is a w/o/w type emulsion preparation, characterized in that the aqueous phase in the w/o/w type emulsion preparation is an aqueous solution containing a medicament, and w/o oil is dispersed in the outer aqueous phase. Dropping, the w/o oil droplet is obtained by containing polyoxyethylene hardened castor oil as a surfactant in the oil phase; and the addition molar number of ethylene oxide of the polyoxyethylene hardened castor oil is 1 or more and 9 the following. The pharmaceutical emulsion preparation according to claim 1, wherein the polyoxyethylene hardened castor oil which is the surfactant has an addition molar number of ethylene oxide of 4 or more and 6 or less. The pharmaceutical emulsion preparation according to claim 1 or 2, which comprises 0.1 to 20% by weight of the aforementioned surfactant in the oil phase. The emulsified pharmaceutical preparation according to any one of claims 1 to 3, wherein the osmotic pressure of the inner aqueous phase and the outer aqueous phase is slightly balanced, and is less than 1 times the osmotic pressure of the physiological saline. The pharmaceutical emulsified preparation according to any one of claims 1 to 4, wherein the w/o particles of the w/o/w type emulsion preparation have a diameter of from 1 μm to 400 μm. A method for producing a pharmaceutical emulsion preparation, which is a method for producing a w/o/w emulsion preparation, and characterized in that the aqueous phase in the w/o/w emulsion preparation is an aqueous solution containing a chemical, and is in an external aqueous phase The w/o oil droplet is dispersed in the oil phase, and the polyoxyethylene hardened castor oil is used as the surfactant in the oil phase; the osmotic pressure of the inner aqueous phase is infiltrated by the external water phase when in use. Press on. A method for producing a pharmaceutical emulsion preparation, which is a method for producing a w/o/w type emulsion preparation, and characterized in that the aqueous phase in the w/o/w type emulsion preparation is an aqueous solution containing a medicament, and is in an external water The w/o oil droplet is dispersed in the phase, and the w/o oil droplet is obtained by containing polyoxyethylene hardened castor oil as a surfactant in the oil phase; in the manufacturing method, the emulsion is manufactured as follows: a stopcock for regulating three or more flow paths, wherein a first syringe filled with an oil phase is connected to a flow path a side of the stopcock, and a second syringe filled with an inner water phase is connected to the flow path b side, and the flow is a third syringe filled with an outer aqueous phase is connected to the side of the road c; (1) the oil phase of the first syringe and the second syringe are moved by moving the plungers of the first syringe and the second syringe The inner aqueous phase is recovered into the second syringe by the primary emulsion formed by the flow path a and the flow path b, and (2) the plunger of the second syringe and the third syringe is moved. The first emulsion of the second syringe and the third syringe The outer water phase is a secondary emulsion through the flow path b and the flow path c; and a connector that can connect the end of the flow path a or the flow path a to the first syringe and/or can be connected to the foregoing A porous body may be provided on the flow path c or the connector of the end of the flow path c and the third syringe. The method for producing a pharmaceutical emulsified preparation according to claim 7, wherein the porous system forms a structure in which the size of the openable opening and the distance between the open pores are adjacent to each other, and the particles are not dried. The method for producing a pharmaceutical emulsion preparation according to claim 7 or 8, wherein the porous body is hydrophilic when the continuous phase of the emulsion produced by the porous body is an aqueous phase, and is hydrophobic when it is an oil phase. The method for producing a pharmaceutical emulsified preparation according to any one of claims 7 to 9, wherein before the manufacture of the emulsion, (1) injecting the outer aqueous phase of the third syringe into the flow path c, and intermediating The porous body is previously wetted by the outer aqueous phase, and degassing of the flow path c is performed, (2) the oil phase of the first syringe is injected into the flow path a, and the intermediate porous body is previously used as the oil. The phase is wet, and the flow path a and the flow path b are filled with the oil phase, and (3) the second syringe filled with the internal water phase is connected to the flow path b.