JP2720101B2 - W / O / W composite emulsion for injection and method for producing the same - Google Patents

Description

The present invention relates to a W / O / W composite emulsion and a method for producing the same, and the composite emulsion is suitable as an emulsion for injection, particularly as an emulsion for intravenous injection. It is.

(Prior art and problems) When it is necessary to intensively administer a small amount of a drug such as an anticancer drug or an antibiotic to a specific site, it is known to inject the drug as a fat emulsion.

Specifically, for example, it is known that an anticancer agent or the like is put into oil droplets, and injected intravenously as an O / W emulsion to treat cancer.It is known that such an O / W emulsion is a fat emulsion. In this case, the drug used is mainly oil-soluble, so that a water-soluble drug cannot be used.

Therefore, the present inventors attempted to prepare a W / O / W-type composite emulsion in which a water-soluble or water-dispersible anticancer drug and other drugs were encapsulated in an internal aqueous phase, and use this as an emulsion for injection. (Japanese Unexamined Patent Publication No. 62-93223), which is not yet complete.

(Means for Solving the Problems) The present invention has been made in view of the current state of the art, and is particularly suitable for W / O / E as an emulsion for injection satisfying all of the following requirements. The purpose was to develop a W-type composite emulsion.

(1) Since the W / O emulsion, which is a dispersant for the W / O / W type composite emulsion, has water droplets inside, it has a disadvantage that it is extremely easily broken as compared with the oil droplets of the O / W type emulsion.
If the dispersoid W / O emulsion is destroyed, the oil droplets may collect with other oil droplets to form large oil droplets, blocking narrow veins. If a vein is blocked,
The nutrients will not go any further, and healthy cells will be damaged.

Thus, in the W / O / W type composite emulsion for injection, the W / O emulsion, which is a dispersoid thereof, is easily destroyed, and is not destroyed in blood vessels during storage and use. Sufficient stability is required, and the emulsifier used for the stabilization and the oily substance serving as the oil phase must be safe for the human body.

(2) As described in the previous section, if the oil droplets become large, there is a risk of occluding the veins. Therefore, the particles must be made into sufficiently small particles. In order to allow easy passage, the particle diameter must be 1.0 μm or less, preferably 0.7 μm or less, and the particle diameters must be uniform.

(3) In order to administer the drug more effectively, it is necessary to increase the amount of the drug-containing internal aqueous phase enclosed in the W / O / W composite emulsion as much as possible.

The present invention provides a W / O / W for injection that satisfies all of these requirements.
It was made for the purpose of creating a mold composite emulsion, and was completed as a result of earnest research from various fields.

That is, the present invention uses lecithin as an emulsifier,
Treating the W / O composition prepared by a conventional method with a porous membrane,
By dispersing in the external aqueous phase to which lecithin has been added,
Contains an extremely large amount of internal water phase and is stable and has a particle size of 1.0 μm
This is the first successful production of a W / O / W composite emulsion containing the following stable particles.

 Hereinafter, the present invention will be described in more detail.

In order to carry out the present invention, first, a W / O emulsion is prepared. At this time, basic operations such as emulsification may be performed according to a conventional method. As the oil phase in the present invention, an oily substance such as a fat or oil or a fatty acid which is safe for administration to the human body is selected.

In the present invention, lecithin is used as an emulsifier.
Lecithins of various origins such as egg yolk, soybean, liver and yeast can be widely used, but from an industrial point of view, egg yolk lecithin, soybean lecithin and the like are preferred. In the present invention,
Lecithin is preferably added to the aqueous phase, especially the external aqueous phase, but more favorable results are obtained if it is added to the oil phase.

Therefore, if desired, lecithin in an amount of 1 to 50%, preferably 3 to 35% with respect to the oil is added to the oily substance, and the mixture is sufficiently stirred at 60 ° C or lower, preferably 55 ° C or lower to dissolve. The temperature of the oily substance should be in the range from the temperature at which the oily substance does not solidify to 55 ° C,
When the temperature exceeds 55 ° C., the stability of a commercialized W / O / W emulsion is deteriorated, which is not preferable.

