JP2838164B2 - Emulsion composition - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an improvement in an emulsion composition, particularly an emulsion composition used as a preparation for parenteral administration.

[Prior Art] Conventionally, various emulsified compositions have been used in the fields of pharmaceuticals, quasi-drugs and the like. As such an emulsified composition,
Conventionally, there is an intravenous fat emulsion in which lipid spheres having an average particle size of about 0.2 μm are dispersed in an aqueous phase. This is generally obtained by emulsifying vegetable oils and fats with a high-pressure homogenizer using lecithin as an emulsifier, and is used as a nutritional supplement for patients or as a preparation for parenteral administration of fat-soluble drugs.

In particular, an aqueous solution is effective as a formulation for intravenous injection of a fat-soluble drug that cannot be injected intravenously, and is used as one of drug delivery systems.

[Problems to be Solved by the Invention] Problems in the Prior Art Recently, research on passive or active directed drug delivery systems using microspheres has been conducted, and particles of 0.100 to 2.000 μm are intravenously, intraarterially or intraperitoneally. When administered intracellularly, it is rapidly taken up from the bloodstream by macrophages of the reticuloendothelial system and becomes localized in the lysosomes of the Kuppel cells in the liver, and particles smaller than 0.050 μm pass through the liver endothelial system and are likely to be collected in tumor tissues (Pharmacy International 2 (3)
1984). From such a viewpoint, the average particle is 0.2
Although the intravenous fat emulsion having a particle size of μm has a particle size that is easily taken up by the reticuloendothelial system, particularly the liver, it is not sufficient as a preparation for parenteral administration of a fat-soluble drug, and it can be administered parenterally. Adjusting particles of μm or less is also a very important technique in formulation.

The known parenterally administrable fat emulsions include the above-mentioned fat emulsion for intravenous injection. However, it is very difficult to prepare parenterally administrable particles having a particle size of 0.050 μm or less, that is, nanolipid spheres, in this fat emulsion system.

Purpose of the invention The present invention has been made in view of the problems of the prior art, the purpose of which is excellent in stability, the average particle diameter is 0.010 ~
An object of the present invention is to obtain an emulsified composition in which a lipid sphere having a diameter of 0.070 μm is dispersed in an aqueous phase.

[Means for Solving the Problems] As a result of intensive studies by the present inventors to achieve the above object, the ratio of glycerin to water during emulsification is set to a specific range, or the ratio of phospholipid to nonionic interface By setting the ratio of the activator to a specific range, it was found that a lipid sphere having fine particles and excellent stability was obtained, and the present invention was completed.

That is, the emulsified composition according to the present invention comprises: (A) a fat-soluble drug and lipid; (B) glycerin and water; (C) a phospholipid and / or a water-soluble nonionic surfactant having a molecular weight of 1,000 or more. ), (B) and (C),
(A) / (C) = 0.5 to 5 (weight ratio), and the ratio (weight ratio) of glycerin to water at the time of emulsification is 3: 7 to 9: 1. In another embodiment, (A) a fat-soluble drug and lipid (B) glycerin and water (C) a phospholipid and a water-soluble nonionic surfactant having a molecular weight of 1000 or more (A), (B) and ( C) at least
(A) / (C) = 0.5 to 5 (weight ratio), and the ratio of the phospholipid to the nonionic surfactant is 9: 1 to 2.5: 7.5.

The average particle diameter used here is all measured by the dynamic light scattering method, and specifically, NICOMP-
270 (manufactured by HIAC / ROYCO).

 Hereinafter, the configuration of the present invention will be described in detail.

Lipids used in the present invention, soybean oil, corn oil, safflower oil, cottonseed oil, vegetable oils such as coconut oil,
Synthetic or semi-synthetic mono, di, triglyceride, cholesterol, sterols such as chenodeoxycholinic acid, cholesteryl linoleate, cholesterol esters such as cholesteryl caprylate, oleyl oleate, ethyl linoleate, monoesters such as ethyl laurate, etc. Sometimes used. In general, the smaller the carbon number of the lipid, the better the drug is dissolved, but the less stable the emulsification. Therefore, when using a mole of di-, triglyceride and / or a monoester having a carbon number of 22 or less, a triglyceride having a carbon number of 45 or more and / or a monoester having a carbon number of 26 or more is contained in the lipid. Must be contained at 1% or more. This is because when an emulsified composition is prepared using a mono-, di-, or triglyceride having a carbon number of 33 or less and / or a monoester having a carbon number of 22 or less, the stability over time is poor and the particle diameter becomes large.

