JPH0676315B2 - 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 type composite emulsion for injection and a method for producing the same.

More specifically, the present invention relates to a W / O / W type composite emulsion suitable for intravenous injection and a method for producing the same.

In general, it is well known that a cancer drug or the like is placed in oil droplets and intravenously injected as an O / W emulsion to treat cancer.

However, if it is an O / W emulsion, a water-soluble anticancer agent cannot be used.

Therefore, it has been attempted to treat a cancer by producing a W / O / W type composite emulsion, including a water-soluble anticancer agent in the inner aqueous phase, and injecting this intravenously.

However, since the W / O type emulsion, which is a dispersoid of the W / O / W type composite emulsion, has water droplets therein, it has a drawback that it is extremely easily broken as compared with the oil droplets of the O / W type emulsion. When the W / O emulsion of dispersoid is destroyed, the oil quality collects with other oil droplets to form large oil droplets, which may block the narrow veins. If the veins are blocked, nutrients will not be able to go ahead, and healthy cells will be damaged.

Thus, in the case of W / O / W type composite emulsion for injection, stabilization of the W / O emulsion, which is the dispersoid, was a major issue, but at the same time, the W / O / W type composite emulsion was It is essential that the emulsifier used to stabilize the emulsion be safe for the human body.

The present inventors have conducted extensive studies to obtain a stable W / O / W type emulsion using safe lecithin, and as a result, 3
By containing ~ 35% lecithin and making the osmotic pressure of the inner water phase higher than that of the outer water phase, we succeeded in obtaining a stable W / O / W emulsion even after long-term storage.

In the present invention, the internal aqueous phase contains a water-soluble or water-suspendable substance,
In addition, the osmotic pressure is adjusted to be higher than that of the external water phase, the oil phase contains lecithin in an amount of 3 to 35%, the external water phase is adjusted to have an osmotic pressure lower than that of the internal water phase, and the W / O emulsion is a dispersoid. The present invention relates to a W / O / W type composite emulsion for injection, which has a particle diameter of 0.7 μm or less and a negative ζ potential value.

Further, the present invention provides an oil phase containing lecithin in an amount of 3 to 35% with respect to the oil,
Disperse the inner water phase containing a water-soluble substance and adjusted to have an osmotic pressure higher than that of the outer water phase, and produce a W / O emulsion at 55 ° C or less. Added to the external water phase adjusted to be lower than the phase, emulsified, and W /
The particle diameter of O emulsion is 0.7 μm or less, and
A method for producing a stable W / O / W type composite emulsion for injection, which comprises dispersing a W / O emulsion having a negative ζ potential value.

The oily phase in the present invention is selected from oily substances such as fats and oils and fatty acids, which are safe for administration to the human body.

To the oily substance, lecithin such as egg yolk lecithin and soybean lecithin of 3 to 35% of oil is added, and sufficiently stirred at 55 ° C or lower,
Dissolve. The temperature of the oily substance is preferably in the range from the temperature at which the oily substance does not solidify to 55 ° C, and if it exceeds 55 ° C, the stability of the W / O / W type emulsion produced as a product is deteriorated, which is not preferable. The inner water phase adjusts the osmotic pressure higher than the outer water phase,
In addition, a water-soluble or water-suspendable substance is contained.

The osmotic pressure of the inner water phase is adjusted to be 0.1 to 100 atm, preferably 0.1 to 50 atm higher than that of the outer water phase by adding a dissociative substance such as salt.

To make the osmotic pressure of the inner water phase higher than that of the outer water phase,
This is a great feature of the present invention, which significantly enhances the stability of the W / O type emulsion, which is a dispersoid, during long-term storage or use of the commercialized W / O / W type emulsion. Is something that can be done.

Examples of the water-soluble or water-suspendable substances include anticancer agents such as bleomycin and other pharmacologically active substances, which are added to the hyperosmotic inner aqueous phase.