The inner aqueous phase adjusts the osmotic pressure lower than the outer aqueous phase, and contains a water-soluble or water-suspendable substance. In some cases, the osmotic pressure may be reversed. In short, in the present invention, in order to further enhance the stability, it is sufficient that an osmotic pressure difference exists between the inner aqueous phase and the outer aqueous phase, and for example, the osmotic pressure may be controlled using a dissociative substance such as salt. is there. However, in this case, it is not preferable to use an excessively high concentration of the dissociative substance because it adversely affects the stability of the emulsification.

Solutes or dispersoids (water-soluble or water-suspendable substances) include, for example, anticancer drugs such as bleomycin, and other pharmacologically active substances, which are added to the internal aqueous phase.

The aqueous phase is added to the oil phase, sufficiently stirred with a stirrer, and then irradiated with ultrasonic waves to produce a W / O emulsion in which the internal water phase is well dispersed.

Oil phase: internal water phase = 4: 1 to 1: 4 (weight ratio) is good, and the temperature of the liquid phase is 55 ° C. or lower, preferably about 15 to 40 ° C.

In the outer aqueous phase, a dissociable substance such as salt is added to adjust the osmotic pressure, and lecithin is added in an amount of 0.0005 to 10%, preferably 0.1%.
Add about 05-1.0%.

In addition, a W / O / W type composite emulsion can be obtained without adding lecithin to the external aqueous phase, but by adding lecithin to the external aqueous phase, a finer, uniform particle size can be obtained and stable. The performance is also improved.

One of the important features in the present invention is that the W / O composition is made into a W / O / W type composite emulsion by treating with a porous film, whereby an emulsion having a desired fine particle diameter can be obtained. It can be prepared uniformly.

As one embodiment of the porous membrane treatment, there is a method of dispersing the W / O composition in an external aqueous phase using a porous membrane.

In a normal homogenization method such as a homomixer or a high-pressure homogenizer, the W / O composition is gradually reduced into a small emulsion. Coarsening is likely to occur, and the size of the internal aqueous phase and the amount of sealing are likely to be non-uniform. Further, in the conventional method, since the emulsion is gradually reduced, the production method is complicated.

On the other hand, when a porous membrane is used, the W / O composition is dispersed in the external aqueous phase in a desired size in one step, so that the dispersion liquid can be prepared in a short time without the need for multi-step refining. Therefore, it is hardly affected by the transfer of lecithin to the aqueous phase and mechanical destruction, and it is possible to easily produce minute and uniform fat globules in which the number and size of water droplets in the internal aqueous phase are uniform.

Therefore, the number and size of water droplets in the inner aqueous phase are uniform, and the size of W / O droplets is also uniform, so that the amount of drug in one droplet can be uniform and quantified.

According to the present invention, the particle size of the W / O / W type composite emulsion to be produced is constant, and the amount of the internal aqueous phase is uniform, so that the particle size, internal water prepared by a normal homogenization method are used. Compared to the W / O / W type composite emulsion having a wide distribution of the encapsulation amount, the whole emulsion is uniform. This means that the obtained W / O / W
This means that the drug is uniformly present in any part of the type complex emulsion, and it can be said that the drug has a suitable performance for a drug that must strictly adhere to the amount used.

The composite emulsion particles to be formed need to have a size that allows them to easily pass through the blood vessel. In addition, it is preferable that the composite emulsion particles have elasticity and can be easily deformed. This is because even if there is a narrow portion in the blood vessel, the blood vessel can be deformed and pass through without stagnation.

In order for emulsion particles to have such properties,
As in the present invention, it is important to use a fluid fat which does not crystallize at body temperature and has fluidity as the oil phase.

In another embodiment of the porous membrane treatment according to the present invention,
A method of producing a W / O type composite emulsion by further adding an aqueous phase to the W / O composition and inverting the phase. The composite emulsion obtained by this method also has the same excellent performance as described above.

The porous membrane used in the present invention has an average pore diameter of 1.
0 μm or less, and 80% or more of all the pores have an average pore diameter of 0.8 to
If it exists between 1.2 times, porous glass, its aminosilane derivative, activated carbon, acid clay, kaolinite, bentonite, alumina, silica gel, hydroxyl apatite and other inorganic or organic porous materials are widely used, For example, an SPG film made of Shirasu porous glass (abbreviated as SPG: Miyazaki Prefectural Industrial Testing Laboratory) is suitable for use in the present invention because of its excellent strength and uniformity of pore diameter.