The fat-soluble drug used in the present invention may be any drug as long as it dissolves in the lipid, and examples thereof include mitomycin, bleomycin, doxorubicin, hexamethylmelamine, phthalafluor oleate, and
Antitumor agents such as dilaurate of FU, penicillin,
Antibacterial agents such as erythromycin, cephalosporin, streptomycin, kanamycin, tetracycline, chloramphenicol, isoniazid, cycloserine, amphotericin B, griseofulvin, antifungal agents, salicylate, indomethacin, aminopyrine, phenacetin,
Non-steroidal anti-inflammatory agents such as ibuprofen, flurbiprofen, ketoprofen, diclofenac, hormonal agents such as prostaglandins and synthetic steroids, immunomodulators such as cyclosporin, fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, etc. Is mentioned.

The phospholipid and the water-soluble nonionic surfactant having a molecular weight of 1000 or more in the present invention function as an emulsifier.

The phospholipid used in the present invention is lecithin derived from egg yolk or plant seed, for example, egg yolk lecithin, soy lecithin, hydrogenated products thereof, fractionated from synthesized or natural products, purified phosphatidylcholine, phosphatidylethanolamine, Phosphatidylinositol, phosphatidylserine, sphingomyelin,
Examples include phosphatidic acid and phytoglycolipid. Examples of nonionic surfactant substances include POE sorbitan fatty acid esters such as polyoxyethylene (hereinafter, referred to as POE) sorbitan monooleate, POE sorbitan monostearate, POE sorbitan trioleate, and POE.
POE sorbit fatty acid esters such as sorbit monooleate, POE sorbit pentaoleate, POE sorbit monostearate, POE glycerin fatty acid esters such as POE glycerin monostearate, POE fatty acid esters such as POE monooleate, POE distearate, POE diolate, etc. , POE oleyl ether, POE stearyl ether, POE alkyl ethers such as POE behenyl ether, POE cholesterol ether, POE sterol ether such as POE cholesterol ether, POE POP block polymers, POE POP cetyl ether etc. Examples include POP alkyl ethers, POE castor oil or hardened castor oil derivatives such as POE castor oil, and polyglycerin fatty acid esters such as decaglycerindiolate. Of these, those having a molecular weight of 1,000 or more are used. Further, the preferred molecular weight is 1500 or more, particularly preferred POE
Examples include stearyl ether, POE oleyl ether, POE monostearate, POE monooleate, POE cholestanol ether, POE cholesterol ether, and POE hydrogenated castor oil derivatives.

Here, the reason why the molecular weight of the nonionic surfactant is 1000 or more is that nonionic surfactants having a molecular weight of less than 1000 are highly irritating to the living body and cause hemolysis when used as an injection. Because there is also.

The phospholipid and the water-soluble nonionic surfactant having a molecular weight of 1000 or more may be used alone or in combination, but it is more preferable to use them in combination. The mixing weight ratio of the phospholipid to the nonionic surfactant is preferably 9.5 to 0.5 to 1: 9, and more preferably 1: 9 to 2: 8.

The particle size of the emulsion composition of the present invention is 0.010 to 0.070 μm, preferably 0.050 or less, more preferably 0.040 μm
It is as follows.

The particle size of the emulsified composition in the present invention depends on the weight ratio of (A) and (C), and the smaller (A) / (C), the smaller the particle size tends to be. Therefore, if the ratio exceeds 5, an emulsified composition having an average particle size of 0.070 μm or less cannot be obtained. In order to obtain an emulsified composition having a preferable particle size of 0.050 μm or less, the ratio must be 3 Must be: However, administration of a large amount of a surfactant that functions as an emulsifier has an adverse effect on the vascular system and blood, and is not preferable. Therefore, it is important to obtain small particles with as little surfactant as possible. Therefore, a preferable ratio is 1.0 or more.

In the present invention, the weight ratio of (A) / (C) is 0.5 to 5
And it is preferably 1.0 to 3.0.

In the present invention, the weight ratio of glycerin and water during emulsification is
3: 7 to 9: 1 is desirable, and more preferably, 1: 7.
1 to 8: 2.

