KR101492290B1 - Vesicle composition and external preparation for skin - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising (a) a lysophospholipid, (b) at least one selected from a higher alcohol or liquid higher fatty acid which is in a liquid phase at 25 ° C, (c) cholesterol or phytosterol, (d) Lt; / RTI >

Description

Vesicle composition, and external preparation for skin [

The present invention relates to a vesicle composition using a lysophospholipid, and a skin external preparation comprising the vesicle dispersion composition.

Vesicle refers to a closed vesicle (closed vesicle) having a bimolecular membrane structure formed by an amphipathic substance. Because of this specific structure, an active ingredient can be contained therein, and it is attracting attention as a carrier in a drag delivery system and the like. In addition, the vesicle is highly effective as an external preparation for skin, because the vesicle has high retentivity in the stratum corneum and can effectively act the active ingredient.

In general, a large number of amphipathic substances capable of constituting a vesicle are present, and in particular, a vesicle made of lysophospholipid is called liposome, and many studies have been made in terms of safety to the living body. For example, there is a liposome having a purity of phosphatidylcholine of 90% or more and a phospholipid having an iodine value of 0.1 or less and a particle diameter of 100 to 150 nm (for example, see Patent Document 1). Further, examination of vesicles using a synthetic surfactant as an amphipathic substance constituting the vesicles has been extensively reviewed. A technique of vesicle preparation using maltitol di-fatty acid ester (for example, see Patent Document 2), and a technique of a liposome preparation using a multi-chain polyunsaturated surfactant (see, for example, Patent Document 3).

On the other hand, lysophospholipids are hydrophilic surfactants and have been used as an emulsifier of an underwater (oil-in-water) emulsified composition. For example, there is a cosmetic having high transparency (see, for example, Patent Document 4) in which a lysophospholipid, a phospholipid and an oil are blended at a specific ratio. A hair cosmetic composition containing a phospholipid and a predetermined cationic surfactant has been proposed, and it has been disclosed that a liposome can be used as a phospholipid (see Patent Literature 5).

Further, there is a technique (for example, see Patent Document 6) used as an emulsifying aid such as a liquid high-grade alcohol or a liquid high-grade fatty acid which further emulsifies the emulsified particles.

In addition, the external preparation for skin, such as cosmetics, is formulated with an electrolyte for the purpose of imparting various cosmetic effects and added value. Examples thereof include organic salts such as amino acids, sodium dl-pyrrolidonecarboxylate, sodium lactate and ascorbic acid derivatives as a whitening ingredient, and inorganic salts such as sodium chloride.

Patent Document 1: Japanese Patent Application Laid-Open No. 2006-124378

Patent Document 2: JP-A-06-157296

Patent Document 3: Japanese Patent Application Laid-Open No. 2006-290894

Patent Document 4: Japanese Patent Application Laid-Open No. 2001-302433

Patent Document 5: Japanese Patent Application Laid-Open No. 2006-193461

Patent Document 6: Japanese Patent Application Laid-Open No. 2004-277341

Although there are many techniques related to the vesicle preparation, there are the following problems. For example, in the technique of Patent Document 1, the feeling of use is excellent, but the pH range is changed to make it stable in the time of aging, and the preparation is stabilized. Thus, application to external preparations such as cosmetics There was a constraint. In the technique of Patent Document 2, there is a case that the permeation feeling to the skin is lower than that of the liposome, and the stickiness is felt in some cases. Further, in the technique of Patent Document 3, a beacycle can be obtained by an easy method using an amino acid-based surfactant, but there are cases where the preservation stability is insufficient. In the presence of electrolytes mixed with a purpose of imparting a moisturizing effect or a whitening effect, etc., these techniques have disadvantages in that the bicolayer structure peculiar to vesicles is destroyed and storage stability at high temperatures is insufficient.

For this reason, development of an external preparation for skin having an excellent feeling of use such as liposomes different from the above-described techniques and having a vesicle excellent in storage stability has been demanded. Furthermore, even in the presence of an electrolyte, There has been a demand for development of this excellent external preparation for skin.

In such a situation, the present inventors have made intensive studies, and as a result, have found that lyophospholipids, one or more kinds selected from higher alcohols which are liquid at 25 DEG C or higher fatty acids in liquid form, cholesterol or phytosterol, , And storage stability. Thus, the present invention has been accomplished.