The internal water phase was added to the oil phase, thoroughly stirred with a stirrer, and then irradiated with ultrasonic waves, etc., so that the internal water phase was well dispersed W /
Make an O emulsion.

The degree of 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.

The temperature at the time of manufacturing the W / O type emulsion is set to 55 ° C or lower, because if the W / O type emulsion is manufactured above 55 ° C, the stability of the commercialized W / O / W type emulsion will deteriorate. For the outer aqueous phase, a dissociative substance such as sodium chloride is added to adjust the osmotic pressure to be lower than the inner aqueous phase. For example, if 1% saline is used for the inner aqueous phase, 0.9% saline (physiological saline) is used for the outer aqueous phase.
Is used.

A W / O emulsion is added to the outer water phase and sufficiently emulsified by an emulsifying machine, a high pressure emulsifying machine, or the like. It is preferable to repeat the emulsification 3 to 10 times under a pressure of 650 kg / cm ² or more by a high pressure emulsifier.

Outer water phase: W / O emulsion = 1: 4 to 100: 1 (weight ratio) is preferable.

The W / O / W type emulsion thus obtained has a particle diameter of 0.7 μm or less, preferably 0.7 to 0.2, which is a W / O emulsion as a dispersoid by centrifugation, filtration with a Millipore filter, or the like.
Adjust to μm. Oil droplets of W / O emulsion of 0.7 μm or less can reach all tissues in the body through capillaries.

In addition, the W / O which is the dispersoid of the obtained W / O / W emulsion
The value of the ζ (zeta) potential of the particles of the emulsion must be negative.

The value of the ζ potential of the particles of the W / O type emulsion of the dispersoid of the W / O / W type emulsion produced by the method of the present invention is −
It is preferably about 1.0 to -40.0.

The negative ζ potential means that it can move freely in the capillaries, which is essential for the particles of W / O emulsion, which is the dispersoid of W / O / W composite emulsion for injection. This is a requirement.

Next, experimental examples and examples of the present invention will be shown.

Experimental Example 1. A comparative experiment was conducted on the physical properties and dosing effect of W / O / W type composite emulsions depending on the composition and manufacturing conditions. The following experimental materials, instruments and devices were all sterilized. .

To 100 g of soybean salad oil at 20 ° C containing 10% yolk lecithin,
Add 30 g of 1% NaCl solution containing 80 mg of vindesine sulfate, 2
After the blade was stirred at 00 rpm for 5 minutes, ultrasonic wave 250 was applied.
Irradiation was performed for 5 minutes at an output of W to obtain a W / O emulsion. This is added to 800g of physiological saline (0.9% NaCl solution) at 30 ° C, and 600kg / cm with a high pressure emulsifier (manton Gorin Co.).
^The emulsification was repeated 5 times under the pressure of ² to obtain a W / O / W type composite emulsion. Based on this, for comparison, the following items were changed to make a W / O / W type composite emulsion.

1. NaCl concentration in the inner aqueous phase: changed from 1.0% to 0.9 and 14%.

2. Temperature when preparing W / O emulsion: Change from 20 ℃ to 70 ℃.

3. Homogenization pressure: changed from 600kg / cm ² to 400kg / cm ² .

4. NaCl concentration in the external water phase: changed from 0.9% to 0.09%.

W / O / W type complex emulsion prepared by changing 1 to 4 items (a and b which changed the item 1 and c which changed the item 2 and d which changed the item 3 Table 1 shows the physical properties of each of the items (4) and (e).

In addition, male rats transplanted with lung cancer cells (body weight 150 g
These W / O / W type composite emulsions were intravenously injected to ± 10, 10 animals per group), and the dosage effect was observed. (1.0m once for intravenous injection)
A W / O / W type fat emulsion containing g of vindesine sulfate was administered every 6 hours. ) Table 2 compares the effect with the survival rate two weeks after the start of administration.