If the weight ratio of glycerin and water at the time of emulsification is smaller than 3: 7, the effect of the addition is not exhibited, and if it is larger than 9: 1, the effect of reducing the particle diameter is not sufficiently exhibited.

The average particle size of the emulsion composition obtained according to the present invention,
0.010 to 0.070 μm.

Further, in the present invention, lipid spheres having a particle diameter of 0.050 μm or less can be obtained by emulsification using an emulsifier capable of giving a strong shearing force, for example, a high-pressure homogenizer or an ultrasonic emulsifier.

For example, when producing three emulsion compositions (A) / (C), when emulsification is performed without adding glycerin, even if the emulsification conditions of a high-pressure homogenizer are variously adjusted and adjusted, particles having a size of 0.100 μm or less can be obtained. It is very difficult to obtain a lipid sphere with a diameter of 0.070 μm or less. However, if emulsification is performed at a weight ratio of glycerin and water of 3: 7 to 9: 1 at the time of emulsification, 0.050 μm
A lipid sphere having the following particle diameter can be obtained.
When (A) / (C) is 1, it is extremely difficult to obtain lipid spheres having a particle diameter of 0.070 μm or less without using glycerin, and it is not possible to obtain lipid spheres of 0.050 μm or less. However, if emulsifying with a weight ratio of glycerin and water at the time of emulsification of 3: 7 to 9: 1, 0.020
It is also possible to obtain a lipid sphere having a particle diameter of not more than μm.

When using a high-pressure homogenizer, it is preferable to emulsify under a pressure of 200 atm or more, more preferably 0.050
In order to obtain particles of μm or less, 300 ° C or less
It is preferable to emulsify under a pressure of not less than atmospheric pressure, and to obtain smaller particles, it is preferable to emulsify at a temperature of not more than 50 ° C. and a pressure of not less than 500 atm.

After the emulsification, such an emulsified composition may be diluted by adding water to a predetermined glycerin concentration.

In the present invention, the predetermined glycerin concentration varies depending on the application but is equal to or higher than the isotonic concentration.

The emulsion composition of the present invention may contain, in addition to the essential components, various parenterally administrable components as needed, as long as the effects of the present invention are not impaired. Among such components, those listed as the aqueous phase component include amino acids and related compounds, electrolytes, and water-soluble vitamins.

As described above, in the prior art, only fine particles having an average particle diameter of micro order were obtained, whereas in the present invention, stable ultra fine particles of nano order were obtained.

Lipid nanospheres of such an emulsified composition, particularly those having a particle size of 0.050 μm or less, are thought to pass through the reticuloendothelial system when administered intravenously, intraarterially or intraperitoneally and possibly to collect in tumor tissues, For parenteral administration, and as a base for drug delivery systems such as anticancer agents.

[Effects of the Invention] As described in detail above, according to the present invention, a fat-soluble drug and a lipid, glycerin and water, a phospholipid and / or a water-soluble nonionic surfactant having a molecular weight of 1000 or more are blended. Thus, an emulsified composition in which stable lipid nanospheres having an average particle diameter of 0.010 to 0.070 μm are dispersed in the aqueous phase is obtained.

[Examples] Next, the emulsion composition according to the present invention will be described in detail with reference to Examples and Comparative Examples. Note that the present invention is not limited to this.

Relationship between (A) / (C) and parallel particle diameter First, the relationship between the weight ratio of fat-soluble drugs and lipids, phospholipids and / or water-soluble nonionic surfactants having a molecular weight of 1000 or more, and the average particle diameter. Will be described.

The formulation at the time of emulsification was adjusted as shown in Table 1 below, and each was treated 30 times with a high-pressure homogenizer at an emulsification pressure of 900 atm,
The average particle size was measured. In addition, the compounding amount is each weight%.

FIG. 1 shows the case where nonyloxycarbonyl MMC (NOC.MMC) 1% soybean oil solution was used as the component A (fat-soluble drug and lipid) and egg yolk phosphatidylcholine was used as the component C (phospholipid). 2) / (C) and the particle size are shown.

As is clear from the figure, (A) / (C) and the particle size are almost directly proportional, and when (A) / (C) is about 5, the particle size is 70 nm (0.070 μm). The particle size becomes too large.

From these results, it is understood that (A) / (C) is closely related to the particle diameter, and that the particle diameter of 70 nm or less, which is the object of the present invention, can be obtained when the ratio is 5 or less.