The present invention relates to novel and novel lipophospholipids which contain lysophospholipids, which are usually used as hydrophilic emulsifiers, together with one or more cholesterol or phytosterol, and purified water, selected from higher alcohols or higher fatty acids which are liquid at 25 占 폚 And to provide a vesicle composition having excellent storage stability.

That is, the present invention relates to the following components (a) to (d);

(a) lysophospholipid

(b) at least one selected from a higher alcohol or liquid higher fatty acid which is in a liquid state at 25 占 폚

(c) cholesterol or phytosterol

(d) Purified water

≪ / RTI >

The present invention also relates to the aforementioned vesicle compositions which further comprise a component (e) electrolyte.

The present invention also relates to the above-mentioned vesicle composition, wherein the mass ratio (b) / (c) of the component (b) and the component (c) is 0.2 to 4.

The present invention also relates to the above-mentioned vesicle composition, wherein the mass ratio (a) / (b) + (c) of the component (a), component (b) and component (c) is 0.25 to 5.

The present invention also relates to the aforementioned vesicle composition, wherein component (b) is at least one member selected from oleyl alcohol, isostearyl alcohol, oleic acid and isostearic acid.

The present invention also relates to the above-mentioned vesicle composition, wherein the electrical conductivity at 25 ° C is 0.02 to 2.5 s / m.

Further, from another aspect, the present invention provides an external skin preparation containing any of the above-described vesicle compositions.

The vesicle composition of the present invention is excellent in storage stability. The vesicle composition of the present invention is useful as an external preparation for skin because it has a high permeability to the skin, a feeling of use without stickiness, and a high quality of additionally moisturizing effect.

Hereinafter, the present invention will be described in detail. In the present specification, the numerical range indicated by using " ~ " means a range including numerical values before and after "to" as a lower limit value and an upper limit value.

The vesicle composition of the present invention comprises (a) a lysophospholipid. (a) Lysophospholipids are used as vesicle constituents. The kind thereof is not particularly limited. Examples of lysophospholipids include soy-derived lysophospholipids, soy-derived hydrogenated lysophospholipids, yolk-based lysophospholipids, yolk-derived hydrogenated lysophospholipids, and the like. These lysophospholipids may be used singly or in combination of two or more thereof, if necessary. (a) Lysophospholipid is a kind of enzyme-modified phospholipid, which is hydrolyzed ester bond at position 2 by phospholipase. The lysophospholipid used in the present invention is preferably a lysophospholipid of lysophospholipid (ratio of lysophospholipid in total phospholipids) of 60% or more and a phosphatidylcholine purity of 20% or more (hereinafter referred to as "PC purity") . Since lysophospholipid has one fatty acid chain, it is highly hydrophilic and has chemical properties different from phospholipids, as compared to phospholipids having two fatty acid chains.

The content of the component (a) lysophospholipid is not particularly limited, but is preferably 0.01 to 5 mass% (hereinafter abbreviated as "%"), more preferably 0.05 to 3 mass%. Within this range, a vesicle composition having better storage stability can be obtained.

In addition, a phospholipid may be used together with a lysophospholipid.

The vesicle composition of the present invention comprises (b) a higher alcohol or a higher fatty acid which is in a liquid phase at 25 占 폚. The component (b) is indispensable as a vesicle constituent, and by containing it, the crystal precipitation of the component (c) can be suppressed and the storage stability can be improved. In addition, by containing the component (b), a feeling of use without permeability to the skin or stickiness can be obtained, and a vesicle composition particularly useful as an external preparation for skin can be obtained. Examples of higher alcohols which are in a liquid phase at 25 占 폚 include octyldodecanol, oleyl alcohol, isostearyl alcohol, isocetyl alcohol, coconut alcohol, olive alcohol, jojoba alcohol, and decyltetradecyl alcohol; Examples of higher fatty acids that are liquid at 25 占 폚 include isostearic acid, oleic acid, and linolic acid. Of these, one type or two or more types can be used. Among them, oleyl alcohol, isostearyl alcohol, oleic acid, and isostearic acid are preferable.

The content of the component (b) is not particularly limited, but is preferably 0.01 to 5%, more preferably 0.05 to 3%. Within this range, a vesicle composition having better storage stability can be obtained.