As can be seen from Table 1 and Table 2, the osmotic pressure difference between the inner water phase and the outer water phase, the adjusted temperature of the W / O emulsion, the particle size, and the ζ potential are 4
It is understood that the W / O / W type complex emulsion exhibiting excellent dosing effect can be obtained only when the two are properly combined.

Experimental Example 2 In the same manner as in Experimental Example 1, a comparative experiment of physical properties and dosing effect depending on the composition of W / O / W type composite emulsion and the manufacturing conditions was conducted. The basis of the W / O / W type composite emulsion was the same as in Experimental Example 1, and the following two points were added.

I. Egg yolk lecithin concentration: changed from 10% to 2.5% and 37%.

II.W / O emulsion preparation temperature: 20 ℃ to 53 ℃ and 60 ℃
Change to ℃.

W / O / W type composite emulsion prepared by changing I and II items (f and g with changed I item, h and i with changed II item) and basic The physical properties and the drug effect were examined in the same manner as in Experimental Example 1. The results are shown in Tables 3 and 4.

As can be seen from Tables 3 and 4, the oil concentration of lecithin and W /
W / O / W when the preparation temperature of O-type emulsion is other than basic and h
It can be seen that the dosage effect of the type complex emulsion is drastically reduced.

Example 1 To 50 g of soybean salad oil at 30 ° C. containing 15% of soybean lecithin, 20 g of 1% NaCl solution containing 0.5 g of bleomycin was added at 30 ° C., and after performing blade stirring at 100 rpm for 5 minutes, ultrasonic waves of 250 W were applied. Was irradiated for 5 minutes to obtain a W / O emulsion. Add this to 700g of normal saline (0.9% NaCl solution) at 30 ° C and add a high-pressure emulsifier (manton-goulin company)
The emulsification was repeated 5 times under a pressure of 650 kg / cm ² to obtain a W / O / W type composite emulsion. The obtained W / O / W type composite emulsion was prepared to have a particle size of 0.1 to 0.7 μm by treatment with a Millipore filter such as filtration and centrifugation.

All the above experimental materials, instruments, and devices were sterilized.

AH66 cells (rat ascites hepatoma) (Odashima, 1964)
150 male SD rats transplanted with the above were untreated, divided into three groups: one in which an antitumor agent was made into an aqueous solution and intravenously injected, and one in which the prepared W / O / W complex emulsion was intravenously injected.

For intravenous injection, an aqueous solution containing 1 mg of bleomycin or a W / O / W complex emulsion was intravenously administered every 12 hours.

When the survival rates of the three groups were compared one month later, the results are shown in Table 5.

It can be seen that a remarkable life-prolonging effect is exhibited by intravenously administering bleomycin as a W / O / W type complex emulsion.

Claims (2)

[Claims] 1. An inner water phase contains a water-soluble or water-suspendable substance, and its osmotic pressure is adjusted to be 0.1 to 50 atm higher than that of an outer water phase, and an oil phase contains lecithin in an amount of 3 to 35% of oil. , The external water phase is adjusted to have an osmotic pressure lower than that of the internal water phase and is W / O
The particle diameter of the emulsion is 0.7 μm or less, and
A W / O / W type composite emulsion for injection characterized in that the value of its ζ potential is negative. 2. An inner aqueous phase containing a water-soluble substance and having an osmotic pressure adjusted to be 0.1 to 50 atm higher than that of the outer aqueous phase is dispersed in an oil phase containing lecithin in an amount of 3 to 35% with respect to an oil, and the dispersion is kept at 55 ° C. or lower. W / O emulsion is produced, and the obtained W / O emulsion is added to the outer water phase whose osmotic pressure is adjusted to be lower than that of the inner water phase, emulsified, and the particle diameter of the W / O emulsion as a dispersoid is 0.7 μm or less. And
Also, a stable W / O / for injection characterized by dispersing a W / O emulsion having a negative ζ potential value
W-type composite emulsion manufacturing method.