The porous membrane can be used not only to prepare a W / O / W type composite emulsion from a W / O composition as described above, but also to disperse an internal aqueous phase in an oil phase to form a W / O emulsion. It can also be used to prepare. Also, the obtained W /
It can also be used to remove large particles from O / W type composite emulsions.

The W / O / W type composite emulsion obtained as described above is used after removing particles of 1.0 μm or more by centrifugation, a porous membrane or the like. In this case, a porous membrane (eg, SPG
The W / O / W type composite emulsion obtained by using the membrane) has an excellent and excellent yield because the particle diameters are uniform.

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Examples.

Test Example 1 20 g of yolk lecithin was mixed with 200 g of soybean salad oil at 50 ° C.
50 g of a 1% aqueous sodium chloride solution containing 150 mg of vindesine sulfate was added to the dissolved oil phase, and the mixture was mixed with a homomixer and irradiated with ultrasonic waves at 250 W for 10 minutes to obtain a W / O composition. The obtained W / O composition was passed through an SPG membrane having a pore diameter of 0.31 μm, dispersed in 500 g of a 0.9% aqueous sodium chloride solution, mixed with 1 g of yolk lecithin and dispersed in an external aqueous phase, and dispersed in an aqueous phase.
A 15% W / O / W composite emulsion was made.

For comparison, a similarly prepared W / O composition was mixed with a similarly prepared outer aqueous phase, and emulsification was repeated twice at 300 kg / cm ² using a high-pressure homogenizer (manufactured by Sanwa Kikai Co., Ltd.). / O / W type composite emulsion was prepared. Table 1 shows the results of comparison between the two.

In each case, the osmotic pressure difference between the outside water and the inside water was 0.9atm, the outside water was lower, and the 外 potential was -10.0mV.

As can be seen from Table 1, the W / O / W type composite emulsion prepared using the SPG membrane has a uniform particle size, a small internal aqueous phase, and is uniformly distributed, and is suitable for injection. , Which have performance exceeding the conventional method.

Test Example 2 Table 2 shows the results obtained by changing the addition amount of egg yolk lecithin in the external aqueous phase in the same composition as in Test Example 1.

As can be seen from Table 2, the particle size of the W / O / W type composite emulsion produced without adding lecithin to the external aqueous phase is slightly larger than that obtained with lecithin, and the particle size distribution is also broadened. I understand.

Test Example 3 The results of changing the osmotic pressure difference by changing the amount of sodium chloride in the inner water phase and the outer water phase with the same formulation as in Test Example 1 are shown.

In each case, the emulsion was prepared using SP with a pore size of 0.28μm.
Table 3 shows the results obtained by using the G film.

Table 3 shows that when the osmotic pressure of the external water is higher than that of the internal water, a W / O / W composite emulsion having a smaller average particle size can be obtained.

Example 1 15 g of egg yolk lecithin was mixed with 100 g of soybean salad oil at 50 ° C.
40 g of a 1.0% aqueous sodium chloride solution containing 1.5 g of bleomycin was added to the dissolved oil phase, and ultrasonic waves were irradiated at 250 W for 10 minutes while mixing with a homomixer to obtain a W / O composition. 30 g of the obtained W / O composition was SP with a pore size of 0.28 μm.
Mixed and dispersed 0.3% yolk lecithin through G membrane
The mixture was dispersed in 170 g of an aqueous sodium chloride solution to obtain a W / O / W composite emulsion.

The measurement results of the obtained W / O / W type composite emulsion were as follows.

Average particle size 0.8 μm Particle size distribution (%) 0-0.5 μm 0.4 0.5-1.0 98.4 1.0-1.5 1.2> 1.50 W / O / W generation rate 92% Inner water is extremely small and well-dispersed, and its dispersion The condition was uniform. Thus, bleomycin is uniformly dispersed throughout the emulsion and is suitable as a drug.