The vesicle composition of the present invention contains (c) cholesterol or phytosterol. (c) Cholesterol or phytosterol contributes to the stability of the bilayer membrane structure in vesicle formation, and storage stability can be improved by containing it.

The content of the component (c) is not particularly limited, but is preferably 0.01 to 5%, more preferably 0.05 to 3%. Within this range, a vesicle composition having better storage stability can be obtained.

In the vesicle composition of the present invention, when the content ratio (b) / (c) of the component (b) and the component (c) is in the range of 0.2 to 4, the preservation stability of the vesicle becomes better, , Storage stability is more preferable. When the mass ratio (a) / (b) + (c) of the components (a), (b) and (c) in the vesicle composition of the present invention is in the range of 0.25 to 5, The storage stability of the composition becomes better, and when it is in the range of 0.4 to 4, the storage stability is more preferable.

The vesicle composition of the present invention contains (d) purified water. (d) Purified water is used as a dispersion medium of the components (a) to (c) and is an essential ingredient for skin external preparation containing vesicles. The specific blending amount thereof is appropriately determined depending on the content of the components (a) to (c), but is usually 50 to 99%.

In the vesicle composition of the present invention, the hydrophilic-lipophilic balance between the hydrophilic component (a) and the lipophilic component (b) and the component (c) results in a bicycle which is a bimolecular structure in the component (d). As described above, the lysophospholipid of the component (a) is disadvantageous for vesicle formation because it is highly hydrophilic compared to ordinary phospholipids. In the present invention, by supplementing this point, by using component (a) lysophospholipid, (b) a higher fatty acid in a liquid phase or a higher fatty acid in liquid form, and (c) cholesterol or phytosterol, To provide a stable and stable vesicle composition.

The vesicle composition of the present invention can be used as an external preparation for skin. In this embodiment, it is preferable to further contain (e) an electrolyte. (e) The electrolyte may be blended for the purpose of imparting a moisturizing effect, an anti-inflammatory effect or a whitening effect.

Examples of the electrolyte having a moisturizing effect include organic compounds such as urea, amino acid, lactic acid, citric acid and pyrrolidonecarboxylic acid and metal salts such as potassium, sodium, magnesium and calcium, inorganic salts such as sodium chloride and magnesium chloride .

Examples of the electrolyte having an anti-inflammatory effect include organic compounds such as glycyrrhizic acid and pantothenic acid, and metal salts thereof such as potassium, sodium, magnesium and calcium.

Examples of the electrolyte having a whitening effect include ascorbic acid phosphoric acid ester, ascorbic acid alkyl ester, ascorbic acid sulfuric acid ester, glucoside ascorbic acid and the like, and ascorbic acids such as metal salts such as sodium, potassium, magnesium and calcium .

Further, natural aqueous solutions containing these electrolytes, such as deep sea water and hot spring water, may be mentioned. These may be used alone or in combination of two or more.

Among them, in the case of being used as an external preparation for skin, (e) the electrolyte is preferably a water-soluble ascorbic acid derivative having a whitening effect, a lactic acid salt having a moisturizing effect, a pyrrolidonecarboxylic acid salt and the like.

Specific examples of the electrolytes used in the external preparation for skin are described in Nakanishi Norimoto et al., &Quot; Fragrance Journal " Fragrance Journal, 1995-1, pp. 71-80; And " Usability of Cosmetics "

The content of the component (e) is not particularly limited, but is preferably 0.01 to 10%, more preferably 0.1 to 5%. Within this range, it is possible to obtain a vesicle composition useful as an external preparation for skin having excellent moisturizing effect, anti-inflammatory effect, or whitening effect without impairing storage stability. The addition of the electrolyte generally destabilizes the vesicle, but since the vesicle composition of the present invention has high stability, good stability can be maintained even when an electrolyte is added as a pharmaceutical ingredient such as a moisturizing effect, an anti-inflammatory effect, or a whitening effect.

The vesicle composition of the present invention may contain various components in addition to the essential components (a) to (d). In particular, by containing a polyhydric alcohol, it is possible to obtain a vehicle composition superior in storage stability, feeling of use and the like. Examples of such polyhydric alcohols are not particularly limited, and examples thereof include propylene glycol, 1,3-butylene glycol, dipropylene glycol, 1,2-pentanediol, glycerin, diglycerin, sorbitol and the like. Among them, 1,3-butylene glycol and dipropylene glycol are particularly preferable.