Although the particle diameter decreases almost directly in proportion to (A) / (C), if (A) / (C) is 3 or less, the linearity deteriorates and the particle diameter decreases in proportion to (A) / (C). The particle size does not decrease. Therefore, it is understood that it is not very efficient that the particle diameter of yolk phosphatidylcholine alone is 50 nm or less, and that a large amount of yolk phosphatidylcholine must be added.

On the other hand, FIG. 2 shows the relationship between (A) / (C) and particle size when a 3: 1 mixture of egg yolk phosphatidylcholine and POE (50) oleyl ether is used as the C component.

As is clear from the figure, good linearity is secured even when (A) / (C) is 3 or less.

Therefore, particularly when obtaining a particle diameter of 50 nm or less, it is preferable to use a water-soluble nonionic surfactant having a molecular weight of 1000 or more in addition to the phospholipid.

Next, the relationship between the ratio of glycerin to water and the particle size during emulsification will be described.

NOC / MMC 1% soybean oil solution 20 parts by weight, emulsifier 10 parts by weight,
A glycerin aqueous solution (70 parts by weight) was mixed, and the mixture was treated 30 times with a high-pressure homogenizer at an emulsifying pressure of 600 atm to obtain an emulsified composition.

Then, the glycerin concentration of the aqueous glycerin solution was sequentially changed, and the particle diameter was measured.

FIG. 3 shows the results. As is clear from the figure,
When egg yolk phosphatidylcholine is used as an emulsifier (shown by a solid line in the figure), the glycerin concentration is 50% or more and the particle size becomes 70 nm or less. Also. The minimum value of the particle size is when the glycerin concentration is 70 to 80% by weight, and when the glycerin concentration is less than that, the particle size tends to increase rapidly.

Also, yolk phosphatidylcholine and POE as emulsifiers
(50) When a 3: 1 mixture of oleyl ether is used (shown by a dotted line in the figure), when the glycerin concentration is 30% by weight or more, the particle diameter becomes 70 nm or less, and the minimum value is also 70 to
It is understood that it is at 80% by weight.

Therefore, the glycerin concentration is preferably 30 to 90% by weight, and particularly when the glycerin concentration is 70 to 80% by weight, an extremely small particle size can be obtained.

Relationship between ratio of phospholipid to nonionic surfactant and particle size 5.0% by weight of tocopherol acetate, 15.0% by weight of soybean oil,
After emulsifying 10% by weight of emulsifier, 30% by weight of water and 40.0% by weight of glycerin in advance, the mixture was emulsified at 50 ° C. using a microfluidizer at 800 atmospheres and 30 times to obtain an emulsified product.

The composition ratio of the emulsifier and the particle size at that time are shown in Table 2 below.
Shown in

As is clear from the above table, lecithin (phospholipid)
And POE (50) stearyl ether (a water-soluble nonionic surfactant with a molecular weight of 1000 or more) has a smaller particle size than when used alone, especially when lecithin is used.
It is understood that the particle size becomes very fine at a ratio of 75 to 50%.

Examples 1 to 9 1.1 parts by weight of diclofenac, 20.9 parts by weight of soybean oil, water 2
After pre-emulsifying 8 parts by weight, 41.3 parts by weight of glycerin, and 8.7 parts by weight of a water-soluble nonionic surfactant (emulsifier) having a phospholipid and / or a molecular weight of 1000 or more shown in Table 3, 5
At 0 ° C, emulsification was carried out using a microfluidizer (Microfluidic) under the conditions of 1000 atmospheres and 20 treatments,
Thereafter, 120 parts by weight of water was added, and the mixture was sterilized using a 0.22 μm membrane filter. Table 3 shows the particle size of these emulsion compositions immediately after preparation. These are translucent or almost transparent.

These were allowed to stand at room temperature, and after 3 months, the state and the particle size were evaluated. As a result, no change was observed.

Comparative Examples 1 to 9 Comparative examples in which glycerin of the formulation shown in Examples 1 to 9 was replaced with water were similarly prepared and used as comparative examples. However, these were sterilized by an autoclave. Table 4 shows the particle size of these emulsion compositions immediately after preparation. These are slightly milky. These were allowed to stand at room temperature, and the state and particle size after 3 months were evaluated. As a result, no change was observed.