The osmotic pressure difference between outside water and inside water is 0.7atm, which is higher in outside water.
The potential was -8.5 mV. The obtained W / O / W composite emulsion did not change its particle size even after storage for one week, and the production rate was 89%.
Thus, a drug suitable as a drug was obtained.

Example 2 15g of egg yolk lecithin was mixed with 100g of soybean salad oil at 50 ° C,
In a dissolved oil phase, 40 g of a 0.9% aqueous sodium chloride solution containing 2.0 g of vindegine sulfate was dispersed through an SPG membrane to form a W / O
A composition was obtained.

Pass the obtained W / O composition through an SPG membrane with a pore diameter of 0.31 μm
It was dispersed in a 1.0% aqueous sodium chloride solution mixed with 0.2% egg yolk lecithin to obtain a W / O / W composite emulsion having a fat percentage of 10%.

The resulting W / O / W type composite emulsion has an average particle size of 1.0
At μm, the W / O / W generation rate was 90%.

(Effect of the Invention) The W / O / W composite emulsion for injection according to the present invention is an emulsion having a fine and uniform particle size and containing a large amount of an internal aqueous phase containing a drug. Therefore, even a water-soluble or water-dispersible drug can be intensively administered to a specific site, and is particularly effective for treating cancer, for example.

The present invention also provides a combination of lecithin and a porous membrane,
It has also succeeded in industrially producing a new and useful W / O / W composite emulsion particularly suitable for injection.

Claims (12)

(57) [Claims] 1. A W / O / W type for injection, which is produced by using a combination of lecithin and a porous membrane, has a particle diameter of 1.0 μm or less, and contains lecithin in an external aqueous phase. Complex emulsion. 2. A W / O composition obtained by dispersing an internal aqueous phase containing a solute or a dispersoid in an oil phase, wherein the W / O composition is dispersed in an external aqueous phase by using a porous membrane, and the particle size is reduced. The W / O / W composite emulsion for injection according to claim 1, wherein the emulsion is 1.0 µm or less. 3. A W / O composition obtained by dispersing an internal aqueous phase containing a solute or a dispersoid in an oil phase, further dispersing an aqueous phase using a porous membrane, and inverting the phase. 1.0μ diameter
m or less for injection.
W / O / W composite emulsion. 4. A method for producing a W / O / W type composite emulsion for injection, which comprises using lecithin and a porous membrane in combination, and adding the lecithin to an external aqueous phase. 5. The method according to claim 1, wherein an internal aqueous phase containing a solute or a dispersoid is dispersed in an oil phase, and the produced W / O composition is dispersed in an external aqueous phase using a porous membrane. 4. The method for producing a W / O / W composite emulsion for injection according to 4. 6. An aqueous phase containing a solute or a dispersoid is dispersed in an oil phase, and the resulting W / O composition is further dispersed in a water phase using a porous membrane to cause phase inversion. 5. The method for producing a W / O / W composite emulsion for injection according to claim 4. 7. A W / O / W type composite emulsion having a particle diameter of 1.0 μm or less is produced.
The method for producing a W / O / W composite emulsion for injection according to any one of the above. 8. Using a conventional disperser and / or a porous membrane
A W / O composition is produced.
The method for producing a W / O / W composite emulsion for injection according to any one of claims 1 to 7. 9. Use of a porous membrane having an average pore diameter of 1.0 μm or less and 80% or more of all pores existing between 0.8 and 1.2 times the average pore diameter as the porous membrane. A method for producing a W / O / W composite emulsion for injection according to any one of claims 4 to 8, characterized in that: 10. The process for producing a W / O / W composite emulsion for injection according to claim 4, wherein the osmotic pressures of the outer aqueous phase and the inner aqueous phase are different. 11. The oil or fat used as the oil phase is an edible oil or fat having fluidity at body temperature.
11. The method for producing a W / O / W composite emulsion for injection according to any one of items 10 to 10. 12. The W / O / C according to any one of claims 1 to 3.
W-type composite emulsion, or, about the W / O / W-type composite emulsion obtained by any one of claims 4 to 11, by performing a porous membrane treatment to fractionate into a desired particle size, A method for producing a W / O / W composite emulsion for injection, characterized by the following.