The electric conductivity of the vesicle composition of the present invention at 25 캜 (measured using an electric conductivity meter CM-60G manufactured by Toh Kagaku Kogyo) is preferably 0.02 to 2.5 s / m. Further, it is more preferably 0.05 to 2 s / m. Within this range, the effect of the electrolyte (e), for example, the moisturizing effect, the anti-inflammatory effect, or the whitening effect can be sufficiently exerted without compromising the storage stability of the vesicles.

The vesicle composition of the present invention can be prepared by various methods. One example thereof is a method in which a solution obtained by dissolving the component (a) and the component (c) in the component (b) at a temperature of about 80 ° C and a component (d) And the mixture is stirred and then slowly cooled to room temperature.

The present invention also relates to an external preparation for skin containing a vesicle composition of the present invention. The external preparation for skin of the present invention may contain an optional component to be blended with a conventional external preparation for skin, specifically an emulsion other than the component (b), an alcohol, a powder, a water-soluble polymer, A surfactant, an oil-soluble gelling agent, an organic modified clay mineral, a resin, an ultraviolet absorber, an antiseptic, an antibacterial agent, a fragrance, an antioxidant, a pH adjusting agent and a chelating agent.

Examples of the application of the external preparation for skin of the present invention include skin care cosmetics such as lotion, emulsion, cream, eye cream, essence, massage material, pack material, hand cream, body cream, and cosmetic base. Further, the method of use may be a method of using with a hand or a finger, a method of impregnating into a nonwoven fabric, or the like.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[Example 1]

Inventive products 1 to 17 and Comparative products 1 to 5:

According to the following process, vesicle compositions having the compositions shown in Tables 1 to 4 were prepared. Verification of vesicle formation was carried out under the observation of a polarizing microscope, and it was judged to be the amount of the morula phasic image.

These vesicle compositions were applied to the skin as a serum, and the feeling of use and the moisturizing effect were evaluated. More specifically, sensory evaluation was performed on (1) permeation sensation, (2) no stickiness, and (3) moisturizing effect by a professional panel. The results are shown in Tables 1 to 4.

(Manufacturing method)

A: Components (1) to (9) are heated to 80 占 폚.

B: Components (10) and (11) are dissolved by heating at 80 占 폚.

C: A is added to B, and the mixture is stirred with a dispenser to form a vesicle.

After cooling D: C to room temperature, components (12) and (13) were added to obtain a vesicle composition.

(Evaluation method: storage stability of vesicle)

To confirm the stability of the vecicle, observation was carried out with a polarizing microscope. Was compared with the state immediately after the preparation of the vesicle composition at a temperature of 40 캜 for 2 months under the constant temperature. The amount of the Maltese crucifix image confirmed at the time of observation was judged using the following (i) 4-step criterion.

   (i) Four-step criteria

(Judgment): (evaluation)

◎: Over 80% of Maltese crisscross phase was confirmed.

○: The amount of the crushed maltese was found to be 60% or more and less than 80%.

△: The amount of crushed maltose was found to be 30% or more and less than 60%.

X: The amount of the crushed maltose was less than 30%.

(Evaluation method: feel and moisturizing effect)

(Ii) about 20% of the female panelists in their 20s to 40s, using the prepared vesicle composition as a cosmetic liquid, (1) permeability, (2) no stickiness, and (3) The sensory evaluation was performed according to the five-step evaluation criteria, and the average value of the overall panel ratings was further judged according to (iii) the four-step criterion.

   (ii) Five-step evaluation criteria

(Rating): (Rated)

Very Feeling: 5 points

I feel a little: 4 points

Medium: 3 points

I do not feel much: 2 points

Do not feel: 1 point

   (iii) Fourth Stage Criteria

(Average value of total panel ratings): (judgment)

Average of 4.5 or higher: ◎

Average point 3.5 or more Less than 4.5: ○

Average point 2.5 to less than 3.5:

Average point less than 2.5: x

(Evaluation method: electric conductivity)

The electrical conductivity of each sample was measured at 25 캜 using an electric conductivity meter (electric conductivity meter CM-60G manufactured by DOHA Corporation).

As is apparent from the results of Tables 1 to 4, Inventive Articles 1 to 17 were excellent in stability over 2 months at a constant temperature of 40 ° C. In addition, when applied to skin as a serum, it was excellent in permeation feeling, and was excellent in moisturizing effect with no feeling of stickiness.