As shown in Tables 3 and 4, the superiority of Examples 1 to 9 in which glycerin according to the present invention was blended was clarified.

Example 10 Soybean oil containing 10% by weight of 5-FU palmitate
15 parts by weight, 16 parts by weight of water, 56 parts by weight of glycerin and 15 parts by weight of POE40 cholestanol ether are pre-emulsified, and then heated to 50 ° C.
In Menton Gorin at 500 atm, emulsification under the conditions of 30 times treatment, then add 100 parts by weight of water, 0.22μ
The solution was sterilized through a membrane filter. The particle size of these emulsified compositions immediately after preparation is 0.022 μm, and they are transparent.
These were allowed to stand at room temperature, and the state and particle size after 3 months were evaluated. As a result, no change was observed.

Example 11 Soybean oil containing 10% by weight of 5-FU palmitate
After pre-emulsifying 20 parts by weight, 16 parts by weight of water, 56 parts by weight of glycerin and 10 parts by weight of POE40 cholestanol ether, 50 ° C.
In Menton Gorin at 500 atm, emulsification under the conditions of 30 times treatment, then add 100 parts by weight of water, 0.22μ
The solution was sterilized through a membrane filter. The particle diameter of these emulsion compositions immediately after preparation is 0.042 μm, and they are almost transparent. These were allowed to stand at room temperature, and the state and particle size after 3 months were evaluated. As a result, no change was observed.

Example 12 Soybean oil containing 10% by weight of 5-FU palmitate
After pre-emulsifying 24 parts by weight, 16 parts by weight of water, 54 parts by weight of glycerin and 8 parts by weight of POE40 cholestanol ester, 50 ° C.
Emulsified under the conditions of 500 atm, 30 treatments using Menton Gorin, and then 100 parts by weight of water was added, and 0.22 μm
The solution was sterilized through a membrane filter. The particle size of these emulsified compositions immediately after adjustment is 0.062 μm, and they are translucent.
These were allowed to stand at room temperature, and the state and particle size after 3 months were evaluated. As a result, no change was observed.

As shown in the results of Examples 10 to 12, it is understood that according to the present invention, the particle diameter is controlled by the ratio of the lipid to the emulsifier.

Example 13 2 parts by weight of futrafur palmitate, 1 part by weight of soybean oil, 19 parts by weight of ethyl oleate, 14 parts by weight of water, 54 parts by weight of glycerin, 5 parts by weight of purified egg yolk lecithin and POE60
After pre-emulsifying 5 parts by weight of hydrogenated castor oil, emulsifying at 50 ° C. using Manton-Gaulin at 500 atmospheres and 10 times, then adding 100 parts by weight of water and aseptic through a 0.22 μm membrane filter. I made it. The particle size of these emulsion compositions immediately after preparation is 0.028 μm, and the emulsion composition is transparent. These were allowed to stand at room temperature, and the state and particle size after 3 months were evaluated. As a result, no change was observed.

Example 14 1 part by weight of cyclosporine, 1 part by weight of soybean oil, 14 parts by weight of ethyl laurate, 16 parts by weight of water, 58 parts by weight of glycerin,
After preliminarily emulsifying 7 parts by weight of purified egg yolk lecithin and 3 parts by weight of POE60 hydrogenated castor oil, the mixture was emulsified at 50 ° C. using manton gaulin at 500 atm and under the conditions of 10 treatments, and then water 1
00 parts by weight were added and sterilized through a 0.22 μm membrane filter. Particles of these emulsion compositions immediately after adjustment are 0.020 μm
And is transparent. These were allowed to stand at room temperature, and the state and particle size after 3 months were evaluated. As a result, no change was observed.

Example 15 2 parts by weight of erythromycin, 1 part by weight of soybean oil, 27 parts by weight of glycerin tricaprylate, 38 parts by weight of water, glycerin
After pre-emulsifying 26 parts by weight, 1 part by weight of purified egg yolk lecithin and 6 parts by weight of POE30 cholestanol ether, the mixture was emulsified at 70 ° C. using a microfluidizer (Microfluidisc) at 1000 atm and 20 times treatment. And then water
100 parts by weight were added and sterilized through a 0.22 μm membrane filter. The particle size of these emulsion compositions immediately after adjustment was 0.06.
2 μm and translucent. Leave these at room temperature
As a result of evaluating the state and particle size after one month, no change was recognized.