On the other hand, Comparative Example 1 containing no component (a) did not form vesicles. In addition, comparative products 2 and 3 not containing components (b) and (c), comparative product 4 containing stearyl alcohol instead of component (c), comparative product 5 containing phospholipid instead of component (a) , There was a problem of storage stability such that cholesterol crystallization and precipitation were observed in all of the time-lapse observations.

[Example 2: Lotion]

(ingredient) (%)

1. An egg yolk hydrogenated lysophospholipid (Note 3) 3.0

2. Jojoba alcohol 0.8

3. Phytosterol 0.6

4. Hydroxystearic acid cholesterol 0.2

5. Dipropylene glycol 10.0

6. Purified water balance

7. L-Serine 2.0

8. Theanine 2.0

9. Glycerin 5.0

10. Ethanol 5.0

11. Antiseptic qs

12. Perfume qs

(Note 3) Rising digestibility 68% PC purity 30%

(quite)

A: Components (1) to (5) are dissolved by heating at 80 占 폚.

B: Component (6) is heated to 80 占 폚.

C: A is added to B, mixed and stirred to form vesicles, and cooled to room temperature.

Components (7) to (12) were added to and mixed with D: C to obtain a lotion.

The cosmetic lotion of Example 2 was a skin external preparation having good preservation stability of vesicles, excellent permeation feeling, no stickiness, and excellent moisturizing effect. The electrical conductivity was 0.05 s / m.

[Example 3: Underwater type emulsion]

(ingredient) (%)

1. Squalane 5.0

2. Decamethylcyclopentasiloxane 5.0

3. Polyoxyethylene (60) hardened castor oil 2.0

4. Cetostearyl alcohol 0.5

6. 1,3-Butylene glycol 7.0

7. Glycerin 5.0

8. Acrylic acid-alkyl methacrylate copolymer (Note 4) 0.2

9. Antiseptic qs

10. Triethanolamine 0.2

11. Dissolve edetate 0.02

12. Purified water balance

13. Perfume qs

14. Soybean-derived hydrogenated lysophospholipids (Note 5) 0.5

15. Hydrogenated soybean phospholipid 0.1

16. Octyldodecanol 1.0

17. Cholesterol 0.6

18. Dipropylene glycol 7.0

19. Purified water 10.0

(Note 4) Pemulene TR-2 (manufactured by NOVEON)

(Note 5) Ripen rate 88% PC purity 80%

(Manufacturing method)

A: Components (1) to (7) are dissolved by heating at 70 占 폚.

B: Components (8) to (12) are heated at 70 占 폚 and then added to A to emulsify.

C: Cool B to room temperature.

D: Components (14) to (18) are dissolved by heating at 80 占 폚.

E: Component (19) is heated to 80 占 폚, and D is added while mixing and stirring to form vesicles.

F: After cooling, E was added to C and further component (13) was added to obtain an oil-in-water emulsion.

The underwater type emulsion of Example 3 was a skin external preparation having good preservation stability of vesicles, excellent permeation feeling, no stickiness, and excellent moisturizing effect. The electrical conductivity was 0.02 s / m.

[Example 4: Underwater type emulsion type cream]

(ingredient) (%)

1. Hydrogenated soybean phospholipid 2.0

2. Polyoxyethylene (20) sorbitan tristearate 3.0

3. Stearyl alcohol 5.0

4. Liquid paraffin 10.0

5. Macadamia nut oil 5.0

6. Hardened Oil 3.0

7. Glycerin 10.0

8. Purified water balance

9. Ethanol 5.0

10. Antiseptic qs

11. Perfume qs

12. Soybean-derived hydrogenated lysophosphatids (Note 1) 3.0

13. Decyl tetradecyl alcohol 0.4

14. Phytosterol 1.0

15. Propylene glycol 10.0

16. Purified water 10.0

(quite)

A: Components (1) to (6) are dissolved by heating at 70 占 폚.

B: The components (7) and (8) are heated and dissolved at 70 占 폚, added to A, and emulsified.

C: After cooling B to room temperature, components (9) to (11) are added.

D: Components (12) to (15) are dissolved by heating at 80 占 폚.