Example 16 Soybean oil 24 containing Prostaglandin E ₂ 1/1000% by weight
After pre-emulsifying 36 parts by weight of water, 36 parts by weight of water, 38 parts by weight of glycerin and 10 parts by weight of cholestanol ether of POE50, the mixture was treated at 1000 ° C. and 20 times at 70 ° C. using a microfluidizer (Microfluidisc) at 1,000 atmospheres. After emulsification, 100 parts by weight of water was added, and the mixture was sterilized through a 0.22 μm membrane filter. The particle size of these emulsion compositions immediately after adjustment is
0.047 μm, and is translucent. These were allowed to stand at room temperature, and the state and particle diameter after 3 months were evaluated. As a result, no change was observed.

Example 17 25 parts by weight of tocopherol acetate, 2 parts by weight of soybean oil, 9 parts by weight of purified egg yolk lecithin, 32 parts by weight of water, and 32 parts by weight of glycerin were preliminarily emulsified. Emulsify under processing conditions, then add water 1
00 parts by weight were added and sterilized through a 0.22 μm membrane filter. Further, 1050 parts by weight of sterile water was added to make an isotonic solution to obtain a vitamin E preparation for intravenous injection. The emulsified particle size of this is 0.05
It was 0 μm.

These were allowed to stand at room temperature, and the state and particle diameter after 3 months were evaluated. As a result, no change was observed.

Example 18 nonyloxycarbonyl mitomycin C 0.2 parts by weight,
Soybean oil 19.8 parts by weight, egg yolk phosphadylcholine 5 parts by weight,
After pre-emulsifying 5 parts by weight of POE (50) monostearate, 30 parts by weight of water, and 40 parts by weight of glycerin, the mixture was emulsified at 50 ° C. using a microfluidizer at 800 atmospheres and 30 times, and then water was added. 100 parts by weight were added and sterilized through a 0.22 μm membrane filter. Further, 300 parts by weight of sterile water was added to obtain intravenous injection of nonyloxycarbonyl mitomycin C. This had an emulsified particle size of 0.32 μm.

These were allowed to stand at room temperature, and the state and particle diameter after 3 months were evaluated. As a result, no change was observed.

Example 19 0.1 part by weight of amteforicin B, 9.9 parts by weight of soybean oil, 8 parts by weight of egg yolk phosphatidylcholine, 2 parts by weight of POE (30) oleyl ether, 30 parts by weight of water, and 50 parts by weight of glycerin Using a microfluidizer, emulsify under the conditions of 800 atm and 30 treatments.
00 parts by weight were added and sterilized through a 0.22 μm membrane filter. Further, 100 parts by weight of sterile water was added, and amphotericin B was added.
An intravenous injection was obtained. The emulsified particle size of this product is 0.018 μm
Met.

These were placed at room temperature, and the state and particle size after 3 months were evaluated. As a result, no change was observed.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram showing the relationship between the particle diameter and the (A) / (C) ratio when a phospholipid is used as the C component, and FIG. 2 is a diagram showing the relationship between the phospholipid and the nonionic surfactant as the C component. FIG. 3 is an explanatory diagram showing the relationship between the particle size and the (A) / (C) ratio when used, and FIG. 3 is an explanatory diagram showing the relationship between the glycerin concentration and the particle size.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-1-143826 (JP, A) JP-A-2-203 (JP, A) (58) Fields investigated (Int.Cl. ⁶ , DB name) A61K 9 / 10,9 / 107 B01J 13/00

Claims (2)

(57) [Claims] (A) a fat-soluble drug and lipid (B) glycerin and water (C) a phospholipid and / or a water-soluble nonionic surfactant having a molecular weight of 1,000 or more (A), (B) and (C) at least,
(A) / (C) = 0.5 to 5 (weight ratio), and the ratio (weight ratio) of glycerin to water at the time of emulsification is 3: 7 to 9: 1. ~ 0.070μm emulsified composition (A) fat-soluble drugs and lipids (B) glycerin and water (C) phospholipids and water-soluble nonionic surfactants having a molecular weight of 1000 or more (A), (B) and (C) ) At least
(A) / (C) = 0.5 to 5 (weight ratio), and the ratio between the phospholipid and the nonionic surfactant is
9: 1 to 2.5: 7.5, the average particle diameter is 0.01
An emulsion composition of 0 to 0.070 μm.