E: The component (16) is heated to 80 占 폚, and D is added while mixing and stirring to form a vesicle.

F: After cooling E, it was added to C to obtain a cream.

The underwater type emulsion type cream of Example 4 was a skin external preparation having good preservation stability of vesicles, excellent permeation feeling, no stickiness, and excellent moisturizing effect. The electrical conductivity was 0.07 s / m.

[Example 5: Sheet-like cosmetic]

(ingredient) (%)

1. An egg yolk hydrogenated lysophospholipid (Note 3) 2.0

2. Oleyl alcohol 0.5

3. Cholesterol 0.5

4. Isostearic acid 0.2

5. Perfume 0.1

6. Diglycerin 5.0

7. Dipropylene glycol 10.0

8. Purified water balance

9. Methyl paraoxybenzoate 0.1

10. Ethanol 5.0

11. ascorbic acid glucoside 3.0

12. Sodium pyrrolidonecarboxylate 2.0

13. Sodium hyaluronate 0.2

14. Sodium hydroxide 0.13

(quite)

A: Components (1) to (7) are dissolved by heating at 80 占 폚.

B: The component (8) is heated to 80 占 폚 and mixed and stirred while adding A to form a vesicle.

C: After cooling B, components (9) to (14) are added and impregnated with nonwoven fabric.

D: C was sealed and filled in a bag-shaped container made of aluminum laminate to obtain a sheet-like cosmetic material.

The sheet-like cosmetic material of Example 5 was a skin external preparation having good preservation stability of vesicles, excellent permeation feeling, no stickiness, and excellent moisturizing effect and whitening effect. The electrical conductivity was 1.18 s / m.

[Example 6: Underwater type cream phase base cosmetic]

(ingredient) (%)

1. Zinc oxide (particle size 200 nm) 2.0

2. Dimethylpolysiloxane 30.0

3. Polyoxyethylene (30) cholesteryl ether 1.0

4. Octyl palmitate 1.5

5. Acrylic-silicone graft copolymer mixture (Note 6) 2.0

6. Purified water balance

7. Ethanol 5.0

8. Propylene glycol 5.0

9. Silica powder 2.0

10. Antiseptic qs

11. Perfume qs

12. Soybean-derived hydrogenated lysophospholipids (Note 5) 0.2

13. Oleic acid 0.05

14. Cholesterol 0.1

15. 1,3-Butylene Glycol 2.0

16. Purified water 5.0

(Note 6) KP-543 (50% acrylic-silicone graft copolymer: 50% butyl acetate mixture, manufactured by Shin-Etsu Chemical Co., Ltd.)

(Manufacturing method)

A: Components (1) to (5) are dispersed with a three roll mill.

B: Components (6) to (11) are uniformly mixed.

C: Add A to B and emulsify.

D: Components (12) to (15) are dissolved by heating at 80 占 폚.

E: The component (16) is heated to 80 占 폚, and D is added while mixing and stirring to form a vesicle.

F: After cooling, E was added to C to obtain an underwater type cream base base cosmetic.

The underwater type cream base base cosmetic of Example 6 was a skin external preparation having good preservation stability of vesicles, excellent permeation feeling, no stickiness, and excellent moisturizing effect. The electrical conductivity was 0.13 s / m.

Claims (7)

The following components (a) to (d);
(a) lysophospholipid
(b) at least one selected from oleyl alcohol and isostearic acid,
(c) cholesterol or phytosterol
(d) Purified water
≪ / RTI >
The content of the component (a) is 0.01 to 5% by mass,
, The content of the component (b) is 0.01 to 5% by mass, and
When the content of the component (c) is 0.01 to 5 mass%
ego,
(B) / (c) of the component (b) and the component (c) is 0.2 to 4, and
The content ratio (a) / (b) + (c) of the components (a), (b) and (c)
A skin external preparation containing a vesicle composition. The method according to claim 1,
(E) a vesicle composition containing an electrolyte. The method according to claim 1,
And further comprising a vesicle composition containing a polyhydric alcohol selected from 1,3-butylene glycol and dipropylene glycol. 3. The method of claim 2,
And further comprising a vesicle composition containing a polyhydric alcohol selected from 1,3-butylene glycol and dipropylene glycol. 5. The method according to any one of claims 1 to 4,
Wherein the electrical conductivity at 25 캜 is 0.02 to 2.5 s / m. delete delete